Ketoconazole is an imidazole fungicidal agent with a very broad spectrum of activity against many fungal species that is used for treatment of superficial and systemic fungal infections. Ketoconazole is a well documented cause of clinically apparent acute drug induced liver injury and is no longer recommended as a first line antifungal agent.


Ketoconazole (kee" toe kon' a zole) is an imidazole derivative and fungicidal agent which is believed to work by several mechanisms, including inhibition of the fungal 14α-ergosterol demethylase which is responsible for converting lanosterol to ergosterol and which blocks fungal cell membrane synthesis. Ketoconazole may also inhibit fungal triglyceride and phospholipid synthesis and fungal oxidative and peroxidative enzyme activity, causing accumulation of hydrogen peroxide, contributing to deterioration of organelles. Ketoconazole has been used in the treatment of many fungal infections including blastomycosis, candidiasis, coccidiomycosis, tinea pityriasis versicolor and histoplasmosis. Ketaconazole has also been used as adjuvant therapy of prostate cancer, because of its effects in lowering androgen production by both the testes and adrenal glands. Ketoconazole was approved for use in the United States in 1981, but has been replaced by other antifungal agents which have fewer side effects and wider range of activity. Because of its potential for severe adverse reactions including hepatotoxicity, ketoconazole has been withdrawn in many countries and has strict labeling in the United States recommending that it be used only when other effective antifungal agents are not available or tolerated. Current indications include systemic fungal infections due to candida, blastomycosis, coccidiomycosis, histoplasmosis, chromomycosis and paracoccidioidomycosis. Ketoconazole is available as 200 mg tablets in several generic forms and previously under the brand name of Nizoral. The recommended dose for fungal infections is 200 to 400 mg once daily by mouth in adults and 3.3 to 6.6 mg/kg in children older than 2 years of age. The dose used for prostate cancer is 400 mg three times daily. Ketoconazole is also available as a cream, solution and shampoo for cutaneous fungal infections. Common side effects include pruritus, nausea, rash, abdominal pain, headache, dizziness, fatigue, impotence, menstrual abnormalities and gynecomastia. Severe adverse events include anaphylaxis, hepatotoxicity, endocrine dysregulation and prolongation of the QTc interval.


Mild and transient elevations in liver enzymes occur in 4% to 20% of patients on oral ketaconazole. These abnormalities are usually transient and asymptomatic and uncommonly require dose adjustment or discontinuation. Clinically apparent hepatotoxicity from ketaconazole is well described in the literature and is estimated to occur in 1:2,000 to 1:15,000 users. The liver injury typically presents with an acute hepatitis-like picture 1 to 6 months after starting therapy. While most cases present with a hepatocellular pattern of injury, cholestatic forms have been described. Rash, fever and eosinophilia are rare as is autoantibody formation. Recovery upon stopping therapy may be delayed and generally takes 1 to 3 months. Severe cases with acute liver failure and death or need for emergency liver transplantation have been described.

Likelihood score: A (well established cause cause of clinically apparent liver injury).

Mechanism of Injury

The cause of clinically apparent hepatotoxicity from ketoconazole is unknown; however, it may correlate with the ability of ketoconazole to inhibit mammalian sterol synthesis. Acute liver injury is clearly idiosyncratic. Ketoconazole is a potent inhibitor of human CYP 3A4 and can alter the serum levels of many drugs that are metabolized via the P450 system, increasing the toxicity of these agents. Indeed, it is often used to assess the effects of CYP 3A4 inhibition on the metabolism of other drugs.

Outcome and Management

The severity of the liver injury from ketoconazole ranges from mild and transient enzyme elevations (Case 1) to symptomatic acute liver injury with jaundice (Case 2), to severe hepatitis and acute liver failure (Case 4), resulting in death or need for emergency liver transplantation. Recovery from ketoconazole hepatitis is typically slow, starting 1 to 4 weeks after stopping the medication and requiring 1 to 3 months for full recovery. At least one case of chronic hepatitis and cirrhosis has been linked to ketoconazole therapy (Case 3). Rechallenge leads to recurrence and should be avoided. There is little information on cross reactivity of hepatic injury between ketoconazole and other antifungal azoles, such as itraconazole, fluconazole, voriconazole and posaconazole, but a few reports suggest that there is little cross reactivity. Nevertheless, other azoles should be started with caution in patients who have suffered clinically apparent hepatotoxicity attributed to ketoconazole.

