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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-.

Itraconazole

Last Update: May 17, 2017.

OVERVIEW

Introduction

Itraconazole is a orally administered, triazole antifungal agent used in the treatment of systemic and superficial fungal infections. Itraconazole therapy is associated with transient, mild-to-moderate serum elevations and can lead to clinically apparent acute drug induced liver injury.

Background

Itraconazole (it" ra kon' a zole) is a synthetic triazole fungicidal agent which acts by inhibition of fungal C14-a- ergosterol demethylase, which leads to a decrease in ergosterol synthesis, a necessary component of fungal cell membranes. Itraconazole is used in the therapy of a broad spectrum of fungal infections including blastomycosis, aspergillosis, histoplasmosis, candidiasis and various superficial mycoses. Itraconazole was approved for use in the United States in 1992 and continues to be widely used as an antifungal agent. Current indications include blastomycosis, histoplasmosis, aspergillosis and onychomycosis. Itraconazole is available in capsules of 100 mg, tablets of 200 mg and oral suspensions of 10 mg/mL in generic forms and under the brand name Sporanox. The typical dose is 100 to 400 mg daily based upon the type and severity of the fungal infection. Common side effects include nausea, vomiting, diarrhea, rash and hypokalemia.

Hepatotoxicity

Transient, mild-to-moderate elevations in serum aminotransferase levels occur in 1% to 5% of patients on itraconazole. These elevations are largely asymptomatic and self-limited, resolving even with continuation of therapy. Clinically apparent hepatotoxicity is rare but has been well described and can be severe and even fatal. The liver injury from itraconazole typically presents 1 to 6 months after starting therapy with symptoms of fatigue and jaundice. The pattern of serum enzyme elevations is typically cholestatic (Case 1), but cases of severe hepatitis with acute liver failure typically have a hepatocellular enzyme pattern (Case 2). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. Recovery upon stopping therapy can be delayed for several weeks and generally takes 4 to 10 weeks, although in some cases recovery may be prolonged.

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

Mechanism of Injury

The cause of clinically apparent hepatotoxicity from itraconazole is unknown; however, it may have some correlation to the ability of itraconazole to alter sterol synthesis and inhibit P450 enzyme activity. Because it is a potent inhibitor of CYP 3A4, it has the potential of causing significant drug-drug interactions leading to increased or decreased plasma levels of other drugs, which can increase toxicity and alter efficacy.

Outcome and Management

The severity of the liver injury ranges from mild and transient enzyme elevations to severe acute hepatitis requiring transplantation or death. At least one instance of chronic cholestasis compatible with vanishing bile duct syndrome due to itraconazole has been reported. More typically, improvements begin 1 to 3 weeks after stopping itraconazole and complete recovery is achieved in 6 to 12 weeks. Rechallenge may lead to recurrence and should be avoided. There is little information on cross reactivity of hepatic injury between itraconazole and other antifungal azoles, such as ketoconazole, voriconazole, 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 itraconazole.

Drug Class: Antifungal Agents

CASE REPORTS

Case 1. Cholestatic hepatitis due to itraconazole.

[Modified from: Talwalkar JA, Soetikno RE, Carr-Locke DL, Berg CL. Severe cholestasis related to itraconazole for the treatment of onychomycosis. Am J Gastroenterol 1999; 94: 3632-3. [PubMed Citation]

A 74 year old woman developed atrial fibrillation during the first week of a course of itraconazole for onychomycosis and was found to have mild elevations in serum ALT (111 U/L) and alkaline phosphatase (283 U/L), but normal serum bilirubin (0.5 mg/dL). The atrial fibrillation was treated with verapamil and she returned to normal sinus rhythm; itraconazole was continued. Three weeks later, she developed jaundice and pruritus and itraconazole was stopped. She was jaundiced, but had no fever or rash. At this point, serum bilirubin had risen to approximately 8.5 mg/dL, ALT 350 U/L and Alk P 750 U/L yielding an R ratio of 1.7 (cholestatic). Tests for hepatitis A, B and C were negative as were autoantibodies. Imaging of the liver showed no evidence of biliary obstruction. Serum bilirubin continued to rise for 3 weeks after stopping itraconazole, peaking at 32 mg/dL and then slowly fell into the normal range (Table). Pruritus persisted for two months. Laboratory results became normal 3 months after onset.

