Diflucan (Fluconazole) Precautions
Fluconazole requires dose reduction by 50% in patients with GFR <45 mL/min/1.73 m² and careful monitoring for drug interactions, particularly with medications metabolized by CYP3A4 and CYP2C9, as well as vigilance for QT prolongation and hepatotoxicity. 1, 2
Renal Function Monitoring and Dose Adjustment
Reduce the maintenance dose of fluconazole by 50% when GFR is <45 mL/min/1.73 m², as the drug is primarily renally excreted unchanged (approximately 60% in 48 hours). 1, 2, 3
For hemodialysis patients, administer the dose after each dialysis session, as a 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. 4, 2
Monitor renal function before initiating therapy and periodically during treatment, particularly in elderly patients who characteristically have reduced creatinine clearance (mean 74 mL/min in elderly vs. higher in younger adults). 2
Critical Drug Interactions Requiring Contraindication
Never coadminister fluconazole with pimozide or quinidine, as fluconazole inhibits their metabolism, leading to increased plasma concentrations that can cause QT prolongation and torsade de pointes. 2
Never coadminister with terfenadine if using fluconazole at doses ≥400 mg daily, due to risk of serious cardiac arrhythmias. 2
Drug Interactions Requiring Dose Adjustment or Monitoring
Monitor blood glucose closely when using fluconazole with sulfonylureas (tolbutamide, glyburide, glipizide), as fluconazole reduces their metabolism and increases plasma concentrations; one fatality from hypoglycemia has been reported with combined fluconazole-glyburide use. 2
Monitor phenytoin concentrations carefully, as fluconazole increases phenytoin plasma levels through CYP2C9 inhibition; dose adjustment of phenytoin may be necessary. 2
Reduce warfarin dose and monitor INR closely, particularly when GFR <30 mL/min/1.73 m², as there is increased bleeding risk and fluconazole potentiates warfarin's anticoagulant effect. 1, 2
Avoid concomitant use with lemborexant, as fluconazole increases lemborexant exposure 4.2-fold (AUC), significantly increasing somnolence risk. 2
Monitor for NSAID toxicity when coadministering fluconazole with NSAIDs metabolized by CYP2C9 (ibuprofen, naproxen, diclofenac), as fluconazole increased flurbiprofen AUC by 81% and S-(+)-ibuprofen AUC by 82%. 2
Hepatotoxicity Monitoring
Monitor liver function tests before and during therapy, as rare exfoliative skin reactions and clinically overt hepatic dysfunction have occurred, particularly in patients with AIDS. 5
Discontinue fluconazole if clinical signs and symptoms consistent with liver disease develop that may be attributable to the drug. 2
Cardiovascular Precautions
Avoid fluconazole in patients with known QT prolongation, congenital long QT syndrome, or those taking other QT-prolonging medications, as fluconazole has been associated with QT prolongation. 2
Use caution in patients with proarrhythmic conditions including electrolyte abnormalities (hypokalemia, hypomagnesemia). 2
Special Population Considerations
In elderly patients (≥65 years), expect higher AUC (76.4 ± 20.3 mcg•h/mL) and longer half-life (46.2 hours) compared to younger adults, primarily due to reduced renal function; consider dose reduction based on creatinine clearance. 2
In premature neonates (gestational age 26-29 weeks), clearance is markedly reduced (0.18 mL/min/kg at birth, increasing to 0.333 mL/min/kg by day 12) with prolonged half-life (73.6 hours initially); dose adjustments are essential. 2
Oral contraceptive efficacy is unlikely to be affected at fluconazole 50 mg daily, but at 200 mg daily, ethinyl estradiol AUC increases 40% and levonorgestrel AUC increases 24%; multiple-dose use at these levels is still unlikely to affect contraceptive efficacy. 2
Rifampin Coadministration
Consider increasing fluconazole dose when coadministered with rifampin, as rifampin enhances fluconazole metabolism and reduces its efficacy. 2
Conversely, monitor for rifabutin toxicity (particularly uveitis) when coadministering, as fluconazole increases rifabutin serum levels up to 80%. 2
Adrenal Insufficiency Risk
- Monitor for adrenal cortex insufficiency when discontinuing fluconazole in patients on long-term prednisone therapy, as one case report documented acute adrenal insufficiency in a liver transplant patient when fluconazole was stopped after 3 months, presumably due to enhanced CYP3A4 activity increasing prednisone metabolism. 2