What medications interact with Paxlovid (nirmatrelvir/ritonavir)?

Paxlovid Drug Interactions

Paxlovid (nirmatrelvir/ritonavir) has extensive and potentially life-threatening drug interactions because ritonavir is a potent CYP3A4 inhibitor, affecting approximately 60% of available medications. 1

Mechanism of Interactions

• Ritonavir strongly inhibits CYP3A4, CYP2D6, P-glycoprotein (P-gp), and OATP1B1 transporters, leading to dramatically increased plasma concentrations of drugs metabolized or transported by these pathways 1
• Nirmatrelvir itself is a CYP3A substrate, so CYP3A inducers can reduce Paxlovid effectiveness and cause treatment failure 1

Absolutely Contraindicated Medications (Do Not Co-Administer)

Cardiovascular Drugs

• Alfuzosin: Risk of severe hypotension 1
• Ranolazine: Serious/life-threatening cardiac events 1
• Antiarrhythmics (amiodarone, dronedarone, flecainide, propafenone, quinidine): Risk of cardiac arrhythmias 1

Statins

• Lovastatin, simvastatin, atorvastatin: Markedly increased statin levels causing rhabdomyolysis risk 2

Sedatives/Hypnotics

• Oral midazolam and triazolam: Excessive sedation and respiratory depression 2, 1

Anticancer Drugs

• Apalutamide, enzalutamide: These CYP3A inducers reduce Paxlovid levels, causing virologic failure 1

Pulmonary Hypertension

• Sildenafil (when used for pulmonary arterial hypertension): Increased risk of hypotension and adverse events 2

Medications Requiring Dose Adjustment or Temporary Discontinuation

Anticoagulants

• Rivaroxaban: Avoid concomitant use due to increased bleeding risk 1
• Dabigatran: Reduce dose or avoid based on indication and renal function; consult dabigatran label 1
• Apixaban: Dose adjustment depends on apixaban indication; refer to product label 1
• Warfarin: Closely monitor INR as levels may increase or decrease unpredictably 1

Immunosuppressants

• Tacrolimus: Should be discontinued entirely or given as a microdose on day 1 only during Paxlovid treatment due to drastic exposure increases 3, 4
• Cyclosporine: Reduce to 20% of baseline dose during antiviral treatment 3
• mTOR inhibitors (sirolimus, everolimus): Require dose adjustment 3

Anticancer Drugs Requiring Caution

• Avoid encorafenib, ivosidenib: QT prolongation risk 1
• Avoid neratinib, venetoclax, ibrutinib: Excessive toxicity 1
• Vincristine, vinblastine: May cause severe hematologic/GI toxicity; consult oncology 1

Psychiatric Medications

• Quetiapine: Use with extreme caution due to increased sedation and metabolic effects 2

Antiretrovirals

• Avoid cobicistat-based regimens with Paxlovid 2
• Efavirenz, etravirine, nevirapine: Contraindicated as they induce CYP3A and reduce Paxlovid levels 2
• Rilpivirine: Use with caution and ECG monitoring for QT prolongation 2
• Atazanavir, darunavir: Take without ritonavir when using Paxlovid to avoid excessive ritonavir exposure 2

Other Medications

• Tamsulosin: Avoid concomitant use due to hypotension risk 1
• Systemic lidocaine, disopyramide: Therapeutic drug monitoring recommended if available 1

CYP3A Inducers That Reduce Paxlovid Effectiveness (Contraindicated)

• Rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort: These reduce nirmatrelvir/ritonavir concentrations, causing treatment failure 1, 5

Special Population Considerations

Renal Impairment

• Moderate renal impairment (eGFR 30-60 mL/min): Reduce Paxlovid dose to nirmatrelvir 150 mg/ritonavir 100 mg twice daily 2
• Severe renal impairment (eGFR <30 mL/min) or dialysis: Use nirmatrelvir 150 mg/ritonavir 100 mg once daily 2

Hepatic Impairment

• Severe hepatic impairment (Child-Pugh Class C): Paxlovid is not recommended 2

Pregnancy

• Paxlovid is an option for pregnant patients with COVID-19, though data on adverse reactions remain limited 2

Practical Management Approach

• Before prescribing Paxlovid, review ALL patient medications using the Liverpool COVID-19 Drug Interaction tool (www.covid19-druginteractions.org) 2, 1
• For the 5-day treatment course, consider temporarily holding interacting medications rather than complex dose adjustments when safe to do so 5, 6
• Monitor patients closely during treatment for adverse effects related to drug accumulation 2
• Pharmacist involvement is essential: Studies show 87% of patients require interventions to prevent drug-related problems, with severe interactions occurring in 17% of cases 6

Common Pitfalls

• Assuming dose reduction of immunosuppressants is sufficient: Tacrolimus should be stopped entirely, not just reduced, as even microdoses can cause severe toxicity including diarrhea leading to diabetic ketoacidosis 4
• Forgetting that interactions persist after stopping Paxlovid: Resume normal doses of interacting medications only after ritonavir is cleared (typically 2-3 days after last dose) 3
• Overlooking renal function: Failure to dose-adjust Paxlovid in renal impairment increases toxicity risk 2