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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: May 21, 2017.



Fluconazole is a triazole fungistatic agent used in the treatment of systemic and superficial fungal infections. Fluconazole therapy can cause transient mild-to-moderate serum aminotransferase elevations and is a known cause of clinically apparent acute drug induced liver injury.


Fluconazole (floo kon' a zole) is a fungicidal agent which inhibits lanasterol-14-α-demethylase, the enzyme responsible for ergosterol synthesis. As a consequence, fluconazole causes an increase in abnormal intracellular sterols, inhibiting the fungal cell’s ability to replicate. Fluconazole was approved for use in the United States in 1990 and currently more than 12 million prescriptions are written for it yearly. Current indications include treatment of fungal infections due to candida and cryptococcus. Fluconazole is available in multiple generic forms and under the brand name Diflucan in tablets of 50, 100, 150 and 200 mg, as well as in oral suspensions and parenteral formulations. The usual recommended dose is 100 to 400 mg daily, depending upon the type and severity of the infection. Common side effects include nausea, vomiting, and headache.


Transient mild-to-moderate elevations in serum aminotransferase levels occur in up to 5% of patients treated with fluconazole, but these abnormalities are usually asymptomatic and resolve even with continuation of the medication. ALT elevations above 8 times the upper limit of normal are reported to occur in 1% of patients taking fluconazole and to represent the most common adverse event leading to early discontinuation of treatment. Clinically apparent hepatotoxicity due to fluconazole is rare, but well described. The liver injury is typically hepatocellular, arises within the first few weeks of therapy and can be accompanied by signs of hypersensitivity such as fever, rash and eosinophilia. Fatal instances of fluconazole induced liver injury have been reported (Case 1), but most cases are self-limited, although recovery may be delayed for several weeks after stopping fluconazole and may be slow requiring 2 to 3 months.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of clinically apparent hepatotoxicity from fluconazole is unknown; however, it may relate to the ability of fluconazole to alter sterol synthesis. Fluconazole is a potent inhibitor of the cytochrome P450 enzyme CYP 3A4, and can lead to significant increases in plasma levels and serious toxicity from medications that are ordinarily metabolized by CYP3A4, particularly the statins and cyclosporine.

Outcome and Management

The severity of liver injury from fluconazole ranges from mild and transient enzyme elevations to clinically apparent hepatitis to acute liver failure and death. Most patients recover with stopping fluconazole, but resolution may be slow requiring 3 to 4 months. Rechallenge may lead to recurrence and should be avoided. There is little information on cross reactivity of hepatic injury between fluconazole and other antifungal azoles, such as ketoconazole, itraconazole, voriconazole and posaconazole, but a few reports suggest that there is little cross reactivity. Nevertheless, other antifungal azoles should be started with caution in patients who have suffered clinically apparent hepatotoxicity attributed to fluconazole.

Drug Class: Antifungal Agents


Case 1. Fluconazole induced acute liver failure.

[Modified from: Jacobson MA, Hanks DK, Ferrell LD. Fatal acute hepatic necrosis due to fluconazole. Am J Med 1994; 96: 188-90. PubMed Citation]

A 32 year old man with HIV infection, Kaposi's sarcoma and cryptococcal meningitis received a two week course of amphotericin B, followed by oral fluconazole (400 mg daily). Liver tests were monitored and were normal when fluconazole was started. One week later, serum ALT levels had risen, but the patient was asymptomatic. After 21 days of fluconazole therapy, however, he presented with progressive weakness, nausea, jaundice and low grade fever. Both serum bilirubin and ALT levels had risen markedly (Table) and prothrombin time was prolonged at 22.3 seconds. He was admitted for management. He was somnolent and icteric. Tests for hepatitis A and B were negative. His other medications included aerosolized pentamidine, prochlorperazine (for nausea), acetaminophen with codeine (for pain), acetazolamide and cimetidine. He was not receiving antiretroviral therapy. Acetaminophen level was 4 mg/L, which was considered a nontoxic level. Despite supportive therapy, he became progressively more unresponsible and died 4 days later in hepatic failure, 25 days after starting fluconazole. Autopsy showed massive necrosis without viral inclusion bodies or steatosis.