Drug Class: Antifungal Agents


Case 1. Acute self-limited serum enzyme elevations during ketoconazole therapy.

[Modified from: Leal-Cerro A, García-Luna PP, Jiménez Mejías E, Astorga R. [Hepatotoxicity of ketoconazole in patients with adrenal pathology]. Med Clin (Barc) 1987; 88: 519. PubMed Citation]

A woman was started on ketoconazole as experimental therapy of Cushings syndrome and had regular blood test monitoring for liver injury at weekly intervals (Table). Serum ALT levels became abnormal after 14 days and peaked at 21 days, with minimal increase in serum alkaline phosphatase and no increase in serum bilirubin or appearance of symptoms. ALT levels fell to normal by week 5 despite continuation of ketoconazole at the same dose.

Key Points

Laboratory Values


A typical example of mild-to-moderate serum aminotransferase elevations during the first few weeks of ketaconazole therapy with spontaneous resolution despite continuing therapy without dose modification. The phenomenon is referred to as "adaptation" and its mechanism is unknown.

Case 2. Ketoconazole induced acute, self-limited hepatitis.

[Modified from: Svejgaard E, Ranek L. Hepatic dysfunction and ketoconazole therapy. Ann Intern Med 1982; 96 (6 Pt 1): 788-9. PubMed Citation]

A 48 year old man developed nausea and fatigue 81 days after starting ketoconazole (200 mg daily) for fingernail onychomycosis. Serum ALT levels were normal before therapy and had been only minimally elevated at 8 weeks. On presentation, he was jaundiced but without fever or rash. Serum bilirubin was 6.3 mg/dL and serum aminotransferase levels were markedly elevated. Tests for hepatitis A and B were negative and ultrasound and CT scans of the abdomen showed no evidence of biliary obstruction or chronic liver disease. The patient remained jaundiced for a month, but serum enzymes then began to fall and were normal 2 months later (Table).

Key Points

Laboratory Values


A typical case of hepatocellular injury due to ketoconazole arising after 3 months of therapy, despite monitoring for liver injury with monthly blood tests as a part of a clinical trial of this azole for superficial onychomycosis. Recovery was spontaneous but was slightly delayed as is typical of ketoconazole hepatotoxicity.

Case 3. Ketoconazole induced liver cirrhosis.

[Modified from: Kim TH, Kim BH, Kim YW, Yang DM, Han YS, Dong SH, Kim HJ, et al. Liver cirrhosis developed after ketoconazole-induced acute hepatic injury. J Gastroenterol Hepatol 2003; 18: 1426-9. PubMed Citation]

A 41 year old woman developed nausea, vomiting, anorexia, and jaundice after taking ketoconazole (200 mg daily) for 4.5 months for onychomycosis. Before starting therapy, serum aminotransferase and bilirubin levels were normal. On presentation, she had jaundice but no fever or rash. Serum bilirubin was 12.8 mg/dL and ALT 1461 U/L. Tests for viral hepatitis A, B, C and E were negative as were autoantibodies including ANA and AMA. Over the next four months bilirubin levels remained high and serum albumin fell. Ascites was found after 4 months and upper endoscopy showed varices. Liver biopsy showed cirrhosis; bile duct damage was not mentioned. During long term follow up, liver tests improved, but remained abnormal even five years after the acute injury and discontinuation of ketoconazole.

Key Points

Laboratory Values

*Some values estimated from Figure 2.


