What are the potential interactions between fluconazole and other medications?

Fluconazole Drug Interactions

Fluconazole has numerous significant drug interactions due to its inhibition of multiple cytochrome P450 enzymes, particularly CYP2C9, CYP3A4, and CYP2C19, which can lead to increased plasma concentrations of many medications and potential toxicity.

Major Drug Interaction Categories

Anticoagulants

• Warfarin: Fluconazole significantly increases prothrombin time and bleeding risk by inhibiting CYP2C9-mediated metabolism of warfarin 1, 2
  • Requires careful INR monitoring and warfarin dose reduction (typically 30-50%)
  • Even low-dose fluconazole (100 mg daily) can increase INR from baseline within 5-8 days 3
  • May require 2-3 fold warfarin dose reduction 1

Cardiovascular Medications

• Calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil, felodipine): Fluconazole increases systemic exposure through CYP3A4 inhibition 2
• QT-prolonging medications: Fluconazole can cause QT prolongation and may amplify this effect when combined with other QT-prolonging drugs 2
  • Avoid concomitant use with amiodarone, especially at high fluconazole doses (800 mg)
  • Contraindicated with quinidine and pimozide due to risk of torsades de pointes

Immunosuppressants

• Cyclosporine: Fluconazole significantly increases cyclosporine levels, requiring dose reduction and monitoring 2
• Tacrolimus: Oral tacrolimus concentrations may increase up to 5-fold, requiring dose reduction based on tacrolimus levels 2
• Sirolimus: Requires dose adjustment based on concentration measurements 2
• Prednisone: Discontinuation of fluconazole after long-term therapy may cause enhanced prednisone metabolism and potential adrenal insufficiency 2

Antiepileptics

• Carbamazepine: Fluconazole inhibits metabolism, increasing serum levels by approximately 30% 2
• Phenytoin: Increases plasma concentrations, requiring careful monitoring 2

Benzodiazepines

• Short-acting benzodiazepines (midazolam): Substantial increases in concentrations and psychomotor effects 2
  • Consider decreasing benzodiazepine dosage and monitor patients closely

Hypoglycemic Agents

• Sulfonylureas (tolbutamide, glyburide, glipizide): Fluconazole reduces metabolism and increases plasma concentrations 2
  • Careful blood glucose monitoring required
  • Fatal hypoglycemia has been reported with glyburide combination

HIV Medications

• Protease inhibitors: Complex interactions requiring careful monitoring 4
• Saquinavir: Fluconazole increases AUC by ~50% and decreases clearance by ~50% 2

Other Antifungals

• Amphotericin B: Concurrent administration shows variable effects - small additive effect against Candida, no interaction with Cryptococcus, and antagonism against Aspergillus 2
  • Clinical significance is unknown

Rifamycins

• Rifampin: Enhances metabolism of fluconazole, potentially requiring increased fluconazole dosing 2
• Rifabutin: Fluconazole increases rifabutin levels up to 80%, with reports of uveitis in co-administered patients 2

Opioids

• Alfentanil: Reduced clearance and prolonged half-life, may require dose adjustment 2
• Methadone: Fluconazole may increase methadone levels 1

Hormonal Contraceptives

• At 200 mg daily, fluconazole increases AUCs of ethinyl estradiol and levonorgestrel by 40% and 24% respectively 2
• Multiple-dose use at these doses unlikely to affect contraceptive efficacy

Clinical Approach to Managing Fluconazole Interactions

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:
     • Warfarin: Reduce dose by 30-50% and monitor INR frequently
     • Oral tacrolimus: Decrease dose based on tacrolimus concentration
     • Cyclosporine: Reduce dose and monitor levels
     • Sulfonylureas: Monitor blood glucose closely

3. Special populations:

   • Renal dysfunction: Dose adjustment of fluconazole needed as it's primarily eliminated renally
   • Older adults: May be more susceptible to adverse effects due to age-related changes in drug metabolism

Important Contraindications

Fluconazole is contraindicated with:

• Pimozide and quinidine due to risk of QT prolongation and torsades de pointes 2
• Erythromycin when combined with high-dose fluconazole 2
• Caution with medications that prolong QT interval and are metabolized via CYP3A4 2

Common Pitfalls to Avoid

1. Failing to monitor INR when adding fluconazole to warfarin therapy - even low doses (100 mg) can significantly increase INR within days 3

2. Overlooking interactions with oral hypoglycemics - fatal hypoglycemia has been reported with fluconazole-glyburide combination 2

3. Not adjusting immunosuppressant doses - can lead to nephrotoxicity with tacrolimus or cyclosporine 2

4. Forgetting that drug interactions persist 4-5 days after discontinuing fluconazole due to its long half-life 2

5. Missing the potential for adrenal insufficiency when discontinuing fluconazole in patients on long-term prednisone 2