fluconazole
Brand: Diflucan
Prototype Drug
Drug Class: antifungal
Drug Family: antifungal
Subclass: triazole antifungal
Organ Systems: infectious-disease
Mechanism of Action
Inhibits fungal CYP51 (lanosterol 14-alpha-demethylase), preventing conversion of lanosterol to ergosterol; depletion of ergosterol disrupts fungal cell membrane integrity; fungistatic against Candida; does not affect human cholesterol synthesis significantly at therapeutic doses.
lanosterol 14-alpha-demethylase (CYP51)
Indications
- oropharyngeal and esophageal candidiasis
- vulvovaginal candidiasis (single 150 mg dose)
- candidemia (non-neutropenic — second-line after echinocandin)
- cryptococcal meningitis (consolidation/maintenance therapy)
- candida UTI
- antifungal prophylaxis in high-risk immunocompromised patients
Contraindications
- concurrent QTc-prolonging drugs with narrow therapeutic index (astemizole, terfenadine, cisapride)
- concomitant voriconazole (both CYP2C19/CYP3A4 inhibitors)
Adverse Effects
Common
- nausea
- headache
- rash
- elevated LFTs
Serious
- hepatotoxicity (rare but serious)
- QTc prolongation
- Stevens-Johnson syndrome (rare)
- drug interactions via CYP inhibition
Pharmacokinetics (ADME)
| Absorption | ~90% oral bioavailability — equivalent oral/IV dosing |
| Distribution | Protein binding 11–12%; Vd ~0.6 L/kg; excellent CSF penetration (~80% of serum levels) |
| Metabolism | CYP2C9, CYP2C19, CYP3A4 inhibitor; minimal hepatic metabolism of fluconazole itself |
| Excretion | Renal; ~80% excreted unchanged; dose reduction for CrCl <50 mL/min |
| Half-life | 30 hours — allows once-daily dosing |
| Onset | 1–2 hours |
| Peak | 1–2 hours |
| Duration | 24 hours |
| Protein Binding | 11–12% |
| Vd | ~0.6 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| warfarin | CYP2C9 inhibition increases warfarin AUC by ~44%; major bleeding risk | major |
| QTc-prolonging drugs | fluconazole prolongs QTc via hERG potassium channel blockade and CYP inhibition of QTc-prolonging drugs | major |
| tacrolimus/cyclosporine | CYP3A4 inhibition doubles tacrolimus/cyclosporine levels | major |
Nursing Considerations
- Monitor LFTs at baseline and with prolonged use; fluconazole hepatotoxicity is rare but potentially serious
- Review medication list for CYP interactions before initiating — fluconazole inhibits CYP2C9, CYP2C19, and CYP3A4, affecting warfarin, phenytoin, cyclosporine, tacrolimus, and dozens of other drugs
- Single-dose 150 mg (Diflucan) for vaginal candidiasis is safe for most women; advise patient that symptoms may take 2–3 days to resolve
- Dose must be halved when CrCl <50 mL/min (once daily to once every 48 hours); in HD patients, give one dose after each dialysis session
Clinical Pearls
- Fluconazole has no activity against Candida krusei (intrinsically resistant) and Candida glabrata (dose-dependent susceptibility); candidemia in ICU patients should initially be treated with echinocandin (anidulafungin, micafungin, caspofungin) regardless of species, then step down to fluconazole for susceptible species
- The oral bioavailability of fluconazole (~90%) is essentially equivalent to IV — switching from IV to oral fluconazole on the same dose provides identical drug exposure at significantly lower cost
Safety Profile
Pregnancy safe
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
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