Key Points

Medication:Itraconazole (100 mg twice daily)
Pattern:Cholestatic (R=1.7)
Severity:3+ (jaundice and hospitalization)
Latency:1 week to ALT elevations, 4 weeks to symptoms and jaundice
Recovery:3 months
Other medications:Verapamil

Laboratory Values

Time After StartingTime After StoppingALT* (U/L)Alk* P (U/L)Bilirubin* (mg/dL)Other
1 week01112830.5Symptoms
4 weeks01403500.5
Itraconazole therapy discontinued
6 weeks2 weeks3507508.5
6.5 weeks2.5 weeks500105017.0
7 weeks3 weeks725151932.0
8 weeks4 weeks500142522.0
9 weeks5 weeks2508008.5
11 weeks7 weeks150504.0
14 weeks10 weeks30801.0
Normal Values <40 <130 <1.2

*Values estimated from Figure 1.

Comment

Very typical case of cholestatic hepatitis due to itraconazole with onset 4 weeks after starting the medication, and persistence of jaundice and pruritus for two months. Serum enzymes and bilirubin levels continued to rise for at least 3 weeks after stopping itraconazole, but then gradually fell into the normal range.

Case 2. Acute liver failure due to itraconazole.

[Modified from: Srebrnik A, Levtov S, Ben-Ami R, Brenner S. Liver failure and transplantation after itraconazole treatment for toenail onychomycosis. J Eur Acad Dermatol Venereol 2005; 19: 205-7. [PubMed Citation]

A 25 year old woman presented with fatigue, jaundice and progressive stupor 3 weeks after completing four 1-week pulse courses of itraconazole (400 mg/day for 1 week every month) for onychomycosis. Blood tests showed marked elevations in serum bilirubin and serum aminotransferase levels and prolongation of the prothrombin time (Table). She was hospitalized and managed in an intensive care unit. Tests for hepatitis A, B and C were negative as were autoantibodies and tests for Wilson disease. A liver biopsy showed massive necrosis and she was transferred to a liver transplant unit where she underwent successful liver transplantation. In follow up her liver tests were normal.

Key Points

Medication:Itraconazole (400 mg daily for one week once monthly for 4 months)
Pattern:Hepatocellular (R=66)
Severity:5+ (acute liver failure requiring emergency liver transplantation)
Latency:3 weeks after completing 4 weekly courses
Recovery:None
Other medications:Thyroxine

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
15 weeks3 weeks250012415.4INR=1.8
3.3 weeks208510721.8INR=2.4
16 weeks4 weeks648Normal26.7Hepatic encephalopathy
Liver transplantation
After transplantation592341.2INR=1.2
Normal Values <40 <130 <1.2

Comment

The patient had been refused treatment with itraconazole twice before because of serum enzyme abnormalities but the nature of the abnormalities were not investigated. The appearance of liver injury after stopping itraconazole may merely reflect the intermittent dosing used. While intermittent or pulse itraconazole therapy is said to be safer than continuous therapy, there is little comparative data to support this; pulse therapy appears to be as effective and is less expensive and perhaps has improved adherence.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Itraconazole – Generic, Sporanox®

DRUG CLASS

Antifungal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Itraconazole 84625-61-6 C35-H38-Cl2-N8-O4
Image of Itraconazole Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 17 May 2017

