What are the potential drug interactions of fluconazole?

Fluconazole Drug Interactions: Clinical Implications and Management

Fluconazole is a potent inhibitor of multiple cytochrome P450 enzymes (particularly CYP2C9, CYP2C19, and CYP3A4) that can cause numerous clinically significant drug interactions requiring careful monitoring, dose adjustments, or alternative therapy selection.

Key Interaction Mechanisms

Fluconazole primarily interacts with other medications through:

• CYP450 enzyme inhibition: Acts as a moderate CYP3A4 inhibitor and strong CYP2C9/CYP2C19 inhibitor 1
• QT interval prolongation: Can directly prolong QT interval and amplify this effect when combined with other QT-prolonging drugs 1
• P-glycoprotein inhibition: May increase systemic levels of drugs affected by this transport system 2

Major Drug Interactions by Class

Anticoagulants

• Warfarin: Fluconazole significantly increases prothrombin time and bleeding risk by inhibiting CYP2C9-mediated metabolism 1, 2
  • Requires careful monitoring of INR and potential warfarin dose reduction
  • Effects can persist 4-5 days after fluconazole discontinuation

Cardiovascular Medications

• Calcium channel blockers (nifedipine, amlodipine, verapamil, felodipine): Increased systemic exposure requiring frequent monitoring 1
• Statins: Risk of rhabdomyolysis, particularly with simvastatin, lovastatin, and atorvastatin 2, 3
  • Consider statin dose reduction or temporary discontinuation
• Amiodarone: Increased QT prolongation risk through both direct effects and inhibition of amiodarone metabolism 1
• Quinidine: Contraindicated due to risk of QT prolongation and torsade de pointes 1

Antiepileptics

• Carbamazepine: Inhibits metabolism, increasing levels by approximately 30%, requiring dose adjustment 1
• Phenytoin: Increases plasma concentrations requiring careful monitoring 1

Immunosuppressants

• Cyclosporine: Significantly increases cyclosporine levels in transplant patients 1
• Tacrolimus: Can increase serum concentrations up to 5 times, requiring dose reduction 1
• Sirolimus: Increases plasma concentrations requiring dose adjustment 1

Hypoglycemic Agents

• Sulfonylureas (tolbutamide, glyburide, glipizide): Increased risk of hypoglycemia 1
  • Tolbutamide AUC increases by 26%
  • Glipizide AUC increases by 49%
  • Glyburide AUC increases by 44%
  • Requires blood glucose monitoring and potential dose reduction

Benzodiazepines

• Short-acting benzodiazepines (midazolam, triazolam): Substantial increases in concentrations and psychomotor effects 1
  • Midazolam AUC increased by 259% with fluconazole
  • Consider dose reduction or alternative benzodiazepine

Antiretroviral Medications

• HIV protease inhibitors: Complex interactions requiring careful monitoring 2
• Zidovudine: Increases AUC by approximately 20% 1

Other Notable Interactions

• Rifampin: Enhances fluconazole metabolism, potentially requiring increased fluconazole dosing 1
• Rifabutin: Fluconazole increases rifabutin levels up to 80%, requiring monitoring for uveitis 1
• Opioids: Increases oxycodone plasma concentrations, potentially causing respiratory depression 4
• Oral contraceptives: At 200mg daily, fluconazole increases ethinyl estradiol and levonorgestrel AUC by 40% and 24% respectively 1
• Theophylline: Increases serum concentrations, requiring monitoring 1
• NSAIDs: Increased exposure to NSAIDs metabolized by CYP2C9 1

Special Populations and Considerations

Renal Dysfunction

• Fluconazole is primarily eliminated renally, so drug interactions may be more pronounced in patients with renal impairment 4, 5
• Dose adjustment of fluconazole is necessary in renal dysfunction

Elderly Patients

• More susceptible to adverse effects due to age-related changes in drug metabolism 4
• May require lower doses of interacting medications

Patients with Cardiac Risk Factors

• Particular caution with QT-prolonging combinations in patients with:
  • Hypokalemia
  • Advanced cardiac failure
  • Structural heart disease
  • Electrolyte abnormalities 1

Management Strategies

1. Before starting fluconazole:

   • Complete medication review for potential interactions
   • Consider alternative antifungals if significant interactions exist
   • Establish baseline monitoring parameters (LFTs, renal function, drug levels)

2. During fluconazole therapy:

   • Monitor for signs of toxicity from interacting medications
   • Adjust doses of affected medications as needed
   • Consider therapeutic drug monitoring for medications with narrow therapeutic indices

3. After discontinuing fluconazole:

   • Continue monitoring for 4-5 days as enzyme inhibition persists
   • Readjust doses of interacting medications as fluconazole effect wanes 4

Common Pitfalls to Avoid

• Overlooking interactions with commonly used medications: Particularly statins, warfarin, and benzodiazepines
• Failing to recognize delayed effects: Fluconazole's enzyme inhibition persists 4-5 days after discontinuation
• Ignoring additive QT prolongation: Especially when combined with other QT-prolonging drugs
• Underestimating interaction severity in renal dysfunction: Reduced clearance of fluconazole increases interaction risk

In clinical practice, always weigh the benefits of fluconazole therapy against the risks of potential drug interactions, particularly in patients on multiple medications or with organ dysfunction.