What are the potential drug interactions with Diflucan (fluconazole)?

Potential Drug Interactions with Fluconazole (Diflucan)

Fluconazole has numerous significant drug interactions due to its strong inhibition of CYP enzymes, particularly CYP2C9, CYP2C19, and moderate inhibition of CYP3A4, which can lead to potentially dangerous increases in plasma concentrations of many commonly prescribed medications. 1

Key Mechanisms of Fluconazole Drug Interactions

Fluconazole interacts with other medications primarily through:

1. Inhibition of cytochrome P450 enzymes:

   • Strong inhibitor of CYP2C19
   • Moderate inhibitor of CYP2C9 and CYP3A4
   • The inhibitory effect persists 4-5 days after discontinuation due to fluconazole's long half-life 1

2. Inhibition of P-glycoprotein transport system 2

Most Critical Drug Interactions

Anticoagulants

• Warfarin: Significantly increases prothrombin time and bleeding risk by inhibiting CYP2C9-mediated metabolism 2, 3
  • Monitor INR closely
  • Warfarin dose reduction may be necessary

Cardiovascular Medications

• QT-prolonging drugs (amiodarone, quinidine): Increased risk of QT prolongation and torsade de pointes 1

  • Concomitant use with quinidine is contraindicated
  • Use extreme caution with amiodarone, especially at high fluconazole doses

• Calcium channel blockers (nifedipine, amlodipine, verapamil, felodipine): Increased systemic exposure 1

  • Frequent monitoring for adverse events recommended

Statins

• HMG-CoA reductase inhibitors: Increased risk of rhabdomyolysis, particularly with simvastatin, lovastatin, and atorvastatin 2
  • Consider statin dose reduction or temporary discontinuation

Benzodiazepines

• Short-acting benzodiazepines (midazolam): Substantial increases in concentrations and psychomotor effects 1
  • Decrease benzodiazepine dosage and monitor patients closely

Immunosuppressants

• Tacrolimus: May increase serum concentrations up to 5 times 1

  • Increased risk of nephrotoxicity
  • Decrease oral tacrolimus dose based on tacrolimus concentration

• Sirolimus: Increased plasma concentrations 1

  • Dosage adjustment based on effect/concentration measurements

• Cyclosporine: Increased plasma concentrations 4

  • Monitor levels and adjust dose accordingly

Antiseizure Medications

• Phenytoin: Increased plasma concentrations 1, 4

  • Monitor phenytoin concentrations carefully

• Carbamazepine: Inhibits metabolism, increasing serum levels by 30% 1

  • Risk of carbamazepine toxicity
  • Adjust dose based on concentration measurements

Hypoglycemic Agents

• Sulfonylureas (tolbutamide, glyburide, glipizide): Reduced metabolism and increased plasma concentrations 1, 4
  • Risk of clinically significant hypoglycemia
  • Monitor blood glucose carefully and adjust sulfonylurea dose as needed

Antimicrobials

• Rifampin: Enhances metabolism of fluconazole 1

  • May need to increase fluconazole dose when co-administered with rifampin

• Rifabutin: Increased rifabutin levels up to 80% 1

  • Risk of uveitis
  • Monitor patients carefully

Other Important Interactions

• NSAIDs: Increased exposure to celecoxib, ibuprofen, diclofenac 1

  • May need to reduce NSAID dose

• Opioids: Increased oxycodone plasma concentrations 2

  • Risk of respiratory depression

• Oral contraceptives: At 200 mg daily, fluconazole increases AUCs of ethinyl estradiol and levonorgestrel 1

  • Multiple-dose use unlikely to affect contraceptive efficacy

Patient-Specific Considerations

Renal Dysfunction

• Fluconazole is primarily eliminated renally
• Drug interactions may be more pronounced in patients with renal impairment 2, 3
• Dose adjustment of fluconazole recommended in renal dysfunction

Cardiac Risk Factors

• Patients with hypokalemia and advanced cardiac failure are at increased risk for life-threatening ventricular arrhythmias and torsade de pointes 1
• Use with extreme caution in patients with pre-existing QT prolongation or electrolyte abnormalities

Clinical Management Approach

1. Before starting fluconazole:

   • Complete a thorough medication review
   • Consider alternative antifungals if significant interactions exist
   • Establish baseline monitoring parameters (LFTs, renal function)

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:

   • Remember that enzyme inhibition persists 4-5 days after discontinuation 1
   • Continue monitoring for interactions during this period

Common Pitfalls to Avoid

• Underestimating interaction potential: Even low doses of fluconazole can cause clinically significant interactions 4
• Overlooking non-prescription medications: Herbal supplements and OTC medications may also interact with fluconazole 5
• Assuming all patients will experience interactions: Drug interactions don't necessarily occur in every patient given a particular combination 5
• Failing to consider patient-specific factors: Age, renal function, and concurrent medications all influence interaction risk 2

By understanding these interactions and implementing appropriate monitoring and dose adjustments, clinicians can minimize the risk of adverse events while maintaining therapeutic efficacy of both fluconazole and concomitant medications.