What are the potential medication interactions with Paxlovid (nirmatrelvir and ritonavir)?

Paxlovid Medication Interactions

Paxlovid (nirmatrelvir/ritonavir) has numerous significant drug interactions primarily due to ritonavir's strong inhibition of CYP3A4, which can result in potentially life-threatening adverse events when combined with certain medications. 1

Mechanism of Drug Interactions

• Ritonavir is a strong inhibitor of CYP3A4, an inhibitor of CYP2D6, P-glycoprotein (P-gp), and OATP1B1 transporters, which can significantly increase plasma concentrations of drugs metabolized by these pathways 1
• Nirmatrelvir is primarily metabolized by CYP3A, making it susceptible to interactions with drugs that induce this enzyme, potentially reducing Paxlovid's therapeutic effect 1
• The combination of these mechanisms creates a complex drug interaction profile that requires careful assessment before prescribing 2

Contraindicated Medications

The following medications are contraindicated with Paxlovid due to risk of serious or life-threatening reactions:

• Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine 1
• Alpha-1 adrenoreceptor antagonist: alfuzosin (risk of hypotension) 1
• Antianginal: ranolazine 1
• Anticancer drugs: apalutamide, enzalutamide (may reduce nirmatrelvir/ritonavir levels) 1
• Statins: lovastatin, simvastatin, atorvastatin 3
• Sedatives/hypnotics: oral midazolam, triazolam 3
• Psychiatric medications: quetiapine 3
• Pulmonary hypertension medication: sildenafil when used for pulmonary arterial hypertension 3
• Other: astemizole, terfenadine, cisapride, ergot derivatives, salmeterol 3

Medications Requiring Dose Adjustment or Close Monitoring

• Anticoagulants:

  • Warfarin: Monitor INR closely 1
  • Rivaroxaban: Avoid concomitant use due to increased bleeding risk 1
  • Dabigatran: May require dose reduction depending on indication and renal function 1
  • Apixaban: Requires dose adjustment based on current dose 1

• Immunosuppressants:

  • Tacrolimus: Consider discontinuation or microdosing on day 1 of Paxlovid treatment 4
  • Cyclosporine: Reduce to 20% of initial dosage during antiviral treatment 4
  • mTOR inhibitors (sirolimus, everolimus): Require dose adjustments 4

• HIV medications:

  • Avoid cobicistat-based regimens 3
  • Efavirenz, etravirine, nevirapine are contraindicated 3
  • Rilpivirine should be used with caution and ECG monitoring 3
  • Atazanavir and darunavir should be taken without ritonavir 3

• Antipsychotics:

  • Clozapine and quetiapine: Increased risk of toxicity 2, 5

• Calcium channel blockers:

  • Nifedipine, manidipine, verapamil: Risk of enhanced effects 2

Special Population Considerations

• Renal impairment: Dose adjustment of Paxlovid is required for patients with moderate to severe renal impairment 3, 1
• Hepatic impairment: Paxlovid is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) 3, 1
• Pregnancy: Paxlovid represents an option for pregnant people with COVID-19, though uncertainty exists regarding potential adverse reactions 3

Practical Approach to Managing Drug Interactions

1. Review all medications the patient is taking before prescribing Paxlovid 1
2. Consult drug interaction resources such as the Liverpool COVID-19 Drug Interaction tool for comprehensive information 3
3. Consider management options:
   • Temporary discontinuation of the interacting medication if clinically appropriate 6
   • Dose adjustment of the interacting medication 6
   • Alternative COVID-19 treatment if interactions cannot be safely managed 6
4. Monitor patients closely for adverse effects during the 5-day treatment course 3

Common Pitfalls and Caveats

• Short treatment duration doesn't eliminate risk: Even though Paxlovid is only a 5-day course, significant interactions can still occur due to ritonavir's potent inhibition of CYP3A4 6
• Delayed effects: Some drug interactions may persist for several days after completing Paxlovid treatment due to the time needed for enzyme activity to normalize 3
• PXR activation: Some drugs and herbs that activate the pregnane X receptor (PXR) can accelerate nirmatrelvir metabolism, potentially reducing Paxlovid effectiveness 7
• Complex polypharmacy: Patients at highest risk for severe COVID-19 often take multiple medications, increasing the likelihood of significant interactions 2, 6

By carefully assessing potential drug interactions and implementing appropriate management strategies, healthcare providers can safely administer Paxlovid to eligible patients while minimizing the risk of adverse events.