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 rare 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.
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.
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. 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.
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.
|Pattern:|| Hepatocellular (R=28)|
||5+ (death from hepatic failure)
||1 day to serum aminotransferase elevations, 1 week to jaundice
|Other medications:||Amprenavir, didanosine, nevirapine, lopinavir/ritonavir|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
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.
REPRESENTATIVE TRADE NAMES
Voriconazole – Generic, Vfend®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 03 December 2013
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Husain S, Paterson DL, Studer S, Pilewski J, Crespo M, Zaldonis D, Shutt K, et al. Voriconazole prophylaxis in lung transplant recipients. Am J Transplant 2006; 6: 3008-16. PubMed Citation (Comparison of voriconazole vs itraconazole prophylaxis against invasive fungal infections after lung transplantation; 45% of patients on voriconazole vs 15% of itraconazole developed ALT levels above 3 times normal, and discontinuation required for ALT elevations in 14% vs 7%; all ultimately resolved).
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Ueda K, Nannya Y, Kumano K, Hangaishi A, Takahashi T, Imai Y, Kurokawa M. Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders. Int J Hematol 2009; 89: 592-9. PubMed Citation (Liver enzyme elevations occurred only with voriconazole levels over 6 mg/L).
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