What is the preferred treatment between Paxlovid (nirmatrelvir/ritonavir) and Lagevrio (molnupiravir) for mild to moderate COVID-19 in high-risk patients?

From the Guidelines

Paxlovid (nirmatrelvir/ritonavir) is the preferred treatment over Lagevrio (molnupiravir) for mild to moderate COVID-19 in high-risk patients. This recommendation is based on the most recent and highest quality study available, which suggests that nirmatrelvir/ritonavir combination therapy is superior to molnupiravir due to its greater reduction in hospitalization and safety concerns associated with molnupiravir 1.

Key Considerations

• Paxlovid is administered as 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one tablet) taken together twice daily for 5 days.
• Treatment should be initiated as soon as possible after diagnosis and within 5 days of symptom onset.
• Paxlovid demonstrates superior efficacy with approximately 89% reduction in hospitalization and death compared to molnupiravir's 30% reduction.
• However, Paxlovid has significant drug interactions due to the ritonavir component, which inhibits CYP3A4 enzyme.
• Patients should be screened for potential drug interactions before starting therapy, and some medications may need to be temporarily discontinued or have dosages adjusted.
• Paxlovid also requires dose adjustment for patients with moderate renal impairment (eGFR 30-60 mL/min).

Alternative Treatment

Molnupiravir (800 mg twice daily for 5 days) may be considered as an alternative when Paxlovid is contraindicated or unavailable, but it should not be used in pregnant patients or those of childbearing potential who cannot use contraception during and shortly after treatment due to potential fetal harm. The American College of Physicians practice points support the use of both molnupiravir and nirmatrelvir/ritonavir combination therapy for outpatient treatment of COVID-19 in high-risk patients 1.

Important Considerations for Clinical Practice

In clinical practice, it is essential to weigh the benefits and risks of each treatment option and consider individual patient factors, such as renal function and potential drug interactions, when making treatment decisions. The most recent and highest quality evidence should always be consulted to ensure that patients receive the best possible care.

From the FDA Drug Label

Paxlovid (nirmatrelvir tablets; ritonavir tablets co-packaged for oral use) is FDA-approved for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. Although Paxlovid is an approved alternative to LAGEVRIO for the treatment of mild-to-moderate COVID-19 in adults and who are at high risk for progression to severe COVID-19, including hospitalization or death, FDA does not consider Paxlovid to be an adequate alternative to LAGEVRIO for this authorized use because it may not be clinically appropriate for patients on medications that are primarily metabolized by CYP3A and/or that are strong CYP3A inducers.

The preferred treatment between Paxlovid and Lagevrio for mild to moderate COVID-19 in high-risk patients is not explicitly stated in the drug labels.

• Paxlovid is FDA-approved for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19.
• Lagevrio is authorized for emergency use for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19. The choice of treatment should be based on individual patient factors, including potential drug interactions and the patient's medical history 2.

From the Research

Comparison of Paxlovid and Lagevrio

• Paxlovid (nirmatrelvir/ritonavir) and Lagevrio (molnupiravir) are two oral antiviral drugs used to treat mild to moderate COVID-19 in high-risk patients 3, 4, 5.
• Both drugs have been shown to reduce the likelihood of hospitalization and death in high-risk patients with COVID-19, although Paxlovid generally appears to be more efficacious 3, 4, 5.
• Paxlovid inhibits viral replication, while Lagevrio induces viral replication errors that lead to viral inactivation 3, 5.

Mechanisms of Action and Efficacy

• Paxlovid targets the SARS-CoV-2 main protease, while Lagevrio targets the viral polymerase 4, 5.
• Paxlovid has been shown to have a greater risk reduction in hospitalization and death compared to Lagevrio 4, 5.
• Both drugs need to be started within 5 days of symptoms onset and given for 5 days' duration 4, 5.

Safety and Drug Interactions

• Paxlovid has a high potential to cause harm from drug-drug interactions due to the ritonavir component, which inhibits the cytochrome P450 3A4 enzyme 6.
• Lagevrio does not have significant drug interactions, but its package insert states that patients should be notified of relevant toxicity issues before administration 3.
• Paxlovid may cause significant drug-to-drug interactions that limit its use in persons taking certain medications metabolized by certain cytochrome P450 enzymes 6.

Clinical Experience and Recommendations

• A case-control study from two hospitals in Saudi Arabia found that Paxlovid was associated with lower ICU admissions and deaths in COVID-19 patients 7.
• The study suggests that Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality, but larger studies are needed for a full assessment of its role in COVID-19 management 7.
• Recommendations for the management of drug-drug interactions between Paxlovid and comedications include preemptive or symptom-driven pausing of the comedication or managing any additional risk through counseling 6.