What medications increase the concentration of sildenafil (Viagra)?

Medications That Increase Sildenafil Concentration

Multiple medications significantly increase sildenafil concentrations by inhibiting CYP3A4, the primary enzyme responsible for sildenafil metabolism, requiring dose reduction to prevent adverse effects. 1, 2

Key CYP3A4 Inhibitors That Increase Sildenafil Levels

Strong Inhibitors

• Ketoconazole: Increases sildenafil levels 2-fold 1
• HIV protease inhibitors:
  • Ritonavir and saquinavir markedly increase sildenafil levels, requiring dose adjustment 1
• Erythromycin:
  • Increases sildenafil systemic exposure (AUC) 3
  • Causes 2.8-fold increase in sildenafil AUC and 2.6-fold increase in Cmax 4
• Clarithromycin:
  • Increases sildenafil AUC by 127-161% and Cmax by 132-157% 5

Moderate Inhibitors

• Ciprofloxacin:
  • Increases sildenafil AUC by 119-159% and Cmax by 127-152% 5
  • Use with caution due to increased sildenafil serum levels 1
• Cimetidine: Increases sildenafil levels 1
• Fluconazole: Considerably increases sildenafil levels, requiring approximately 60% dose reduction 6

Other Medications

• Bosentan: Paradoxically, while bosentan is a CYP3A4 inducer, sildenafil levels fall 50% while bosentan levels increase 50% when used together 1
• Beta-blockers: Population pharmacokinetic analysis shows approximately 34% reduction in sildenafil clearance when co-administered with beta-blockers 2

Clinical Implications and Management

Dose Adjustment Recommendations

• For patients taking CYP3A4 inhibitors:
  • Consider starting with a lower sildenafil dose (25mg) 4
  • For erythromycin or other potent CYP3A4 inhibitors, a lower starting dose of sildenafil (25mg) should be considered 4
  • With fluconazole, reduce sildenafil dose by approximately 60% 6

Monitoring Recommendations

• Monitor for enhanced sildenafil effects:
  • Hypotension
  • Headache
  • Flushing
  • Visual disturbances
  • Prolonged erection

Contraindications

• Absolute contraindication: Concurrent use with nitrates or nicorandil due to risk of profound systemic hypotension 1

Special Populations at Higher Risk

• Elderly patients (≥65 years): Already have reduced clearance of sildenafil (84% higher plasma concentrations) 2
• Patients with hepatic impairment: Have reduced sildenafil clearance with increases in AUC (84%) and Cmax (47%) 2
• Patients with severe renal impairment: Experience approximately doubling of AUC and Cmax 2

Clinical Pearls

• The interaction magnitude varies depending on the potency of the CYP3A4 inhibitor
• Azithromycin, unlike other macrolides, does not significantly affect sildenafil pharmacokinetics 4
• Grapefruit juice, a weak CYP3A4 inhibitor, modestly increases sildenafil levels 1
• When prescribing sildenafil with CYP3A4 inhibitors, always consider the patient's cardiovascular status and other medications that might potentiate hypotensive effects

Always check for potential drug interactions before prescribing sildenafil, particularly in patients taking multiple medications or those with hepatic or renal impairment.