Does indinavir (HIV protease inhibitor) interact with sildenafil (phosphodiesterase type 5 inhibitor)?

Indinavir and Sildenafil Interaction: Significant Risk of Elevated Sildenafil Levels

Indinavir significantly increases sildenafil blood levels by approximately 340%, creating a serious risk of sildenafil toxicity. When these medications must be used together, sildenafil dosage should be reduced to no more than 25mg per 48 hours to prevent adverse effects. 1

Mechanism of Interaction

The interaction between indinavir and sildenafil occurs through the following mechanisms:

• Indinavir is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), the primary enzyme responsible for sildenafil metabolism 2
• This inhibition prevents normal sildenafil breakdown, leading to:
  • 340% increase in sildenafil AUC (area under the curve) 1
  • 48% increase in sildenafil peak concentration (Cmax) 1
  • Prolonged sildenafil half-life and duration of action 3

Clinical Evidence

The FDA-approved drug label for indinavir specifically documents this interaction based on a study of HIV-infected men where:

• A single 25mg dose of sildenafil combined with indinavir (800mg every 8 hours) resulted in sildenafil levels more than 4 times higher than expected 1, 3
• In vitro studies confirmed indinavir as a potent inhibitor of sildenafil hepatic metabolism with an IC50 of 0.39 ± 0.17 microM 3

Clinical Implications and Management

This interaction has significant clinical implications:

1. Increased risk of adverse effects:

   • Hypotension (potentially severe)
   • Prolonged erections/priapism
   • Visual disturbances
   • Headache
   • Flushing

2. Dosing recommendations:

   • Reduce sildenafil dose to maximum 25mg per 48-hour period when used with indinavir 1
   • Monitor for sildenafil-related adverse effects
   • Consider therapeutic drug monitoring in complex cases 4

3. Contraindications:

   • Absolute contraindication if patient is taking nitrates due to risk of severe, potentially fatal hypotension 5
   • Use extreme caution in patients with cardiovascular disease 2

Similar Interactions with Other Protease Inhibitors

This interaction is not unique to indinavir but is a class effect of HIV protease inhibitors:

• Ritonavir, darunavir, lopinavir, and other protease inhibitors similarly increase sildenafil levels 6, 7, 4
• The European Society of Cardiology specifically lists HIV protease inhibitors (including indinavir) and sildenafil as a combination that increases risk of myopathy and rhabdomyolysis 2

Clinical Monitoring

When co-administration cannot be avoided:

• Start with the lowest possible sildenafil dose (25mg)
• Extend dosing interval to at least 48 hours between doses
• Monitor blood pressure and heart rate
• Educate patient about symptoms requiring immediate medical attention (prolonged erection >4 hours, significant drop in blood pressure, visual changes)
• Consider alternative erectile dysfunction treatments when possible

This significant drug interaction requires careful management to prevent potentially serious adverse effects while maintaining therapeutic efficacy of both medications.