Outpatient COVID-19 Treatment
For high-risk outpatients with confirmed mild-to-moderate COVID-19 within 5 days of symptom onset, prescribe nirmatrelvir/ritonavir (Paxlovid) as first-line therapy after checking for drug interactions, or use molnupiravir when Paxlovid is contraindicated or unavailable. 1, 2
Patient Selection Criteria
Treatment is indicated for patients meeting ALL of the following:
- Confirmed COVID-19 with mild-to-moderate symptoms 2
- Within 5 days of symptom onset (initiate as soon as possible after diagnosis) 1, 3
- High-risk features including any of: 2, 4
- Unvaccinated status
- Age ≥65 years
- Immunosuppression
- Multiple comorbidities (≥3)
- Hematological disease
- Radiographic evidence of pneumonia
Do not treat low-risk patients without risk factors for severe disease, as potential risks outweigh benefits in this population. 4
First-Line Treatment: Nirmatrelvir/Ritonavir (Paxlovid)
Dosing Regimen
Standard dose: Nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg (one tablet) taken together orally twice daily for 5 days. 3
Renal impairment adjustments: 3
- Moderate impairment (eGFR 30-59 mL/min): Nirmatrelvir 150 mg with ritonavir 100 mg twice daily for 5 days
- Severe impairment (eGFR <30 mL/min): Nirmatrelvir 300 mg with ritonavir 100 mg once on Day 1, then nirmatrelvir 150 mg with ritonavir 100 mg once daily on Days 2-5
- Hemodialysis patients: Administer dose after dialysis 3
Hepatic impairment: Not recommended in severe hepatic impairment (Child-Pugh Class C). 3
Critical Drug Interaction Management
Before prescribing, you MUST perform a comprehensive medication review using a drug interaction checker (such as the Liverpool COVID-19 Drug Interaction Tool) because ritonavir is a strong CYP3A inhibitor that can cause potentially life-threatening drug interactions. 2, 3
Common high-risk interactions requiring management: 5, 6
- Immunosuppressants: Tacrolimus should be discontinued or given as a microdose on day 1; cyclosporine reduced to 20% of initial dose; mTOR inhibitors require dose adjustment
- Calcium channel blockers: May require dose reduction or temporary discontinuation
- Statins: Certain statins (simvastatin, lovastatin) are contraindicated; others require temporary discontinuation
Absolute contraindications include drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening events. 3
Evidence for Efficacy
Nirmatrelvir/ritonavir reduces: 1
- All-cause mortality (4 studies showed reduction)
- COVID-19-specific mortality
- COVID-19 hospital admissions (2 studies showed reduction)
- Time to recovery
Adverse Effects
Most common (≥1%): 3
- Dysgeusia (taste disturbance): 5%
- Diarrhea: 3%
Serious but rare: 3
- Anaphylaxis and hypersensitivity reactions (discontinue immediately if occurs)
- Toxic epidermal necrolysis and Stevens-Johnson syndrome
- Hepatotoxicity (monitor hepatic function if baseline abnormalities present)
Second-Line Treatment: Molnupiravir
Use molnupiravir when nirmatrelvir/ritonavir is contraindicated or unavailable due to unmanageable drug interactions or patient refusal. 1, 2
Evidence for Efficacy
Molnupiravir reduces: 1
- All-cause mortality (3 studies showed reduction)
- Time to recovery
- No difference in serious adverse events or overall adverse events compared to placebo
Treatments NOT Recommended
Do not prescribe the following for outpatient COVID-19: 1, 2
- Ivermectin
- Sotrovimab (monoclonal antibody)
- Azithromycin
- Systemic corticosteroids
- Vitamin D
Critical Timing Considerations
Treatment effectiveness is time-dependent. 4, 7
- Must be initiated within 5 days of symptom onset
- Efficacy significantly decreases if delayed beyond 5 days
- Start as soon as possible after COVID-19 diagnosis
Monitoring During Treatment
- Assess for hypersensitivity reactions throughout treatment course 3
- Monitor hepatic function if baseline liver abnormalities present 2, 3
- Ensure patient continues isolation per public health recommendations 2, 4
- For immunosuppressant users: Therapeutic drug monitoring of immunosuppressants during and after Paxlovid course 5
Important Caveats
SARS-CoV-2 rebound: Some patients experience symptom or viral rebound after treatment, but this should not deter prescribing as rebound cases remain mild with no reported hospitalizations or deaths, and no significant difference in rebound rates exists between treated and untreated patients. 8
HIV resistance risk: In patients with uncontrolled or undiagnosed HIV-1 infection, ritonavir exposure may lead to HIV-1 protease inhibitor resistance. 3
Pregnancy and lactation: Limited data exists, though indirect evidence from ritonavir use in HIV treatment suggests no significant teratogenicity; consider risk-benefit on case-by-case basis. 9