Azole antifungals are known for treating various types of yeast, molds, and dimorphic fungi, however, their safety profiles significantly vary, especially when it comes to hepatotoxicity, QT prolongation, and gastrointestinal (GI) effects. We will break down and compare oral azole adverse effects across the available oral azoles: fluconazole, itraconazole, ketoconazole, voriconazole, and posaconazole.

Hepatotoxicity – Azole Comparison

The first notable azole adverse effect is hepatotoxicity. In terms of this effect, fluconazole stands out with a relatively lower risk of hepatotoxicity, likely due to its primary renal excretion rather than hepatic metabolism. However, clinical trials have found that transaminase elevations (> 8x ULN) occurred in about 1% of patients, often those with severe underlying diseases like AIDS or malignancies. Notably, these elevations were usually reversible and not dose-dependent.

Itraconazole, on the other hand, is extensively metabolized by the liver and carries a modest risk of hepatotoxicity. Around 3% of patients may experience abnormal liver functions. Routine monitoring is crucial, especially in those with pre-existing liver impairment.

Ketoconazole is arguably the most hepatotoxic of the azoles, as it has a black box warning for serious liver injury (remember this one for board exams! including fatalities and liver transplants. Cases occurred even in patients with no predisposing liver conditions and across all dosing regimens. Hepatitis, jaundice, and cholestasis are known risks, making it a less favorable choice when safer alternatives are available.

Voriconazole poses a moderate to high risk. In clinical trials, liver function abnormalities were reported in up to 12% of adults, and serious events like fulminant hepatic failure have occurred, particularly in patients with hematologic malignancies. Like fluconazole, hepatic injury is reversed upon discontinuation.

Posaconazole is relatively safer compared to the other azoles and is also reversible. Severe hepatotoxicity is mostly associated with higher doses (800 mg/day), or patients with underlying conditions. However, LFTs should still be monitored during therapy.

QT Prolongation

QT (or QTc) prolongation is a very important azole adverse effect. When it comes to effects on the heart and QT prolongation, ketoconazole takes the lead in the risk. It carries a black box warning for QT prolongation and is contraindicated with multiple QT-prolonging drugs. Life threatening arrhythmias, including torsades de pointes, have been reported.

Itraconazole and voriconazole also have QT prolongation potential and should be used cautiously in patients with predisposing cardiac conditions or those on interacting medications. Although itraconazole has the potential to prolong QT, the risk is less well-characterized compared to ketoconazole and voriconazole. However, itraconazole does possess a black box warning for heart failure, indirectly implying caution with cardiac adverse effects.

Posaconazole and fluconazole both possess lower risk for QT prolongation. Specifically for posaconazole, there were no cases of QTc >/= 500 msec or > 60 msec increases from baseline in health volunteers. Additionally, the incidence of QT prolongation in phase II and III clinical trials was about 1% of patients (1 out of 428) treated for neutropenic fever or refractory invasive fungal infections. Caution is still advised while taking these medications, especially if taking concurrent QT-prolonging medications or in patients with electrolyte abnormalities. 

Gastrointestinal (GI) Effects

The last of the azole adverse effects that we are going to cover is a more common one. GI side effects happen more frequently than the previously mentioned side effects but are generally manageable across all azoles. Ketoconazole shows the highest incidence with up to 50% of patients experiencing nausea and vomiting at higher doses. Despite this, GI symptoms are typically not dose-limiting.

Fluconazole, voriconazole, and posaconazole tend to have milder GI profiles. Nausea, vomiting, and abdominal discomfort occur occasionally but are usually transient. Itraconazole may also cause GI discomfort but is less frequently discussed in comparison to its hepatic and cardiac warnings. 

Overall, fluconazole may be the best option in terms of hepatic safety, least risk for QT-prolonging, and least GI discomfort. This is a significant reason why we see this medication used more frequently. Ketoconazole takes the cake for being most hepatotoxic, most risky for QT prolongation, and most GI discomfort. Itraconazole, posaconazole, and voriconazole fall in between, however, there are no perfect azoles and the “best” option depends on the patient’s comorbidities, concurrent medications, and infection type. Understanding these comparative risks help us make more informed choices and optimize patient’s medication experience.

There you have it, our comparison of azole adverse effects. We hope you found this beneficial. You’ll also love these free resources from meded101.com that are exclusive to subscribers (see below).

This article was written by Gaochoua Vang, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP.

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References

1. Björnsson, E. S., & Hoofnagle, J. H. (2017). Ketoconazole-induced liver injury in the United States: A case series and review of the literature. International Journal of Molecular Sciences, 18(8), 1722. https://doi.org/10.3390/ijms18081722
   (Note: This is the article found at the PMC link you shared.)
2. Dodds Ashley, E. S., & Perfect, J. R. (2023). Pharmacology of azoles. In C. A. Kauffman (Ed.), UpToDate. Wolters Kluwer. Retrieved April 23, 2025, from https://www.uptodate.com/contents/pharmacology-of-azoles
3. IBM Micromedex. (n.d.). Fluconazole. IBM Corporation. Retrieved April 23, 2025, from https://www-micromedexsolutions-com.ezp1.lib.umn.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=topHome&isToolPage=true#
4. IBM Micromedex. (n.d.). Itraconazole. IBM Corporation. Retrieved April 23, 2025, from https://www-micromedexsolutions-com.ezp1.lib.umn.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=topHome&isToolPage=true#
5. IBM Micromedex. (n.d.). Ketoconazole. IBM Corporation. Retrieved April 23, 2025, from https://www-micromedexsolutions-com.ezp1.lib.umn.edu/micromedex2/librarian/CS/600576/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/BE8F58/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=ketoconazole&UserSearchTerm=ketoconazole&SearchFilter=filterNone&navitem=searchALL#
6. IBM Micromedex. (n.d.). Voriconazole. IBM Corporation. Retrieved April 23, 2025, from https://www-micromedexsolutions-com.ezp1.lib.umn.edu/micromedex2/librarian/CS/21A388/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/52AA3B/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=voriconazole&UserSearchTerm=voriconazole&SearchFilter=filterNone&navitem=searchALL#
7. IBM Micromedex. (n.d.). Posaconazole. IBM Corporation. Retrieved April 23, 2025, from https://www-micromedexsolutions-com.ezp1.lib.umn.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=topHome&isToolPage=true#close
8. U.S. Food and Drug Administration. (2011). Diflucan (fluconazole) [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019949s051lbl.pdf
9. U.S. Food and Drug Administration. (2009). Sporanox (itraconazole) [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020083s040s041s044lbl.pdf
10. U.S. Food and Drug Administration. (2014). Nizoral (ketoconazole) [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018533s041lbl.pdf
11. U.S. Food and Drug Administration. (2010). Vfend (voriconazole) [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021266s032lbl.pdf
12. U.S. Food and Drug Administration. (2010). Noxafil (posaconazole) [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022003s008,022027s001lbl.pdf