What are the cautions with Paxlovid (nirmatrelvir and ritonavir)?

Cautions with Paxlovid (Nirmatrelvir/Ritonavir)

The most critical caution with Paxlovid is the potential for severe, life-threatening, or fatal drug-drug interactions due to ritonavir being a potent CYP3A4 inhibitor, requiring mandatory review of all concomitant medications before prescribing. 1

Drug-Drug Interactions: The Primary Safety Concern

Mandatory Pre-Prescribing Actions

• You must review every medication the patient is taking before prescribing Paxlovid to identify drugs that are contraindicated, require dose adjustment, temporary discontinuation, or additional monitoring 1
• Use the Liverpool COVID-19 Drug Interaction Tool to systematically check for specific interactions, as this is explicitly recommended in guidelines 2, 3, 4
• Ritonavir causes drug interactions during active treatment and possibly for several days after treatment completion 2

Contraindicated Medications

• Do not prescribe Paxlovid with drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious or life-threatening reactions 1
• Do not prescribe with potent CYP3A inducers as they significantly reduce nirmatrelvir/ritonavir plasma concentrations, leading to loss of virologic response and possible resistance 1

High-Risk Medication Classes Requiring Special Management

• Immunosuppressive drugs require drastic dose reductions: tacrolimus should be discontinued or given as a microdose on day 1, cyclosporine should be reduced to 20% of initial dose, and mTOR inhibitors require adjustment 5
• Real-world data shows 81.4% of patients had drug-drug interactions, with 17% having severe interactions 6
• Ritonavir inhibits CYP3A4, CYP2D6, and P-glycoprotein, creating multiple interaction pathways 7

Renal Impairment: Dose Adjustment Required

Specific Dosing by Renal Function

• Moderate renal impairment (eGFR 30-59 mL/min): Reduce dose to 150 mg nirmatrelvir with 100 mg ritonavir twice daily for all 5 days 2, 1
• Severe renal impairment (eGFR <30 mL/min) including hemodialysis: Give 300 mg/100 mg once on day 1, then 150 mg/100 mg once daily on days 2-5; administer after hemodialysis on dialysis days 1
• Paxlovid was contraindicated in 2.1% of patients due to severe renal impairment in real-world practice 6
• Patients with advanced age and renally excreted comedications had significantly higher plasma concentrations, with those >65 years having 11.2 times higher odds of excessive plasma levels 8

Hepatic Impairment Considerations

• Paxlovid is not recommended in severe hepatic impairment (Child-Pugh Class C) 1
• Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir 1
• Trials excluded patients with severe liver impairment, so use with caution in this population 2

Hypersensitivity Reactions

• Immediately discontinue Paxlovid if signs of clinically significant hypersensitivity or anaphylaxis occur 1
• Anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and other serious hypersensitivity reactions have been reported 1
• Do not prescribe to patients with history of clinically significant hypersensitivity to nirmatrelvir or ritonavir 1

HIV-1 Drug Resistance Risk

• Paxlovid may lead to HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection 1
• This is a unique consideration given ritonavir's role as an HIV protease inhibitor 1

Timing and Administration Cautions

• Treatment must be initiated within 5 days of symptom onset for optimal effectiveness 2, 3, 4, 1
• Nirmatrelvir must be co-administered with ritonavir—failure to do so results in insufficient nirmatrelvir plasma levels and loss of therapeutic effect 1
• Complete the full 5-day course even if symptoms improve to maximize viral clearance and minimize SARS-CoV-2 transmission 1

Special Populations

Pregnancy and Breastfeeding

• Paxlovid represents an option for pregnant people to reduce disease progression, though uncertainty exists regarding potential serious adverse reactions 2
• No reports of serious adverse reactions in parent or child have been documented in WHO Vigibase to date 2

Elderly Patients

• Patients older than 65 years had significantly higher plasma trough concentrations (odds ratio 11.2) and warrant closer monitoring 8

Common Adverse Effects to Monitor

• Dysgeusia (loss of taste) and diarrhea occur more frequently with Paxlovid than placebo 2, 4
• These adverse effects did not lead to increased drug discontinuation rates in trials 2

Critical Implementation Pitfall

The most common error is failing to systematically review drug interactions before prescribing. Real-world data shows 87.1% of patients required pharmacist interventions to prevent drug-related problems, with 63.6% needing intervention at dispensing 6. This underscores that drug interaction screening is not optional—it is a mandatory safety step that must occur before every Paxlovid prescription.