What are the guidelines for using Paxlovid (nirmatrelvir/ritonavir) to treat COVID-19?

Paxlovid (Nirmatrelvir/Ritonavir) Guidelines for COVID-19 Treatment

Paxlovid is strongly recommended for non-severe COVID-19 patients at high risk of hospitalization, must be initiated within 5 days of symptom onset, and requires mandatory drug interaction screening before prescribing due to ritonavir's potent CYP3A4 inhibition. 1, 2, 3

Patient Selection by Risk Stratification

High-Risk Patients (Strong Recommendation)

• Strongly recommend Paxlovid for patients with mild-to-moderate COVID-19 at high risk for progression to severe disease, hospitalization, or death 1, 2, 3
• High-certainty evidence demonstrates important reduction in hospitalization and moderate certainty of survival benefit 2

Moderate-Risk Patients (Conditional Recommendation)

• Conditionally recommend Paxlovid for moderate-risk patients, acknowledging high certainty of important hospitalization reduction, though the benefit is smaller than in high-risk groups 2

Low-Risk Patients (Recommend Against)

• Conditionally recommend against Paxlovid use in low-risk patients, as benefits are trivial with high certainty for both mortality and hospitalization outcomes 2

Dosing and Administration

Standard Dosing (Normal Renal Function)

• 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), taken together twice daily for 5 days 3
• Administer orally with or without food 3
• Take at approximately the same time each day 3

Renal Impairment Dose Adjustments

Moderate Renal Impairment (eGFR ≥30 to <60 mL/min):

• 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily for all 5 days 1, 3

Severe Renal Impairment (eGFR <30 mL/min, including hemodialysis):

• Day 1: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once 3
• Days 2-5: 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily 3
• On hemodialysis days, administer after dialysis 3

Hepatic Impairment

• Not recommended in patients with severe hepatic impairment (Child-Pugh Class C) 3
• Use with caution in severe liver impairment, as trials excluded these patients 1

Critical Timing Requirement

• Treatment must be initiated within 5 days of symptom onset for optimal effectiveness 1, 2, 3
• Start as soon as possible after COVID-19 diagnosis 3
• This necessitates rapid access to diagnostic testing and prescription fulfillment 2

Drug-Drug Interactions: The Primary Safety Concern

Mandatory Interaction Screening

• Use the Liverpool COVID-19 Drug Interaction Tool to systematically check for specific interactions before prescribing 1, 2
• Ritonavir is a strong CYP3A4 inhibitor that causes numerous clinically significant drug-drug interactions 1, 2, 3, 4
• Ritonavir also inhibits CYP2D6 and P-glycoprotein to a lesser extent 5

Contraindicated Medications

• Do not co-administer with drugs highly dependent on CYP3A for clearance where elevated concentrations are associated with serious and/or life-threatening reactions 3
• Do not co-administer with potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may lead to loss of virologic response and possible resistance 3

Management Strategies

• Review all medications taken by the patient before prescribing 3
• Determine if concomitant medications require dose adjustment, interruption, and/or additional monitoring 3
• Pragmatic options include preemptive or symptom-driven pausing of the comedication during the 5-day treatment course 4
• Ritonavir causes drug interactions during active treatment and possibly for several days after treatment completion 1

Special Populations

Pregnancy

• Paxlovid may be an option for pregnant people to reduce disease progression, though uncertainty exists regarding potential serious adverse reactions 1
• No reports of serious adverse reactions in parent or child have been documented in WHO Vigibase to date 1

Pediatrics

• Approved for persons aged ≥12 years weighing ≥40 kg 6
• Dosing recommendations support 300/100 mg twice daily in pediatrics (12 to <18 years) weighing ≥40 kg 7

Common Adverse Effects

• Dysgeusia (altered taste) and diarrhea occur more frequently with Paxlovid than placebo 1
• These adverse effects did not lead to increased drug discontinuation rates in trials 1
• Monitor for potential hepatotoxicity: hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir 3

Hypersensitivity Reactions

• Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported 3
• If signs or symptoms of clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue Paxlovid and initiate appropriate medications and/or supportive care 3
• Contraindicated in patients with history of clinically significant hypersensitivity reactions to nirmatrelvir, ritonavir, or any other components 3

Mechanism of Action and Variant Activity

• Nirmatrelvir targets the SARS-CoV-2 main protease (Mpro), which has remained highly conserved across all variants 2
• Viral mutations have predominantly occurred in the spike protein rather than in the viral protease or polymerase regions, allowing protease inhibitors to maintain activity 2
• Ritonavir inhibits nirmatrelvir's CYP3A4-mediated metabolism, making renal elimination the primary route when dosed concomitantly 5

Limitations of Use

• Not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19 3