Incidence of Itraconazole Induced Liver Injury
Itraconazole is associated with rare cases of serious hepatotoxicity, including liver failure and death, with some cases developing within the first week of treatment even in patients without pre-existing liver disease. 1
Frequency and Severity of Hepatotoxicity
- Serious hepatic adverse events with itraconazole are rare, though the exact incidence is not precisely quantified in large epidemiological studies 2
- Liver toxicity is one of the primary serious adverse events associated with itraconazole use, though it occurs infrequently 2
- Hepatotoxicity can range from mild, asymptomatic elevation of liver enzymes to severe liver injury resulting in acute hepatic failure 1, 3
- Cases of severe hepatotoxicity have been reported after both short-term (within first week) and long-term use (after months of therapy) 1, 4, 3
Risk Factors and Patterns of Liver Injury
- Patients with abnormal liver function tests before itraconazole treatment are at higher risk for developing hepatic damage during treatment (p = 0.001 in one study) 5
- The pattern of liver injury is typically cholestatic, with damage to interlobular bile ducts 6
- Some cases suggest itraconazole may cause prolonged drug-induced cholangiopathy and potentially lead to vanishing bile duct syndrome 6
- Hepatotoxicity appears to be idiosyncratic rather than dose-dependent in most cases 6
Clinical Presentation and Monitoring
- Symptomatic hepatic injury typically develops 5-6 weeks after starting itraconazole treatment 7
- Signs and symptoms of liver dysfunction may include:
- Unusual fatigue
- Anorexia
- Nausea and/or vomiting
- Jaundice
- Dark urine
- Pale stools 1
- Monitoring recommendations:
- Liver function testing should be considered in all patients receiving itraconazole 1
- Monitoring is especially important for patients with pre-existing liver disease and those on treatment for longer than one month 5, 7
- Treatment should be stopped immediately if signs or symptoms of liver dysfunction develop 1
Special Populations and Considerations
- Itraconazole is contraindicated in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk 1
- Drug interactions through inhibition of CYP3A4 isoenzymes can increase the risk of adverse effects, including hepatotoxicity 2
- Therapeutic drug monitoring (TDM) should be considered for itraconazole to achieve adequate plasma concentration while minimizing toxicity 2
- Most experts recommend dosing itraconazole to achieve trough concentrations >0.5–1 μg/mL (combined itraconazole/hydroxyitraconazole troughs >1.5 μg/mL) 2
Clinical Management of Hepatotoxicity
- If hepatotoxicity occurs, immediate discontinuation of itraconazole is recommended 1
- Reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk 1
- Supportive care and monitoring of liver function until normalization is the standard approach 4
- In severe cases, hospitalization and specific treatments for liver failure may be necessary 3
Comparison with Other Azoles
- Fluconazole and posaconazole are generally well tolerated with serious adverse events, primarily liver toxicity, being rare 2
- Voriconazole has a different toxicity profile with neurologic and ophthalmic adverse events being more common 2
- Isavuconazonium sulfate may be considered when other azoles are contraindicated due to drug interactions or QTc prolongation risk 2