An unusual case of drug induced liver injury. The initial presentation with acute, severe hepatocellular jaundice arising 5 months after starting ketoconazole in a middle aged woman was typical of this form of drug induced liver injury. However, the evidence of liver injury persisted and four months later clinical evidence of cirrhosis was present. Laboratory values remained abnormal even five years after the initial presentation and discontinuation of ketoconazole. The liver biopsy showed cirrhosis, but the report does not mention evidence of biliary damage as might be seen in vanishing bile duct syndrome or primary biliary cirrhosis or sclerosing cholangitis. Most drugs that have been implicated in causing cirrhosis are given for prolonged periods (minocycline, methyldopa, amiodarone, valproate) and induction of chronic hepatitis by an limited course of therapy is usually accompanied by features of autoimmunity such as antinuclear antibody. Alternatively, the clinical syndrome may represent “post-hepatitic” inactive cirrhosis due to the severity of the acute hepatitis and that is not associated with progressive liver injury.

Case 4. Acute liver failure due to ketoconazole.

[Modified from: Knight T, Shikuma C, Knight J. Ketoconazole-induced fulminant hepatitis necessitating liver transplantation. J Am Acad Dermatol 1991; 25: 398-400. PubMed Citation]

A 45 year old woman treated with ketoconazole for candidal onychomycosis developed anorexia, nausea, malaise, and dark-colored urine after 58 days of therapy. She discontinued the medication promptly. Physical examination revealed hepatic tenderness and mild jaundice but no fever or rash. Blood tests showed bilirubin of 4.2 mg/dL, alkaline phosphatase 102 U/L, and AST 1328 U/L. During the second week of illness, she developed worsening symptoms and jaundice that progressed to liver failure and hepatic coma that prompted emergency liver transplantation.

Key Points


A example of ketaconazole hepatotoxicity, presenting after two months of therapy with an acute hepatitis-like syndrome, but then progressing to acute liver failure. Improvement upon stopping therapy can be delayed with progressive worsening over the 1 to 4 weeks after discontinuation of treatment. Minor allergic signs and symptoms (rash and eosinophilia) may be present early in the course, but are rarely severe. Corticosteroid therapy has been applied to patients with ketaconazole hepatotoxicity, but its efficacy in ameliorating the course of illness has not been shown.



