Can Fluconazole Cause Cholestasis?
Fluconazole can cause hepatotoxicity including cholestatic liver injury, though this is rare; the primary hepatic adverse effect is transaminase elevation rather than cholestasis specifically, and serious liver toxicity occurs in less than 1-2% of patients. 1, 2
Hepatotoxicity Profile of Fluconazole
The hepatic adverse effects of fluconazole are well-documented but uncommon:
Asymptomatic transaminase elevations occur in 1-13% of patients receiving azole antifungals, with fluconazole being among the better-tolerated agents in this class. 2 This represents the most common hepatic manifestation rather than cholestasis per se.
Serious hepatotoxicity, including fatal hepatitis, is rare with fluconazole compared to other azoles like voriconazole or itraconazole. 1, 3 Population-based studies demonstrate serious adverse liver events occur at a rate of only 1.4 per 100,000 prescriptions. 4
While fluconazole can worsen pre-existing liver dysfunction, cholestatic injury specifically is not the predominant pattern of hepatotoxicity described in clinical guidelines. 5 The drug-induced cholestasis literature does not prominently feature fluconazole as a causative agent. 6
Special Population Considerations: Neonatal Cholestasis
An important caveat exists in extremely low birth weight (ELBW) infants:
Fluconazole prophylaxis in ELBW infants has been associated with cholestasis in some studies, though this relationship remains controversial. 7, 8 One study found no difference in cholestasis rates between fluconazole-treated and control groups, 7 while another reported increased severity of cholestasis with frequent dosing schedules. 8
Less frequent dosing (twice weekly) appears to reduce the severity of cholestasis in premature infants while maintaining efficacy against invasive fungal infections. 8 This suggests a dose-dependent relationship in this vulnerable population.
Monitoring Recommendations
Given the hepatotoxic potential, albeit rare:
The National Comprehensive Cancer Network recommends monitoring hepatic enzymes before starting fluconazole, at 2 and 4 weeks after initiation, and every 3 months during ongoing therapy. 1
Patients with underlying liver dysfunction require closer monitoring, as fluconazole can worsen pre-existing hepatic impairment. 5 HIV-positive patients may be at increased risk for hepatotoxicity. 5
The British Association of Dermatologists recommends baseline liver function tests before starting fluconazole therapy, particularly for high-dose or prolonged treatment courses. 1
Clinical Context
Fluconazole is generally well-tolerated with a favorable safety profile compared to other systemic antifungals. 1, 9 The incidence of abnormal liver function tests from oral antifungal therapy is extremely low, though reversible hepatic damage can rarely occur. 9
In adults, cholestasis is not the characteristic pattern of fluconazole hepatotoxicity—transaminase elevation is far more common. 1, 2 When drug-induced cholestasis occurs from any medication, withdrawal of the offending agent is the primary treatment. 6