What are the common drug interactions with Paxlovid (nirmatrelvir and ritonavir)?

Common Drug Interactions with Paxlovid

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

Mechanism of Drug Interactions

Paxlovid's interaction potential stems primarily from:

• Ritonavir: Acts as a strong inhibitor of:

  • CYP3A4 (primary mechanism)
  • CYP2D6
  • P-glycoprotein (P-gp)
  • OATP1B1 transporters 1

• Nirmatrelvir: Functions as both a substrate and inhibitor of:

  • CYP3A enzymes
  • P-gp transporter protein 2

Contraindicated Medications

The following medications are absolutely contraindicated with Paxlovid:

Cardiovascular Medications

• Antiarrhythmics: Amiodarone, dronedarone, flecainide, propafenone, quinidine 1
• Antianginals: Ranolazine 1
• Alpha-1 adrenoreceptor antagonists: Alfuzosin 1

Anticancer Drugs

• Androgen receptor inhibitors: Apalutamide, enzalutamide 1

Other Notable Contraindications

• Sildenafil (when used for pulmonary arterial hypertension) 3
• Ergot derivatives
• HMG-CoA reductase inhibitors: Lovastatin, simvastatin

High-Risk Interactions Requiring Dose Adjustments

Anticoagulants

• Warfarin: Requires close INR monitoring 1
• Direct Oral Anticoagulants (DOACs):
  • Rivaroxaban: Avoid concomitant use due to increased bleeding risk 1
  • Apixaban: Requires dose adjustment based on indication 1
  • Dabigatran: May require dose reduction or avoidance based on renal function 1

Anticancer Medications

• Kinase inhibitors: Abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax 1
• Vinca alkaloids: Vinblastine, vincristine (may cause significant hematologic or gastrointestinal side effects) 1

Immunosuppressants

• Calcineurin inhibitors: Tacrolimus, cyclosporine (require significant dose reduction and therapeutic drug monitoring) 2

Cardiovascular Medications

• Antiarrhythmics: Lidocaine (systemic), disopyramide (require therapeutic concentration monitoring) 1
• Alpha-1 adrenoreceptor antagonists: Tamsulosin (avoid concomitant use) 1
• Calcium channel blockers: Nifedipine, manidipine, verapamil (increased risk of toxicity) 2

Erectile Dysfunction Medications

• PDE5 inhibitors:
  • Sildenafil for erectile dysfunction: Maximum 25 mg in 48 hours 3
  • Tadalafil: Requires significant dose reduction
  • Vardenafil: Requires significant dose reduction

Psychiatric Medications

• Antipsychotics: Clozapine, quetiapine (increased risk of toxicity) 2
• Sedatives/Hypnotics: Midazolam, triazolam (avoid or significantly reduce dose)

Monitoring Recommendations

1. Prior to prescribing Paxlovid:

   • Review all medications to assess potential drug-drug interactions
   • Determine if concomitant medications require dose adjustment, interruption, or additional monitoring 1

2. During treatment:

   • Monitor for signs of toxicity with medications that have narrow therapeutic windows
   • For anticoagulants like warfarin, check INR more frequently 1
   • For patients on immunosuppressants, monitor drug levels closely
   • For patients on antiarrhythmics, monitor ECG and therapeutic drug levels when available 1

Common Pitfalls and Caveats

1. Duration of interaction: The inhibitory effects of ritonavir may persist for several days after discontinuation of Paxlovid 3

2. QT prolongation risk: Combining Paxlovid with other QT-prolonging medications may increase risk of cardiac arrhythmias 4

3. Renal impairment: Patients with renal impairment may require dose adjustments of both Paxlovid and concomitant medications 4

4. Inducers of CYP3A: Medications that induce CYP3A (like rifampin, carbamazepine, phenytoin) may decrease nirmatrelvir and ritonavir concentrations, reducing Paxlovid's therapeutic effect 1

5. Incomplete interaction lists: The FDA label notes that the listed interactions are not comprehensive, and healthcare providers should consult additional resources for complete information 1

Management Approach

1. Assess risk vs. benefit: Determine if the benefit of Paxlovid treatment outweighs the risk of potential drug interactions 4

2. Consider alternatives: For patients on multiple interacting medications, consider alternative COVID-19 treatments 4

3. Temporary discontinuation: When possible, consider temporarily discontinuing the interacting medication during the 5-day Paxlovid treatment course 3

4. Dose adjustment: For medications that cannot be discontinued, adjust dosing according to established guidelines 1

5. Enhanced monitoring: Implement more frequent monitoring of drug levels or clinical effects when interactions cannot be avoided 1

By carefully managing these interactions, the mortality and morbidity benefits of Paxlovid can be preserved while minimizing the risk of adverse events from drug interactions.