Ketoconazole – Generic, Nizoral®


Antifungal Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 17 May 2017

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    (59 year old woman developed jaundice 6 months after starting ketoconazole [bilirubin 8.0 mg/dL, ALT 1475 U/L, Alk P 234 U/L], resolving within 7 weeks of stopping, but subsequent inadvertent rechallenge for 7 days led to jaundice 1 week later [bilirubin 2.6 mg/dL, ALT 503 U/L]).
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    (62 year old woman developed abdominal pain and fever 3 days after starting ketoconazole [bilirubin normal, ALT 1.5 times ULN, Alk P 2.5 times ULN], resolving clinically within 2 and biochemically within 7 days of stopping).
  • Benson GD, Anderson PK, Combes B, Ishak KG. Prolonged jaundice following ketoconazole-induced hepatic injury. Dig Dis Sci 1988; 33: 240-6. [PubMed: 3338372]
    (55 and 39 year old men developed prolonged jaundice 27 and 23 days after starting ketoconazole [bilirubin 3.6 rising to 27.0 and 3.6 rising to 19 mg/dL, peak ALT 640 and 304 U/L, Alk P 436 and 223 U/L], with worsening for 1-2 months and jaundice with pruritus persisting for 3-4 months after stopping).
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    (Randomized trial of fluconazole vs ketoconazole in 37 patients with HIV infection and oropharyngeal candidiasis; ALT or AST elevations occurred in 1 of 18 [6%] on fluconazole vs 4 of 19 [21%] on ketoconazole; fluconazole also more effective).
  • Cabeza Lamban F, Simal Gil E, Mur Villacampa M, Guerrero Navarro L. [Hepatotoxicity caused by ketoconazole]. Rev Esp Enferm Apar Dig 1989; 76: 92. [PubMed: 2799042]
    (5 year old boy with cutaneous candidiasis developed abnormal liver tests 6 months after starting ketoconazole [bilirubin 3.2 mg/dL, ALT 475 U/L, Alk P 559 U/L] resolving rapidly upon stopping).
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    (Review of efficacy and safety of griseofulvin and ketoconazole for superficial mycoses; rate of hepatotoxicity from ketoconazole ranges from 1:10,000 to 1:15,000, and is more common among women and in persons over 40 years of age; authors recommend routine monitoring of liver enzymes; in contrast, griseofulvin is “remarkably safe” and no deaths have been attributed directly to the drug).
  • Vilela MP, Ferraz ML, Franco DR. [Toxic hepatitis caused by ketoconazole: a report of 4 cases]. Rev Paul Med 1989; 107: 57-8. Portuguese. [PubMed: 2616978]
    (Four women developed symptomatic hepatotoxicity 2-4 months after starting ketoconazole, [bilirubin 1.0, 2.1, 8.9 and 9.1 mg/dL, ALT 180-1500 U/L, Alk P 218-360 U/L], resolving within 2-3 months of stopping).
  • Gradon JD, Sepkowitz DV. Massive hepatic enlargement with fatty change associated with ketoconazole. DICP 1990; 24: 1175-6. [PubMed: 2089825]
    (37 year old woman with AIDS developed hepatomegaly 11 months after starting ketoconzaole [bilirubin not mentioned, ALT 116 U/L, Alk P 180 U/L], liver biopsy showing fatty liver; also on zidovudine, a more likely candidate to cause this pattern of liver injury).
  • Ritchie D. Comment: consideration of amphotericin B hepatotoxicity. DCIP 1991; 25: 559-60. [PubMed: 2068844]
    (Agrees that the case described by Gradon et al. was likely due to ketoconazole, but stresses that amphotericin B can also cause liver injury).
  • Brusko C, Marten J. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis. DCIP 1991; 25: 1321-5. [PubMed: 1815425]
    (39 year old woman developed abnormal liver tests [ALT 367] one month after starting ketoconazole for chronic fatigue syndrome and candida with worsening over the next 6 months [bilirubin rising to 43 mg/dL, ALT 838 U/L, Alk P 186 U/L]; despite prompt discontinuation of ketoconazole, ultimately evolving into hepatic failure).
  • Knight T, Shikuma C, Knight J. Ketoconazole-induced fulminant hepatitis necessitating liver transplantation. J Am Acad Dermatol 1991; 25: 398-400. [PubMed: 1832694]
    (A 39 year old woman developed elevated ALT levels 2 months after starting ketoconazole and, despite stopping, had progressive liver injury resulting in hepatic failure and death, [bilirubin 0.4 rising to 43 mg/dL, ALT 367 rising to 1170 U/L]: Case 4).
  • Simon DL. Comment: ketoconazole hepatotoxicity. Ann Pharmacother 1992; 26: 564-5. [PubMed: 1576399]
