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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-.


Last Update: May 17, 2017.



Voriconazole is a triazole antifungal agent used primarily in the treatment or prevention of aspergillosis and candidal infections. Voriconazole therapy is associated with transient, asymptomatic serum aminotransferase elevations and is a known cause of clinically apparent acute drug induced liver injury.


Voriconazole (vor" i kon' a zole) is a synthetic triazole and a derivative of fluconazole, which is believed to act through inhibition of the fungal 14α-ergosterol demethylase that is responsible for converting lanosterol to ergosterol, which blocks cell membrane synthesis. Voriconazole has a broad spectrum of activity particularly against candida and aspergillus. Voriconazole was approved for use in the United States in 2002. Current indications include treatment of invasive aspergillosis, esophageal candidiasis and serious candidal infections. It is also used as empiric antifungal therapy in patients with neutropenia and persistent fever as well as preventive antifungal therapy in high risk individuals. Voriconazole is available as tablets of 50 and 200 mg, in an oral suspension (40 mg/mL) and in a parenteral formulation generically and under the brand name Vfend. Serious fungal infections are typically treated initially with intravenous voriconazole (4 to 6 mg/kg every 12 hours) for 3 to 10 days, followed by more prolonged therapy with oral forms (20 mg every 12 hours). Common side effects include nausea, photosensitivity, hallucinations, headache, visual disturbances and rash.


Transient elevations in serum aminotransferase levels occur in 11% to 19% of patients on voriconazole. These elevations are usually asymptomatic and self-limited, but approximately 1% of patients require discontinuation of voriconazole because of ALT elevations. Clinically apparent hepatotoxicity is uncommon, but may be more frequent than with fluconazole and itraconazole. The injury arises within the first month of therapy and the pattern of serum enzyme elevations has been variable from cholestatic to hepatocellular. Several cases of acute liver failure attributed to voriconazole have been reported. Immunoallergic features and autoantibodies are uncommon. Recovery upon stopping therapy generally takes 6 to 10 weeks but, in some cases, the time to complete resolution may be prolonged.

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

Mechanism of Injury

The cause of clinically apparent hepatotoxicity from voriconazole is unknown; however, it may have some correlation to the ability of voriconazole to alter human sterol synthesis. Because voriconazole is a substrate for several P450 enzymes (CYP 2C19, 2C9, 3A4), it has the potential to cause significant drug-drug interactions, including elevations in plasma levels of other medications that are metabolized by these P450 enzymes, sometimes resulting in toxicity. Alternatively, voriconazole plasma levels might be affected by CYP inhibitors.

Outcome and Management

The severity of the liver injury from voriconazole ranges from mild and transient enzyme elevations to symptomatic or severe hepatitis leading to liver transplantation or death. Cases of acute liver failure have been described due to voriconazole, but not chronic liver injury or vanishing bile duct syndrome. Most cases of voriconazole hepatotoxicity resolve with discontinuation of the medication, but the improvements may be delayed and typically require 1 to 3 months. Rechallenge may lead to recurrence and should be avoided. Testing for serum bilirubin and aminotransferase levels is rercommended at the time of starting and weekly during the first month of voriconazole therapy and monthly thereafter. The relationship between voriconazole trough plasma levels of hepatotoxicity is, however, controversial. There is little information on cross reactivity of hepatic injury between voriconazole and other antifungal azoles, such as ketoconazole, itraconazole, fluconazole and posaconazole. While a few reports suggest that there is little cross reactivity, other azoles should be started with caution in patients who have suffered clinically apparent hepatotoxicity attributed to voriconazole.

Drug Class: Antifungal Agents


Case 1. Fulminant liver failure following voriconazole therapy in a child with AIDS.

[Modified from: Scherpbier H, Hilhorst M, Kuijpers T. Liver failure in a child receiving highly active antiretroviral therapy and voriconazole. Clin Infect Dis 2003; 37: 828-30. PubMed Citation]

A 10 year old with HIV infection and AIDS developed serum enzyme elevations within a day of starting voriconazole for esophageal candidiasis after failure of itraconazole, fluconazole, amphotericin B and flucytosine. Serum aminotransferase levels continued to rise and voriconazole was stopped on day 7. The patient’s liver function deteriorated rapidly even after stopping voriconazole treatment. Tests for hepatitis A, B and C were negative. Because of worsening hepatic function, her antiretroviral medications were also stopped, but her liver disease progressed to hepatic failure, coma and death 28 days after starting voriconazole.

Key Points

Pattern:Hepatocellular (R=28)
Severity:5+ (death from hepatic failure)
Latency:1 day to serum aminotransferase elevations, 1 week to jaundice
Other medications:Amprenavir, didanosine, nevirapine, lopinavir/ritonavir

Laboratory Values

Time After StartingTime After StoppingALT (U/L)AST (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
-12 days2354104
1 day0531271130.2Voriconazole started
7 days0Voriconazole stopped
9 days2 days20914012152.0
12 days5 days5535977-3.2Antiretrovirals stopped
16 days9 days8428534-5.9
4 weeks3 weeks334593-6.3Death
Normal Values <45 <40 <120 <1.2


While there was a temporal relationship between starting voriconazole and the onset of serum aminotransferase elevations, this child was receiving several other potentially hepatotoxic agents and serum enzymes were slightly elevated before voriconazole was started. Although she had been on a stable antiretroviral regimen for many months, the voriconazole, by inhibiting CYP 3A4 activity, may have caused elevations in her antiretroviral drug levels leading to hepatotoxicity. Also unusual was the discrepancy between AST and ALT elevations which suggests muscle or heart injury as well. Nevertheless, other aspects of the case suggest the role of voriconazole in an acute hepatitis-like clinical syndrome arising within a week of starting medication. As is typical, recovery can be delayed, and the disease may progress during the 1 to 4 weeks after stopping medication.



Voriconazole – Generic, Vfend®


Antifungal Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Voriconazole 137234-62-9 C16-H14-F3-N5-O
Image of Voriconazole Chemical Structure


References updated: 17 May 2017

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  • Zonios D, Yamazaki H, Murayama N, Natarajan V, Palmore T, Childs R, Skinner J, et al. Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype. J Infect Dis 2014; 209: 1941-8. [PMC free article: PMC4038142] [PubMed: 24403552]
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  • 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 478 persons treated with oral vorconazole analyzed from a Kaiser Permanente clinical database, the incidence of ALT or AST elevations above 200 U/L was 18.2% and severe acute liver injury 1.7%; rates that were an order of magnitude higher than those with fluconazole, ketoconazole and itraconazole).
  • Lopez JL, Tayek JA. Voriconazole-induced hepatitis via simvastatin- and lansoprazole-mediated drug interactions: a case report and review of the literature. Drug Metab Dispos 2016; 44: 124-6. [PubMed: 26502771]
    (44 year old man taking voriconazole for more than a year developed jaundice within 10 days of starting lansoprazole [bilirubin 13.0 mg/dL, ALT 362 U/L, Alk P 406 U/L], which resolved on stopping but recurred 16 months later two weeks after starting simvastatin [bilirubin 15.4 mg/dL, ALT 893 U/L, Alk P 789 U/L], resolving rapidly on stopping; authors hypothesize that voriconazole was the cause of the liver injury, its plasma levels being affected by effects of the lanosprazole and simvastatin on drug metabolism).
  • 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).