Key Points

Medication:Fluconazole (400 mg daily)
Pattern:Hepatocellular (R=24)
Severity:5+ (acute liver failure and death)
Latency:3 weeks
Other medications:Pentamidine, prochlorperazine, acetazolamide, cimetidine, acetaminophen and codeine

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
070981.0Fluconazole started
5 days1731010.8
18 days155019.0
21 days1 day182524713.4Fluconazole stopped
22 days2 days160522219.0Protime 28 sec
23 days3 days110519023.5
24 days4 days78021028.6
Died of fulminant hepatic failure 25 days after starting fluconzole
Normal Values<40<130<1.2


A dramatic example of an acute hepatitis-like syndrome arising within 2 to 3 weeks of starting fluconazole, with rapid progression to acute liver failure and death.



Fluconazole – Generic, Diflucan®


Antifungal Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Fluconazole chemical structure


References updated: 21 May 2017

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    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, voriconazole ranked 21st with 52 cases [odds ratio 10.7] and fluconazole 30th with 42 cases [odds ratio 8.6]; no other antifungal agent listed in the top 41 causes).
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  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]
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    (Systematic review of 90 published articles on side effects of fluconazole in 4209 children or neonates, found hepatotoxicity to be the most common adverse event [378 cases, about half of adverse events], but most were self-limited represented by elevated liver enzymes only).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to fluconazole or other antifungal agents).
  • Kao WY, Su CW, Huang YS, Chou YC, Chen YC, Chung WH, Hou MC, et al. Risk of oral anti-fungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol 2014; 77: 180-9. [PMC free article: PMC3895359] [PubMed: 23750489]
    (Analysis of Taiwan National Health Insurance database from 2002-2008 identified 52 patients with drug induced liver injury among 90,847 users of oral antifungal agents, rates were 32 per 10,000 persons for fluconazole [12 cases, 6 of which were fatal]).
  • Kurt H, Toprak O, Bülbül E. The possible efficacy of artichoke in fluconazole related hepatotoxicity. Case Reports Hepatol 2014; 2014: 697359. [PMC free article: PMC4207603] [PubMed: 25374729]
    (40 year old woman with multiple sclerosis received 10 days of intravenous methylprednisolone and then a single tablet of fluconazole, developing symptoms of liver injury over the next 5-12 days [bilirubin 5.2 mg/dL, ALT 1180 U/L, Alk P 85 U/L, INR 1.38], bilirubin rising to 36 mg/dL, but resolving over next 2 months while taking artichoke leaf tea 3 times daily).
  • Raschi E, Poluzzi E, Koci A, Caraceni P, Ponti FD. Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database. World J Hepatol 2014; 6: 601-12. [PMC free article: PMC4163743] [PubMed: 25232453]
    (Analysis of the FDA database on adverse reactions [2004 to 2011] identified 68,115 reports of liver injury including 1964 due to antifungal agents, the most common being terbinafine [422], fluconazole [412], voriconazole [361], amphotericin B [265], itraconazole [182], ketaconazole [94] and posaconazole [70]; among 112 cases with acute liver failure with, the major causes were fluconazole [31], terbinafine [27], and voriconazole [19]).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 14 cases [1.6%] were attributed to antifungal agents including 6 triazoles [3 with jaundice and 2 hospitalized, no deaths], 4 due to fluconazole, 1 ketoconazole and 1 voriconazole).
  • Lo Re V 3rd, Carbonari DM, Lewis JD, Forde KA, Goldberg DS, Reddy KR, Haynes K, et al. Oral azole antifungal medications and risk of acute liver injury, overall and by chronic liver disease status. Am J Med 2016; 129: 283-91. [PMC free article: PMC5549881] [PubMed: 26597673]
    (Among 178,879 persons treated with oral fluconazole analyzed from a Kaiser Permanente clinical database, the incidence of ALT or AST elevations above 200 U/L was 1.3% and severe acute liver injury 0.2%; rates that were similar to those with ketoconazole and less than for posaconazole and vorconazole).
  • Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf 2017; 16: 149-65. [PubMed: 27927037]
    (Review of the hepatotoxicity of antifungal agents states that all antifungal agents may cause hepatic toxicity and discusses fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole, but not ketoconazole).


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