    (Comment on case reported by Knight et al. [1991] suggesting that chronic acetaminophen ingestion may have caused the persistent injury).
  • Klausner MA. Ketoconazole and hepatitis. J Am Acad Dermatol 1992; 26: 1028-30. [PubMed: 1535078]
    (Response by Janssen to review articles on ketaconazole, stressing the importance of hepatotoxicity and need to monitor liver tests during therapy).
  • Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol 1993; 29: S50-4. [PubMed: 8315062]
    (Review article on hepatotoxicity of antifungal agents, griseofulvin, ketoconazole, fluconazole, itraconazole and terbinafine; does not recommend routine monitoring, but stresses need to discontinue agent for hepatic injury with symptoms).
  • Gearhart M. Worsening of liver function with fluconazole and review of azole antifungal hepatotoxicity. Ann Pharmacother 1994; 28: 1177-81. [PubMed: 7841574]
    (50 year old woman with probable chronic hepatitis C and cirrhosis had acute worsening of liver disease within a few days of starting fluconazole [bilirubin 1.6 rising to 6.6 mg/dL, AST rising from 66 to 1556 U/L, protime 19.2 rising to 29.8 sec], improving when fluconazole was stopped; discussion of azole antifungal agents and hepatotoxicity mentions that ketoconazole has been most frequently implicated in drug induced liver injury, perhaps because it is extensively metabolized by the liver).
  • Chien R, Yang L, Lin P, Liaw Y. Hepatic injury during ketoconazole therapy in patients with onchomycosis: a controlled cohort study. Hepatology 1997; 25: 103-7. [PubMed: 8985273]
    (Controlled trial of ketaconazole vs griseofulvin in 211 patients with onchomycosis; ALT elevations occurred in 17.5% of ketaconazole vs none of griseofulvin recipients; 4 ketoconazole recipients developed symptoms after 28, 28, 35 and 63 days with ALT 254-963 U/L [median=490 U/L], minimal Alk P elevations [median=127 U/L] and jaundice in 3 patients; all recovered within 7 weeks ).
  • Bernuau J, Durand F, Pessayre D. Ketoconazole-induced hepatotoxicity. Hepatology 1997; 26: 802. [PubMed: 9303518]
    (Letter disagreeing with the conclusions of Chien [1997] about role of monitoring ALT and speed of reversibility of hepatotoxicity).
  • Findor JA, Sorda JA, Igartua EB, Avagnina A. Ketoconazole-induced liver damage. Medicina 1998; 58: 277-81. [PubMed: 9713096]
    (Five cases, 2 fatal, of ketoconazole related liver damage; in the 2 fatal cases there was a delay in stopping ketaconazole).
  • Van Puijenbroek EP, Metselaar HJ, Berghuis PH, Zondervan PE, Stricker BH. [Acute hepatocytic necrosis during ketoconazole therapy for treatment of onchomycosis. National Foundation for Registry and Evaluation of Adverse Effects]. Ned Tijdschr Geneeskd 1998; 142: 2416-8. Dutch. [PubMed: 9864540]
    (Between 1986 and 1998, 18 cases of severe liver injury due to ketoconazole were reported to a Dutch National Registry including 3 men and 15 women, ages 21 to 65 years, latency 1 to 16 weeks, one third with fever, rash or eosinophilia, 69% with hepatocellular injury, 31% cholestatic-mixed; 15 with jaundice, 1 liver transplant and 1 death).
  • Bok RA, Small EJ. The treatment of advanced prostate cancer with ketoconazole: safety issues. Drug Saf 1999; 20: 451-8. [PubMed: 10348095]
    (Ketaconazole inhibits synthesis of androgenic steroids by both testes and adrenals and has been used in higher doses [400 mg three times daily] to treat prostate cancer; side effects include liver test abnormalities in 4-20% and fulminant hepatitis in 0.01-0.1%; in studies in prostate cancer, hepatotoxicity occurred in 4.2%, mostly ALT and Alk P elevations that resolve with discontinuation).
  • García Rodriguez L, Duque A, Castellsague J, Pérez-Gutthann S, Stricker B. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48: 847-52. [PMC free article: PMC2014312] [PubMed: 10594489]
    (Population based study identified 5 cases of acute liver injury during antifungal therapy in 69,830 patients; relative risk for ketoconazole was 228 [~2:1,000 patients], itraconazole 17.7 [~1:10,000] and terbinafine 4.2 [~.2:10,000]).
  • Chien RN, Sheen IS, Liaw YF. Unintentional rechallenge resulting in a causative relationship between ketoconazole and acute liver injury. Int J Clin Pract 2003; 57: 829-30. [PubMed: 14686574]
