What are the recommended medications for a patient with confirmed COVID‑19, stratified by disease severity (mild outpatient versus moderate to severe hospitalized) and relevant contraindications?

COVID-19 Medication Recommendations by Disease Severity

For mild outpatient COVID-19 in high-risk patients, start nirmatrelvir/ritonavir (Paxlovid) immediately within 5 days of symptom onset; for hospitalized patients requiring supplemental oxygen, use dexamethasone 6 mg daily plus remdesivir 5-day course; for severe/critical disease requiring high-flow oxygen or mechanical ventilation, add tocilizumab or sarilumab to dexamethasone. 1

Mild Outpatient COVID-19 (High-Risk Patients)

First-Line Treatment

• Nirmatrelvir/ritonavir (Paxlovid) is the preferred first-line agent for high-risk outpatients with mild COVID-19, initiated within 5 days of symptom onset 1
• Treatment must be started as soon as possible after diagnosis to prevent progression to severe disease 1

Alternative Outpatient Options

• Remdesivir 3-day course can be considered for patients with contraindications to nirmatrelvir/ritonavir, particularly in immunocompromised patients or those with hematological malignancies 2, 1
• Remdesivir is indicated for outpatients with symptom onset within 7 days and at least one risk factor for progression (immunosuppression, malignancy) 2
• Molnupiravir may be used if nirmatrelvir/ritonavir is unavailable or contraindicated 1

Critical Contraindications for Paxlovid

• Ritonavir is a potent CYP3A4 inhibitor affecting approximately 60% of available medications 3
• For patients on tacrolimus, reduce dose to 2-5% of baseline; similar dramatic reductions required for cyclosporine, sirolimus, and everolimus 4, 3
• Severe renal impairment (eGFR <30 mL/min) or severe hepatic impairment are absolute contraindications 2

Moderate COVID-19 (Hospitalized, Requiring Supplemental Oxygen)

Cornerstone Therapy

• Dexamethasone 6 mg daily for 10 days reduces mortality by approximately 4% and is essential for all hospitalized patients requiring supplemental oxygen 1
• This represents the single most important intervention for hospitalized patients with oxygen requirements 1

Add Remdesivir

• Remdesivir 200 mg IV loading dose on day 1, followed by 100 mg IV daily for 5 days total should be added to dexamethasone 2, 1
• Initiate remdesivir for patients with oxygen saturation ≤94% on room air, tachypnea, radiographic infiltrates, or need for supplemental oxygen 2
• Greatest mortality benefit occurs in patients requiring low-flow oxygen at baseline, with risk ratios of 0.21-0.24 for mortality reduction 2
• Remdesivir increases recovery by 9.7% at 29 days (62.1% vs 52.4% with placebo) and reduces time to recovery from 15 to 11 days 2

Remdesivir Contraindications

• Do not use if eGFR <30 mL/min/1.73 m² 2
• Do not use if ALT ≥5 times upper limit of normal 2
• Discontinue if ALT increases to >10 times upper limit of normal or if ALT elevation accompanies signs of liver inflammation 2, 3

When to Extend Treatment

• If patient worsens during 5-day course to require supplemental oxygen but not mechanical ventilation, extending to 10 days should be based on clinical judgment 2
• If patient progresses to requiring mechanical ventilation or ECMO during initial 5 days, extend treatment to 10 days 2

Severe/Critical COVID-19 (High-Flow Oxygen, NIV, or Mechanical Ventilation)

Essential Therapy

• Dexamethasone 6 mg daily for 10 days remains the cornerstone 1
• Do NOT initiate remdesivir in patients already on mechanical ventilation or ECMO at baseline, as evidence shows potential for increased mortality 2

Add IL-6 Receptor Antagonist

• Tocilizumab or sarilumab should be added to dexamethasone for patients requiring high-flow oxygen, non-invasive ventilation, or invasive mechanical ventilation 1
• Initiate IL-6 antagonist for patients with evidence of COVID-19-related inflammation (CRP ≥75 mg/L) 1
• Give within 24 hours of requiring ventilatory support to maximize benefit 1

Alternative JAK Inhibitor

• Baricitinib 4 mg daily orally for 14 days or until discharge can be used for severe or critical COVID-19, initiated at the same time as systemic corticosteroids 4
• Dose adjustments needed for leucopenia, renal impairment, or hepatic impairment 4
• Ruxolitinib or tofacitinib should NOT be used unless neither baricitinib nor IL-6 receptor blockers are available 4

Thromboprophylaxis Considerations

When to Use Pharmacological Thromboprophylaxis

• Hold anticoagulation only if platelet count <25 × 10⁹/L or active bleeding 4
• Abnormal PT or PTT is NOT a contraindication to thromboprophylaxis 4
• Therapeutic anticoagulation may need to be held if platelet count <30-50 × 10⁹/L or fibrinogen <1.0 g/L 4

Preferred Agents

• UFH may be preferred in patients at high bleeding risk, with renal failure, or needing imminent procedures 4
• LMWH or UFH preferred over oral anticoagulants due to potential drug-drug interactions and shorter half-lives 4

Treatments to AVOID

Strongly Contraindicated

• Hydroxychloroquine is strongly recommended against due to no benefit and increased mortality in some studies, with risk of prolonged QT intervals when combined with azithromycin 4, 1
• Lopinavir/ritonavir is strongly recommended against due to no clinical benefit, high adverse event rate, and unfavorable pharmacodynamics 4, 1
• Azithromycin should not be used in the absence of bacterial infection 1

Special Populations

Immunocompromised Patients

• Require aggressive early intervention, including consideration of pre-exposure and post-exposure prophylaxis with long-acting anti-SARS-CoV-2 monoclonal antibodies 1
• Particularly important for those with hematological malignancies due to prolonged viral replication phase 2
• High-titer convalescent plasma may be considered when monoclonal antibodies are unavailable, ideally within 72 hours of symptom onset 1

Renal Impairment

• Remdesivir and molnupiravir doses do not require adjustment in renal impairment 5
• Paxlovid dose adjustment required for mild to moderate renal impairment; not allowed for severe renal impairment 5

Hepatic Impairment

• Remdesivir and molnupiravir doses do not require adjustment in hepatic impairment 5
• Paxlovid dose adjustment required for mild to moderate hepatic impairment; not allowed for severe hepatic impairment 5

Common Pitfalls and How to Avoid Them

Timing Errors

• Starting antivirals too late reduces effectiveness—outpatient antivirals must be initiated within 5-7 days of symptom onset 2, 1
• Delaying IL-6 antagonists reduces benefit—give within 24 hours of requiring ventilatory support 1

Drug-Drug Interactions

• Failure to recognize CYP3A4 interactions with ritonavir can lead to toxicity or therapeutic failure 3, 6
• More than half of interactions in COVID-19 patients involve hydroxychloroquine and azithromycin, which should not be used 7
• Concomitant drugs for comorbid conditions leading to polypharmacy significantly increase DDI risk 7

Inappropriate Use of Remdesivir

• Do not initiate remdesivir in patients already mechanically ventilated—this may increase mortality 2
• Always check baseline renal and hepatic function before starting 2, 3