What medications should be held when prescribing Paxlovid (nirmatrelvir/ritonavir) for COVID-19?

Medications to Hold or Adjust When Prescribing Paxlovid

Due to ritonavir's potent CYP3A4 inhibition, you must hold or adjust multiple medication classes when prescribing Paxlovid to prevent potentially life-threatening drug interactions. 1

Critical Drug Classes Requiring Action

Statins - HOLD Most, Switch to Pravastatin

• Hold atorvastatin, simvastatin, and lovastatin during the 5-day Paxlovid course due to severe risk of rhabdomyolysis from CYP3A4 inhibition 2, 3
• Switch to pravastatin (metabolized by glucuronidation, not CYP3A4) as the preferred alternative during treatment 2
• Fluvastatin is another acceptable alternative with minimal CYP3A4 involvement 2

Immunosuppressants - Drastically Reduce or Hold

• Tacrolimus: HOLD completely or give only a microdose on day 1, then discontinue for the remaining 4 days of Paxlovid treatment 4
• Cyclosporine: Reduce to 20% of baseline dose during the 5-day antiviral course 4
• mTOR inhibitors (sirolimus, everolimus): Reduce dosage with close therapeutic drug monitoring 4
• Mycophenolic acid and corticosteroids require less adjustment but monitor closely 4

Anticoagulants - Adjust Doses and Monitor INR

• Rivaroxaban: Reduce to 10 mg daily during Paxlovid treatment to prevent bleeding complications from elevated drug levels 5
• Warfarin: Monitor INR closely - ritonavir decreases S-warfarin but increases R-warfarin, causing unpredictable INR changes that persist for 2 weeks post-treatment 5
• Dabigatran and apixaban: Hold or reduce dose due to significant CYP3A4/P-gp interactions 6, 3

Calcium Channel Blockers - Hold or Reduce

• Hold or significantly reduce nifedipine, amlodipine, verapamil, and diltiazem due to risk of severe hypotension and cardiac toxicity from CYP3A4 inhibition 3
• Monitor blood pressure closely if continuation is necessary 6

Antiarrhythmics - CONTRAINDICATED

• Amiodarone is contraindicated with Paxlovid due to life-threatening cardiac toxicity risk 1, 3
• Other QT-prolonging antiarrhythmics should be avoided or used with extreme caution and ECG monitoring 6

Opioids - Reduce Doses Significantly

• Reduce fentanyl, oxycodone, and hydrocodone doses by 50-75% due to ritonavir's CYP3A4 inhibition causing respiratory depression risk 6, 3
• Morphine requires less adjustment but monitor for increased effects 6
• Tramadol carries additional risk due to both CYP3A4 interaction and cardiac toxicity 6

Benzodiazepines - Hold Oral Formulations

• Hold oral midazolam, alprazolam, and triazolam - contraindicated due to excessive sedation risk 6, 1
• IV midazolam may continue with dose reduction and monitoring 6
• Oxazepam has no significant interaction and is the preferred alternative 6

Antipsychotics - Hold or Monitor Closely

• Hold clozapine and quetiapine due to severe toxicity risk from CYP3A4 inhibition 3
• Haloperidol requires dose reduction and cardiac monitoring for QT prolongation 6

Hepatitis C DAAs - CONTRAINDICATED

• Protease inhibitor-containing regimens (elbasvir-grazoprevir, glecaprevir-pibrentasvir, sofosbuvir-velpatasvir-voxilaprevir) are absolutely contraindicated with lopinavir-ritonavir and by extension Paxlovid due to severe hepatotoxicity risk 6

Hepatitis B Antivirals - Switch if Needed

• Tenofovir (TDF/TAF): Consider switching to entecavir during Paxlovid treatment to avoid 32-316% increase in tenofovir levels and renal toxicity risk 6
• Never stop nucleoside analogues for HBV during COVID-19 treatment to prevent viral reactivation 6

Practical Implementation Algorithm

1. Before prescribing Paxlovid:

   • Review complete medication list using Liverpool COVID-19 Drug Interaction Checker 6, 1
   • Identify all CYP3A4 substrates and P-gp substrates 1, 3

2. For identified interactions:

   • Contraindicated drugs: Hold completely for 5 days plus 2-3 days washout 1
   • Major interactions: Reduce dose by 50-80% or switch to alternative 4, 5
   • Moderate interactions: Reduce dose by 25-50% with monitoring 6

3. Post-Paxlovid (after day 5):

   • Resume original medications 2-3 days after last Paxlovid dose to allow CYP3A4 recovery 5
   • For warfarin, continue INR monitoring for 2 weeks 5
   • For immunosuppressants, resume with therapeutic drug monitoring 4

Critical Warnings

• Ritonavir inhibits CYP3A4 for several days after discontinuation - drug interactions persist beyond the 5-day treatment course 6
• QT prolongation risk is additive - avoid combining Paxlovid with other QT-prolonging drugs (hydroxychloroquine, ondansetron, certain antipsychotics) 6
• Renal impairment intensifies interactions - reduce Paxlovid dose to 150/100 mg twice daily if eGFR 30-59 mL/min, which may still require medication adjustments 6, 1