    (50 year old developed fatigue 2 months after starting ketoconazole [bilirubin 6.0 rising to 19.9 mg/dL, ALT 1326 U/L, Alk P 165 U/L, prothrombin time 13.3 seconds], resolving spontaneously starting 4 days after stopping; recurrence after 2 days of reexposure [bilirubin 4.9 mg/dL, ALT 1375 U/L, eosinophils 2%]).
  • Kim TH, Kim BH, Kim YW, Yang DM, Han YS, Dong SH, Kim HJ, et al. Liver cirrhosis developed after ketoconazole-induced acute hepatic injury. J Gastroenterol Hepatol 2003; 18: 1426-9. [PubMed: 14675275]
    (41 year old woman developed nausea and jaundice 5 months after starting ketoconazole [bilirubin 12.8 mg/dL, ALT 1318 U/L, Alk P 268 U/L], with persistent jaundice and appearance of ascites and varices 4 months later, cirrhosis on biopsy and mildly abnormal liver tests for several years: Case 3).
  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]
    (Among ~50,000 liver transplants done in the United States between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 6 were attributed to ketoconazole and 1 to itraconazole).
  • Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal medications in bone marrow transplant recipients. Clin Infect Dis 2005; 41: 301-7. [PubMed: 16007524]
    (Among 587 patients undergoing bone marrow transplantation, 123 had evidence of liver injury after transplant; case control analysis found increased rate of liver injury associated with fluconazole and amphotericin; ketoconazole, itraconazole and voriconazole were infrequently used and could not be evaluated).
  • Wingard J, Leather H. Hepatotoxicity associated with antifungal therapy after bone marrow transplantation. Clin Infect Dis 2005; 41: 308-10. [PubMed: 16007525]
    (Editorial in response to the article by Fisher et al. [2005]; discusses the difficulties of detection, diagnosis, attribution and management of liver test abnormalities after bone marrow transplantation).
  • Videla C, Vega J, Borja H. Hepatotoxicity associated with cyclosporine monitoring using C2 recommendations in adults renal recipients receiving ketoconazole. Transplant Proc 2005; 37: 1574-6. [PubMed: 15866677]
    (The interaction of cyclosporine and ketoconazole may result in toxic cyclosporine levels and liver injury; 6 cases of hepatotoxicity, 3 with jaundice between 4-21 days after renal transplant; improved with lowering cyclosporine dose and patients tolerated re-introduction of ketoconazole).
  • Song J, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig Drugs 2005; 6: 170-7. [PubMed: 15751740]
    (Extensive review of hepatotoxicity from antifungals; liver toxicity is a well documented complication of ketoconazole, asymptomatic ALT elevations in 2-10% of patients and symptomatic hepatitis in 1:10,000 to 1:15,000, usually hepatocellular; among antifungal agents, ketoconazole has been the agent most frequently linked to acute liver injury).
  • Cruciani M, Mengoli C, Malena M, Bosco O, Serpelloni G, Grossi P. Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis. Liver Transpl 2006; 12: 850-8. [PubMed: 16628697]
    (Metaanalysis found 6 studies with total of 698 patients comparing fluconazole, itraconazole or amphotericin vs placebo for prevention of fungal infections after liver transplantation; side effects were more with prophylaxis but liver toxicity was not discussed).
  • Girois SB, Chapuis F, Decullier E, Revol BG. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2006; 25: 138-49. [PubMed: 16622909]
    (Systematic review of adverse effects of antifungal therapy in 54 studies with 9228 patients; hepatotoxicity reported in 14.1-18.6% on amphotericin, 1.9% on fluconazole and 31.6% on itraconazole; but great variation in definitions and intensity of monitoring; ketoconazole not discussed).
  • Stein CA, Goel S, Ghavamian R. Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy. Invest New Drugs 2007; 25: 277-8. [PubMed: 17216557]
    (84 year old man on long term lovastatin therapy developed fatigue and dark urine 4 weeks after starting ketoconazole for refractory prostate cancer [bilirubin and Alk P normal, ALT 829 U/L, CPK 47,250 U/L and myoglobin in the urine], resolving 3 weeks after stopping; suggested that ketoconazole caused increase in lovastatin to toxic levels becauseof inhibition of CYP 3A4 activity).
  • Lin C, Hu J, Yang S, Shin C, Huang S. Unexpected emergence of acute hepatic injury in patients treated repeatedly with ketoconazole. J Clin Gastroenterol 2008; 42: 432-3. [PubMed: 18277890]
