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

Paxlovid Drug Interactions: Critical Management Considerations

Primary Mechanism of Interactions

Paxlovid (nirmatrelvir/ritonavir) is a potent CYP3A4 inhibitor and also inhibits CYP2D6, P-glycoprotein (P-gp), and OATP1B1 transporters, creating extensive drug-drug interaction potential that requires systematic medication review before prescribing. 1

The ritonavir component causes rapid and potent inhibition of CYP3A4, which metabolizes a vast array of commonly prescribed medications, making even a 5-day treatment course capable of causing serious adverse events or treatment failures. 2

Absolute Contraindications

Do not co-administer Paxlovid with the following medications due to life-threatening risks:

• Antiarrhythmics: Amiodarone, dronedarone, flecainide, propafenone, quinidine (risk of cardiac arrhythmias) 1
• Alpha-blockers: Alfuzosin (risk of severe hypotension) 1
• Antianginals: Ranolazine (serious/life-threatening reactions) 1
• Anticancer drugs: Apalutamide, enzalutamide (loss of Paxlovid efficacy) 1
• CYP3A inducers: Rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort (reduce Paxlovid concentrations and therapeutic effect) 3, 1

High-Risk Interactions Requiring Intervention

Anticoagulants

For apixaban (Eliquis): Reduce dose by 25% during the 5-day Paxlovid course, or preferably switch to low molecular weight heparin to eliminate interaction risk entirely. 4 Monitor closely for bleeding signs throughout treatment and for 2-3 days post-completion, especially in patients >75 years or on concurrent antiplatelet therapy. 4

For rivaroxaban: Avoid concomitant use due to increased bleeding risk. 1

For dabigatran: Reduce dose or avoid based on indication and renal function; refer to dabigatran label for specific guidance. 1

For warfarin: Closely monitor INR throughout and after Paxlovid treatment as effects are unpredictable (can increase or decrease warfarin levels). 1, 5

Immunosuppressants

For tacrolimus: Discontinue entirely or give only a microdose on day 1 of Paxlovid, as ritonavir causes drastic increases in tacrolimus exposure. 6 The original guideline recommendation to reduce tacrolimus to 2-5% of baseline dose applies. 3

For cyclosporine: Reduce to 20% of initial dosage during antiviral treatment. 6

For sirolimus and everolimus (mTOR inhibitors): Significant dose reductions required; consult therapeutic drug monitoring. 3, 6

For mycophenolate and azathioprine: Minimal interactions expected; no dose adjustment typically needed. 3, 6

Statins

Contraindicated statins: Lovastatin and simvastatin (risk of severe myopathy/rhabdomyolysis). 3

Safe options: Pravastatin and pitavastatin have minimal interactions as they undergo glucuronidation rather than CYP3A metabolism. 3

Use with caution: Atorvastatin and rosuvastatin can be continued but consider temporary discontinuation during the 5-day course or use lowest possible dose with patient counseling about muscle pain/weakness. 3, 5

Calcium Channel Blockers

Significant risk: Amlodipine, nifedipine, verapamil, and diltiazem levels increase substantially, risking hypotension and bradycardia. 5, 7 Consider holding these medications during Paxlovid treatment or reducing doses by 50-75% with blood pressure monitoring.

Antiarrhythmics Requiring Monitoring

For lidocaine (systemic) and disopyramide: Continue with caution and implement therapeutic concentration monitoring if available. 1

Oncology Medications

Avoid: Neratinib, venetoclax, ibrutinib, encorafenib, ivosidenib (risk of QT prolongation and serious adverse events). 1

Use extreme caution: Vincristine and vinblastine (risk of significant hematologic/gastrointestinal toxicity). 1

Medications with Minimal Interaction Risk

• Edoxaban: Represents the safest direct oral anticoagulant option with Paxlovid, requiring no dose adjustment. 4
• Mycophenolate mofetil and azathioprine: No significant interactions. 3
• Corticosteroids: Generally less impacted by Paxlovid. 6

Practical Management Algorithm

1. Before prescribing Paxlovid: Obtain complete medication list including over-the-counter drugs, herbals, and supplements. 3, 2

2. Screen for contraindications: Use interaction checker tools (www.hep-druginteractions.org or similar) to identify absolute contraindications. 3, 8

3. For high-risk medications:

   • Option 1: Temporarily discontinue the comedication for 5-7 days if clinically safe
   • Option 2: Reduce dose according to specific recommendations above
   • Option 3: Switch to alternative with lower interaction potential
   • Option 4: Defer Paxlovid if interaction risk outweighs COVID-19 treatment benefit

4. Implement monitoring: Counsel patients on specific adverse effects to report based on their medication profile. 4, 2

5. Post-treatment: Resume original medications and doses 2-3 days after completing Paxlovid to allow ritonavir washout. 2

Critical Pitfalls to Avoid

Do not assume a 5-day course is too short to cause harm—ritonavir's CYP3A4 inhibition is immediate and potent, with effects persisting several days after discontinuation. 2, 7

Do not overlook renal impairment—patients with severe renal dysfunction (eGFR <30 mL/min) require Paxlovid dose reduction to 150 mg nirmatrelvir/100 mg ritonavir once daily, which may alter interaction profiles. 3, 1

Pharmacist involvement is essential—studies show 87% of Paxlovid prescriptions require intervention to prevent drug-related problems, with 17% involving severe interactions. 8

Patient education is mandatory: Instruct patients to immediately report unusual bruising, bleeding, blood in urine/stool, severe headache, dizziness, muscle pain/weakness, or signs specific to their comedications. 4, 7