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Monday, July 28, 2025

Molnupiravir (Lagevrio)


Generic Name: Molnupiravir
Brand Name: Lagevrio
Pharmacological Class: Antiviral, nucleoside analog
Therapeutic Use: COVID-19 antiviral treatment
Legal Classification: Prescription-only; Emergency Use Authorization (EUA) in several countries
Developer: Merck & Co., Ridgeback Biotherapeutics

Mechanism of Action

Molnupiravir is a prodrug of N4-hydroxycytidine (NHC), a ribonucleoside analog. After oral administration, molnupiravir is rapidly converted in plasma to NHC, which enters infected host cells and is phosphorylated to its active 5’-triphosphate form. This active metabolite is incorporated into viral RNA by RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. NHC induces errors in viral RNA replication by mispairing with both guanosine and adenosine, leading to lethal mutagenesis or error catastrophe. This results in nonfunctional viruses and inhibition of replication.

Indications

Molnupiravir is authorized under emergency provisions (not formally FDA-approved) for:

  • Treatment of mild to moderate COVID-19 in adults

  • Patients must have confirmed SARS-CoV-2 infection

  • Must be at high risk of progression to severe illness, including hospitalization or death

  • Intended for use within 5 days of symptom onset

  • For patients in whom alternative FDA-approved/authorized COVID-19 treatment options are not accessible or appropriate

  • Not authorized for initiation in patients already hospitalized due to COVID-19

Dosage and Administration

  • Adult dose: 800 mg orally every 12 hours for 5 days

  • Each dose consists of four 200 mg capsules taken together

  • Treatment should begin as soon as possible after diagnosis and within 5 days of symptom onset

  • Capsules must be swallowed whole with or without food

  • If a dose is missed and it is within 10 hours of the scheduled time, it should be taken immediately. If more than 10 hours have passed, skip the missed dose and resume the regular schedule

Formulations

  • Capsules: 200 mg

  • Total treatment course: 40 capsules over 5 days

Contraindications

  • Known hypersensitivity to molnupiravir or any excipients

  • Use in patients <18 years old is not authorized due to potential effects on bone and cartilage growth

  • Use during pregnancy is contraindicated, due to potential embryotoxic and teratogenic effects observed in animal studies

  • Not authorized for prophylactic use or longer than 5 days

Warnings and Precautions

  • Embryofetal toxicity: Avoid in pregnancy. Effective contraception is recommended during treatment and for at least 4 days after the final dose in women and 3 months for men

  • Potential mutagenicity: NHC incorporation into human DNA has been a concern; however, risk appears low with short-term use

  • Not recommended during breastfeeding: The risk to neonates is unknown; breastfeeding should be interrupted during and for 4 days after treatment

  • Genomic alterations in viral RNA: Increased viral mutational load raises concerns about future resistance patterns, though no evidence supports emergence of more pathogenic variants

  • Limited efficacy in later-stage disease: Not for use in hospitalized patients as no benefit has been demonstrated

Adverse Effects

Most common adverse events reported in clinical trials include:

  • Diarrhea (2.3%)

  • Nausea (1.4%)

  • Dizziness (1.0%)

  • Headache

  • Rash (rare)

  • Hypersensitivity reactions, including angioedema, are possible but rare

Adverse events are typically mild to moderate in severity and self-limiting. No significant serious adverse events directly linked to molnupiravir have been consistently observed in short-term trials.

Special Populations

Pregnancy

  • Contraindicated. Based on animal data, molnupiravir may cause fetal harm

  • Women of childbearing potential should have a negative pregnancy test prior to treatment and use effective contraception during and for 4 days post-treatment

Lactation

  • Not recommended. Unknown if molnupiravir is excreted in human milk

  • Breastfeeding should be discontinued during treatment and for 4 days after the last dose

Pediatrics

  • Not authorized for use in individuals under 18 years due to potential impact on bone and cartilage development

Geriatrics

  • No specific dosage adjustment is necessary

  • Use with caution in patients with multiple comorbidities

Drug Interactions

Molnupiravir has a low potential for drug-drug interactions, as it is not significantly metabolized by cytochrome P450 enzymes and does not induce or inhibit these pathways.

  • No clinically relevant interactions with commonly used medications were observed in trials

  • Does not require co-administration with a pharmacokinetic booster, unlike nirmatrelvir/ritonavir

Pharmacokinetics

  • Absorption: Oral bioavailability of molnupiravir is high; peak plasma concentration (Cmax) reached ~1.5 hours after dosing

  • Distribution: NHC distributes widely in tissues

  • Metabolism: Rapid hydrolysis to NHC; further metabolism via uridine monophosphate pathways

  • Elimination half-life: ~3.3 hours

  • Excretion: Predominantly renal as metabolites

Clinical Trial Data

MOVe-OUT Trial (Phase 3):

  • Enrolled non-hospitalized unvaccinated adults with mild to moderate COVID-19 and at least one risk factor for severe disease

  • Molnupiravir reduced the risk of hospitalization or death by 30% compared to placebo (6.8% vs 9.7%)

  • Most effective when administered within 3 days of symptom onset

  • No significant benefit was observed in vaccinated populations or those already requiring hospitalization

Comparative Notes:

  • Less effective than Paxlovid (nirmatrelvir/ritonavir), which showed up to 89% reduction in risk

  • Considered a second-line option when Paxlovid is contraindicated (e.g., due to drug interactions) or unavailable

Storage and Handling

  • Store at 20–25°C (68–77°F)

  • Protect from moisture and heat

  • Do not freeze

  • Keep out of reach of children

  • Follow local medical waste disposal regulations for expired or unused capsules

Use Considerations

Molnupiravir should be considered only when:

  • Initiated early in disease course (≤5 days from symptom onset)

  • The patient is not a candidate for monoclonal antibodies, Paxlovid, or intravenous remdesivir

  • There are no contraindications such as pregnancy or age under 18

  • A careful risk-benefit assessment supports its use based on disease severity, comorbidities, and therapeutic accessibility

The limited clinical benefit, theoretical mutagenesis risk, and lack of use in pregnant or pediatric populations make molnupiravir a specialized and cautiously used treatment. While it fills a treatment gap for some patients, ongoing pharmacovigilance is necessary to track its long-term safety, especially in real-world use




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