What are the major Paxlovid (nirmatrelvir/ritonavir) drug interactions?

Major Paxlovid Drug Interactions

Paxlovid (nirmatrelvir/ritonavir) has numerous significant drug interactions due to ritonavir's strong inhibition of CYP3A4 and inhibition of CYP2D6, P-gp, and OATP1B1, which can lead to potentially severe, life-threatening, or fatal events. 1

Contraindicated Medications

Paxlovid must not be co-administered with the following medications:

• Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine (risk of cardiac arrhythmias) 1
• Alpha 1-adrenoreceptor antagonist: alfuzosin (risk of hypotension) 1
• Antianginal: ranolazine (risk of serious/life-threatening reactions) 1
• Anticancer drugs: apalutamide (reduces Paxlovid effectiveness) 1
• Statins: rosuvastatin (19-fold increase in exposure) 2
• Erectile dysfunction/PAH medication: sildenafil for pulmonary arterial hypertension (severe hypotension, syncope, visual disturbances) 2

High-Risk Interactions Requiring Management

Anticoagulants

• Warfarin: Closely monitor INR 1
• Rivaroxaban: Avoid concomitant use due to increased bleeding risk 1
• Apixaban: Increased bleeding risk; dosing adjustments required based on apixaban dose 1
• Dabigatran: Increased bleeding risk; reduce dose or avoid based on indication and renal function 1

Cardiovascular Medications

• Antiarrhythmics (lidocaine systemic, disopyramide): Therapeutic concentration monitoring recommended 1
• Alpha-blockers: Tamsulosin - avoid concomitant use 1

Anticancer Drugs

• Avoid co-administration with: encorafenib, ivosidenib, neratinib, venetoclax, ibrutinib 1
• Use with caution: abemaciclib, ceritinib, dasatinib, nilotinib, vinblastine, vincristine (risk of hematologic or GI side effects) 1, 3

Erectile Dysfunction Medications

• Sildenafil for ED: Limited to 25mg in a 48-hour period (risk of hypotension, visual changes, priapism) 2
• Other PDE5 inhibitors: Require significant dose adjustments 2

Immunosuppressants

• Tacrolimus: Increased risk of toxicity; requires close monitoring and potential dose adjustment 4

Psychiatric Medications

• Antipsychotics: Clozapine, quetiapine - increased risk of toxicity 4

Other Notable Interactions

• Calcium channel blockers (nifedipine, manidipine, verapamil): Increased risk of toxicity 4
• HIV medications: Potential complex interactions; may require dose adjustments 5

Special Population Considerations

• Renal impairment: Requires dose adjustments of both Paxlovid and concomitant medications 2
• Elderly patients: Have reduced clearance of interacting medications, requiring additional caution 2
• Hepatic impairment: Affects clearance of many medications that interact with Paxlovid 2

Management Approach

1. Complete medication review before prescribing Paxlovid
2. Consult drug interaction resources - FDA label provides guidance but is not comprehensive 1
3. Consider alternatives to interacting medications when possible
4. Implement dose adjustments where appropriate and safe
5. Monitor for toxicity with medications that have narrow therapeutic windows 2
6. Pharmacist consultation is essential for identifying and managing potential drug interactions 6

Clinical Implications

The short 5-day course of Paxlovid limits management options for drug interactions. Approaches typically include:

1. Temporarily pausing the interacting medication if clinically appropriate
2. Adjusting doses of the interacting medication
3. Selecting an alternative COVID-19 treatment if interactions cannot be managed safely

In a study of Paxlovid prescribing, 87.1% of patients required interventions to prevent drug-related problems, with drug-drug interactions being the most common issue (57.1%) 6.