What is the recommended treatment regimen for Paxlovid (nirmatrelvir/ritonavir) in non-hospitalized adults with Covid-19?

Paxlovid for COVID-19: Treatment Recommendations

Recommended Treatment Regimen

For non-hospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease, administer Paxlovid (nirmatrelvir 300 mg with ritonavir 100 mg) orally twice daily for 5 days, initiated within 5 days of symptom onset. 1, 2

Patient Selection Criteria

High-Risk Patients (Strong Recommendation)

• Strongly recommend Paxlovid for patients at high risk of hospitalization, which includes older adults (particularly ≥65 years), immunocompromised individuals, those with multiple comorbidities, and unvaccinated patients 1, 3
• Treatment reduces hospitalization risk by 89% (0.77% vs 7.01% in placebo) and mortality by 61% in real-world data 4, 3

Moderate-Risk Patients (Conditional Recommendation)

• Consider Paxlovid for patients at moderate risk of hospitalization, though the absolute benefit is smaller than in high-risk patients 1
• The conditional recommendation reflects uncertainty in baseline risk estimates and patient preference variability 1

Low-Risk Patients (Recommend Against)

• Do not use Paxlovid in low-risk patients, as any benefit is trivial with high certainty 1

Dosing and Administration

Standard Dosing

• 300 mg nirmatrelvir (two 150 mg tablets) plus 100 mg ritonavir (one 100 mg tablet) taken together twice daily for 5 days 2, 1
• Administer with or without food at approximately the same time each day 2
• Initiate treatment as soon as possible after diagnosis and within 5 days of symptom onset 2, 1

Renal Impairment Dose Adjustments

Moderate renal impairment (eGFR 30-59 mL/min):

• 150 mg nirmatrelvir (one tablet) with 100 mg ritonavir twice daily for all 5 days 2, 5

Severe renal impairment (eGFR <30 mL/min) including hemodialysis:

• Day 1: 300 mg nirmatrelvir with 100 mg ritonavir once daily
• Days 2-5: 150 mg nirmatrelvir with 100 mg ritonavir once daily
• On hemodialysis days, administer after dialysis 2

Hepatic Impairment

• Not recommended in severe hepatic impairment (Child-Pugh Class C) 2
• Use with caution in patients with severe liver impairment, as trials excluded this population 5

Critical Drug Interaction Management

Mandatory Pre-Treatment Assessment

Before prescribing Paxlovid, you must systematically review all patient medications using the Liverpool COVID-19 Drug Interaction Tool 5, 2

Contraindicated Medications

• Do not co-administer with drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions 2
• Do not co-administer with potent CYP3A inducers that significantly reduce nirmatrelvir/ritonavir levels 2
• Specific concern with benzodiazepines and narcotics, which can cause altered mental status and acute encephalopathy 6

Interaction Duration

• Ritonavir causes drug interactions during active treatment and possibly for several days after completion 5
• Patients with renally excreted comedications and advanced age (>65 years) have 11-fold higher risk of excessive plasma concentrations 7

Special Populations

Pregnancy

• Paxlovid may be an option for pregnant individuals to reduce disease progression, though uncertainty exists regarding potential serious adverse reactions 5
• No reports of serious adverse reactions in parent or child documented in WHO Vigibase to date 5

Vaccinated Patients

• Paxlovid remains effective in vaccinated patients, with similar absolute risk reduction for hospitalization compared to unvaccinated patients 3
• Among real-world patients receiving Paxlovid, 73% had received ≥3 vaccine doses 8

Older Adults (≥65 Years)

• Prioritize Paxlovid for patients ≥65 years, as absolute risk reduction for hospitalization is much greater in this age group 3
• Significantly higher risk of excessive plasma concentrations in patients >65 years (odds ratio 11.2) 7

Monitoring and Adverse Effects

Common Adverse Effects

• Dysgeusia (altered taste) occurs in 5.6% and diarrhea in 3.1% of patients, both more frequent than placebo but not leading to increased discontinuation 2, 5

Serious Adverse Events to Monitor

• Anaphylaxis and serious skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome) require immediate discontinuation 2
• Hepatotoxicity: Monitor for hepatic transaminase elevations, clinical hepatitis, and jaundice 2
• COVID-19 rebound: Recurrence of symptoms or positive test 2-8 days after treatment occurs but rarely leads to severe outcomes 8

Real-World Safety Data

• Among 5,287 patients treated with Paxlovid, <1% had hospitalizations or ED encounters during days 5-15 post-treatment 8
• Serious adverse events occurred in 1.6% vs 6.6% with placebo in clinical trials 4

Contraindications

Absolute contraindications include: 2

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir
• Co-administration with drugs highly dependent on CYP3A clearance with serious/life-threatening elevation risks
• Co-administration with potent CYP3A inducers

HIV Considerations

• Paxlovid use may lead to HIV-1 resistance to protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection 2

Limitations of Use

• Paxlovid is not approved for pre-exposure or post-exposure prophylaxis for COVID-19 prevention 2

Comparative Effectiveness

Paxlovid is superior to alternative antivirals: 1

• Greater reduction in hospitalization compared to molnupiravir (moderate certainty evidence)
• Superior to remdesivir due to oral administration vs intravenous requirement
• Molnupiravir has additional safety concerns regarding potential mutation rates 1