Fluconazole Significantly Increases Sildenafil Levels and Risk of Adverse Effects
Fluconazole significantly increases sildenafil plasma concentrations by inhibiting CYP3A4 enzymes, requiring a dose reduction of sildenafil by approximately 60% when these medications are used concurrently to avoid potentially serious adverse effects. 1
Mechanism of Interaction
Sildenafil is primarily metabolized by the cytochrome P450 enzyme CYP3A4 in the liver. Fluconazole is a potent inhibitor of this enzyme, which leads to:
- Decreased metabolism of sildenafil
- Increased plasma concentrations of sildenafil
- Prolonged half-life of sildenafil in the body 1
PBPK modeling studies have demonstrated that this interaction can increase sildenafil's AUC (area under the curve) by approximately 2.8-fold in certain populations 2.
Clinical Implications
Increased Risk of Adverse Effects
When fluconazole and sildenafil are used together, patients may experience enhanced and prolonged sildenafil-related adverse effects:
- More pronounced hypotensive effects
- Increased incidence and severity of headache, flushing, and dizziness
- Potential for prolonged erections
- Increased risk of cardiovascular events 1, 3
Animal studies with itraconazole (another azole antifungal with similar mechanism) showed that when co-administered with sildenafil, drug-related effects such as increased heart rate and decreased QT interval were significantly enhanced and prolonged compared to sildenafil alone 3.
Dose Adjustment Requirements
Based on the pharmacokinetic interaction:
- A sildenafil dose reduction of approximately 60% is recommended when used concurrently with fluconazole 1, 2
- For erectile dysfunction treatment, consider reducing the standard 50mg dose to 20-25mg
- For pulmonary arterial hypertension treatment, consider reducing the standard 20mg TID dose to 10mg TID 4
Monitoring Recommendations
When co-administration cannot be avoided:
- Monitor blood pressure closely, particularly within the first few hours after sildenafil administration
- Watch for signs of sildenafil toxicity including severe headache, pronounced flushing, dizziness, and visual disturbances
- Be alert for cardiovascular symptoms, especially in patients with pre-existing cardiovascular disease 1, 5
Special Populations Considerations
The interaction may be more pronounced in:
- Elderly patients
- Patients with hepatic impairment
- Patients with renal impairment
- Patients taking multiple medications that inhibit CYP3A4 3
In these populations, even greater dose reductions of sildenafil may be necessary, and more careful monitoring is warranted.
Clinical Decision Algorithm
- Assess necessity of concurrent therapy
- If concurrent therapy is required:
- Reduce sildenafil dose by approximately 60%
- Start at the lowest effective dose
- Monitor for adverse effects
- Consider alternative antifungal therapy if appropriate
- Educate patient about potential side effects and when to seek medical attention
This drug interaction is clinically significant and requires careful management to minimize risks while maintaining therapeutic efficacy.