    (3 cases of severe hepatitis in patients who took multiple courses of ketoconazole, usually within 1-3 days of restarting with mild eosinophilia but no rash or fever; few specific details given).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, two cases were attributed to fluconazole, and one to ketoconazole, one to itraconazole, none to voriconazole).
  • Antifungal drugs. Treat Guidel Med Lett 2009; 7: 95-102. (Concise summary of therapy of fungal infections with recommendations on agents, dosage and duration of treatment and safety; ketoconazole is seldom used; other azoles have fewer side effects and are preferred; ketoconazole can cause hepatic toxicity and some cases are fatal)
  • Wang JL, Chang CH, Young-Xu Y, Chan KA. Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob Agents Chemother 2010; 54: 2409-19. [PMC free article: PMC2876415] [PubMed: 20308378]
    (Systematic review of 39 controlled trials in more than 8000 patients, found liver enzyme elevations in 14.5% of patients on amphotericin (pooled estimate); 19.7% on voriconazole; 18.9% itraconazole; 10% fluconazole; 2.8% anidulafungin; 7.2% caspofungin; and 5.7% micafungin; ketoconazole not discussed).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury and 6 to antifungal agents, including 2 to ketoconazole).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (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]; no other antifungal agent listed in the top 41 causes).
  • Antifungal drugs. Treat Guidel Med Lett 2012;10: 61-8. [PubMed: 22825657]
    (Concise summary of therapy of fungal infections with recommendations on agents, dosage and duration of treatment and safety; side effects of ketoconazole include blurred vision, photophobia, fever, nausea, rash, photosensitivity, Stevens-Johnson syndrome, periostitis, confusion, anaphylactoid infusion reactions, and increased "transaminase levels").
  • Yan JY, Nie XL, Tao QM, Zhan SY, Zhang YD. Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomed Environ Sci 2013; 26: 605-10. [PubMed: 23895707]
    (Analysis of 2404 publications on liver test abnormalities in patients receiving ketoconazole found an overall rate of 3.6-4.3% with no clear cut relation to total daily dose or indication, but lower rates in children [1.4%]).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to ketaconazole or other antifungal agents).
  • Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, Caron P, et al. Ketoconazole in Cushing's disease: is it worth a try? J Clin Endocrinol Metab 2014; 99: 1623-30. [PubMed: 24471573]
    (Retrospective analysis of 200 patients with Cushing disease treated with ketoconazole found liver enzyme elevations above 5 times ULN in 16%, but elevations resolved in all patients with dose reduction [50%] or stopping therapy [50%], and there were no deaths from acute liver failure).
  • 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, 28 of which [54%] were attributed to ketoconazole [4.9 per 10,000 persons], the rate increasing with increasing duration of therapy).
  • Greenblatt HK, Greenblatt DJ. Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol 2014; 54: 1321-9. [PubMed: 25216238]
    (Review of the literature on hepatotoxicity of ketoconazole and alternatives to its use as an antifungal agent and as a tool in pharmacokinetic studies based upon its inhibition of CYP 3A4).
  • 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], and ketoconazole [6]).
  • 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).
  • Gupta AK, Daigle D, Foley KA. Drug safety assessment of oral formulations of ketoconazole. Expert Opin Drug Saf 2015; 14: 325-34. [PubMed: 25409549]
    (Review of literature and regulatory actions regarding ketoconazole hepatotoxicity; mentions that oral ketoconazole was withdrawal from the market in Europe and Australia in 2013 and was subjected to more strigent safety warnings and more limited written indications in the US and Canada).
  • 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 14,296 persons treated with oral ketoconazole analyzed from a Kaiser Permanente clinical database, the incidence of ALT or AST elevations above 200 U/L was 1.9% and severe acute liver injury 0.3%; one patient developed acute liver failure and required liver transplantation).
  • 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).