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    (Expert review of hepatotoxicity of antifungal agents published in 1999; mentions that itraconazole has been implicated in 5 cases of clinically apparent liver injury; 3 were cholestatic).
  • Moseley RH. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 463-81.
    (Review of hepatotoxicity of antifungal agents; reports that asymptomatic serum aminotransferase elevations occur in up to 7% of patients on itraconazole; reported cases of liver injury include at least 3 instances of vanishing bile duct syndrome).
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    (Textbook of pharmacology and therapeutics; itraconazole is a synthetic triazole that has largely replaced ketoconazole, but it is potent inhibitor of CYP 3A4 and has been linked to serious hepatotoxicity).
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    (51 year old woman developed jaundice after 116 days of itraconazole therapy [bilirubin 13.1 mg/dL, ALT 844 U/L, Alk P 214 U/L], with slow recovery on discontinuation).
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    (74 year old woman developed abnormal serum enzymes after 1 week and jaundice and pruritus after 4 weeks of itraconazole therapy, bilirubin rising to 32 mg/dL [peak ALT 725 U/L; Alk P 1519 U/L] and pruritus persisting for two months and resolving slowly: Case 1).
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    (Experience in treating 20 patients with itraconazole [12 also on amphotericin] for 44-495 days; ALT elevations occurred in 11 of 12 who received combination therapy, levels 2-10 times normal, all resolving, some with stopping amphotericin alone).
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    (38 year old woman found to have 2.1 cm hepatic mass diagnosed as focal nodular hyperplasia 2 months after stopping a 4 month course of intraconazole; not present on ultrasound done one year earlier).
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    (Among 438 patients undergoing bone marrow transplantation, 123 developed ALT or AST above 3 times ULN; factors associated with significant increases were liposomal amphotericin [Odds Ratio=3.8] and fluconazole [2.6], but not standard amphotericin [2.0]).
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    (Mentions that FDA has received reports of 24 cases of drug induced liver injury and 11 deaths due to itraconazole; Case of 25 year old who developed jaundice and stupor 3 weeks after stopping itraconazole [1 week every month for 4 months] with bilirubin 15.4 mg/L, ALT 2500 U/L and Alk P 124 U/L, and progressive hepatic failure, requiring liver transplantation: Case 2).
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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]; intraconazole was not listed in the top 41 causes).
  • Yoshikado T, Takada T, Yamamoto T, Yamaji H, Ito K, Santa T, Yokota H, et al. Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4. Mol Pharmacol 2011; 79: 241-50. [PubMed: 21056966]
    (2 women and 1 man, ages 36 to 67 years, developed liver test abnormalities 2 to 62 days after starting itraconazole [bilirubin 0.8, 1.4 and 4.3
    mg/dL, ALT 81, 874 and 269 U/L, Alk P 312, 539 and 178 U/L], resolving upon stopping and two with recurrence on restarting; two had high drug levels and in vitro results suggested inhibition of MDR3 function by itraconazole).
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    (Concise summary of therapy of fungal infections with recommendations on agents, dosage and duration of treatment and safety; the most common side effects of itraconazole include nausea, diarrhea, vomiting and rash. "Stevens-Johnson syndrome and serious hepatic toxicity can occur").
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    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to itraconazole 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, 3 of which [6%] were attributed to itraconazole [3.6 per 10,000 persons exposed], the rate increasing with increasing duration of therapy; none of 6 fatal cases were due to itraconazole).
  • 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 causes included fluconazole [31], terbinafine [27], voriconazole [19], amphotericin [14], ketoconazole [6], posaconazole [5], and itraconazole [4]).
  • 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 but none were attributed to itraconazole).
  • Pettit NN, Pisano J, Weber S, Ridgway J. Hepatic failure in a patient receiving itraconazole for pulmonary histoplasmosis - case report and literature review. Am J Ther 2016; 23: e1215-21. (65 year old woman developed acute liver failure with mental confusion 6 months after starting itraconazole for pulmonary histoplasmosis [bilirubin 1.9 rising to 3.5 mg/dL, ALT 683 to 3695 U/L, Alk P 69 U/L, CPK 7685 U/L, ammonia 118 μg. [PubMed: 26291595]
    /dL, INR 2.0], resolving rapidly upon stopping).
  • 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 1653 persons treated with oral itraconazole analyzed from a Kaiser Permanente clinical database, the incidence of ALT or AST elevations above 200 U/L was 2.5% and severe acute liver injury 0%; rates that were similar to those for ketoconazole and fluconazole, but 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).