What is the interaction between Paxlovid (Nirmatrelvir/Ritonavir) and Sildenafil (Viagra)?

Interaction Between Paxlovid and Sildenafil

Concomitant use of Paxlovid (nirmatrelvir/ritonavir) with sildenafil is contraindicated when sildenafil is used for pulmonary arterial hypertension, and requires significant dose reduction when sildenafil is used for erectile dysfunction due to dangerous increases in sildenafil plasma concentrations. 1

Mechanism of Interaction

The interaction between Paxlovid and sildenafil occurs primarily through:

• CYP3A4 inhibition: Ritonavir in Paxlovid is a potent inhibitor of CYP3A4, the primary enzyme responsible for sildenafil metabolism 1
• P-glycoprotein inhibition: Both nirmatrelvir and ritonavir can inhibit P-gp transporters, potentially affecting sildenafil disposition 2, 3

Clinical Implications

For Pulmonary Arterial Hypertension (PAH)

• Sildenafil used for PAH is absolutely contraindicated with Paxlovid 4
• The significantly increased sildenafil exposure can lead to:
  • Severe hypotension
  • Syncope
  • Visual disturbances
  • Prolonged erection
  • Other serious adverse events

For Erectile Dysfunction

• If sildenafil is used for erectile dysfunction, significant dose adjustments are required:
  • Recommended dose adjustment: Use no more than 25 mg of sildenafil in a 48-hour period 1
  • Without dose adjustment, patients may experience:
    • Hypotension
    • Visual changes
    • Priapism
    • Other adverse effects related to sildenafil toxicity

Management Approach

1. For PAH patients:

   • Do not co-administer Paxlovid and sildenafil
   • Consider alternative COVID-19 treatments if the patient requires ongoing sildenafil for PAH

2. For erectile dysfunction patients:

   • Reduce sildenafil dose to maximum 25 mg in 48 hours
   • Counsel patients about potential adverse effects
   • Consider temporarily discontinuing sildenafil during the 5-day Paxlovid treatment course if possible

3. Monitoring:

   • If co-administration cannot be avoided, monitor for:
     • Blood pressure changes
     • Symptoms of hypotension (dizziness, lightheadedness)
     • Visual disturbances
     • Priapism (erection lasting >4 hours)

Important Considerations

• The interaction persists throughout the entire 5-day course of Paxlovid treatment 5
• The effect of ritonavir on CYP3A4 inhibition occurs rapidly and potently 2
• Even a short course of ritonavir can significantly increase exposure to CYP3A4 substrates like sildenafil 5
• This interaction is classified as high-risk in multiple drug interaction analyses 6, 7

Pitfalls to Avoid

• Don't assume a reduced dose eliminates all risk: Even with dose reduction, patients should be monitored for adverse effects
• Don't forget about the duration of effect: Ritonavir's enzyme inhibition may persist briefly after discontinuation
• Don't overlook patient education: Patients must understand the importance of dose reduction and monitoring for adverse effects
• Don't miss alternative options: Consider if temporary discontinuation of sildenafil is feasible during Paxlovid treatment

This interaction represents a significant clinical concern requiring careful management to prevent potentially serious adverse events.