Original Article
Copyright ©2014 Baishideng Publishing Group Inc.
World J Hepatol. Aug 27, 2014; 6(8): 601-612
Published online Aug 27, 2014. doi: 10.4254/wjh.v6.i8.601
Table 1 MedDRA preferred terms used to retrieve liver events in FAERS
PTLiver injuryAcute hepatic failure
Acute hepatic failureX
Alanine aminotransferase abnormalX
Alanine aminotransferase increasedX
Ammonia increasedX
Aspartate aminotransferase abnormalX
Aspartate aminotransferase increasedX
Bilirubin conjugated increasedX
Bilirubin urineX
Blood bilirubin abnormalX
Blood bilirubin increasedX
Blood bilirubin unconjugated increasedX
Coma hepaticX
Cytolytic hepatitisX
Hepatic encephalopathyX
Hepatic enzyme abnormalX
Hepatic enzyme increasedX
Hepatic failureX
Hepatic function abnormalX
Hepatic necrosisX
Hepatitis acuteX
Hepatitis cholestaticX
Hepatitis fulminantX
Hepatitis toxicX
Hepatocellular damageX
Jaundice cholestaticX
Jaundice hepatocellularX
Liver function test abnormalX
Liver injuryX
Liver transplantX
Mixed hepatocellular-cholestatic injuryX
Subacute hepatic failureX
Transaminases abnormalX
Transaminases increasedX
Urine bilirubin increasedX
Table 2 Top-10 drugs ranked in FAERS according to their reporting frequency for overall liver injury
ATC codeActive substanceCases LICases ALFCases OLIROR (95%CI) LIROR (95%CI) ALFROR (95%CI) OLI
N02BE01Paracetamol278064534253.69 (3.54-3.84)19.58 (8.82-10.41)14.31 (4.16-4.48)1
C10AA05Atorvastatin176313118943.46 (3.29-3.64)12.62 (2.20-3.12)13.43 (3.27-3.60)1
C10AA01Simvastatin15168015962.62 (2.49-2.77)11.44 (1.15-1.80)12.54 (2.41-2.67)1
N06AX21Duloxetine14565915153.34 (3.15-3.53)11.42 (1.10-1.83)13.32 (3.14-3.50)1
L03AB07Interferon beta-113774614230.73 (0.70-0.78)0.27 (0.20-0.36)0.69 (0.66-0.73)
J05AF05Lamivudine116213012924.68 (4.40-4.98)15.22 (4.38-6.22)14.86 (4.57-5.16)1
L01BA01Methotrexate12008612862.89 (2.72-3.07)12.15 (1.74-2.66)12.85 (2.69-3.02)1
J01CR02Amoxicillin/clavulanic acid11649412585.86 (5.49-11.36)14.50 (3.67-5.53)15.89 (5.54-6.27)1
C02KX01Bosentan11774912269.53 (8.91-10.19)13.35 (3.53-4.45)19.20 (8.61-9.83)1
L01XE05Sorafenib92027111914.98 (4.64-5.35)115.39 (13.58-17.44)16.22 (5.83-6.63)1
Table 3 Key results of drug-induced liver injury associated with antimycotics: Number of cases with relevant disproportionality analyses
Pharmacological classActivesubstanceCases LICasesALFCasesOLIROR (95%CI) LIROR (95%CI)ALFROR (95%CI)OLI
AntibioticsAmphotericin B251142655.33 (4.65-6.10)12.86 (1.69-4.84)15.20 (4.55-5.94)1
Imidazole derivativesMiconazole216-160.33 (0.20-0.54)-0.30 (0.18-0.50)
Ketoconazole2886946.68 (5.28-8.44)14.22 (1.88-9.45)16.64 (5.28-8.34)1
Triazole derivativesFluconazole381314124.25 (3.81-4.74)13.46 (2.42-4.93)14.26 (3.83-4.73)1
Itraconazole17841823.73 (3.19-4.37)10.84 (0.32-2.25)3.50 (2.99-4.09)1
Voriconazole342193615.61 (4.99-6.31)12.97 (1.89-4.67)15.48 (4.89-6.14)1
Posaconazole655705.39 (4.12-7.04)14.00 (1.65-9.66)15.39 (4.16-6.99)1
Other antimycotics for systemic useFlucytosine6-63.06 (1.31-7.13)1-2.80 (1.20-6.52)1
Caspofungin16171687.03 (5.90-7.37)12.79 (1.32-5.87)16.78 (5.71-8.05)1
Micafungin482506.90 (5.02-9.49)1-6.64 (4.86-9.09)1
Anidulafungin131144.97 (2.75-9.00)1-4.97 (2.79-8.84)1
Antimycotics used for topical indications (dermatological use) with systemic absorptionGriseofulvin33-32.00 (0.62-6.47)-1.83 (0.57-5.92)
Terbinafine3395274225.11 (4.58-5.69)13.39 (2.32-4.96)15.06 (4.55-5.62)1
Antimycotics for topical use with potential systemic absorption (e.g., gynecological and intestinal use)Nystatin12-122.01 (1.12-3.62)1-1.84 (1.02-3.31)1
Econazole6-63.25 (1.39-7.60)1-2.97 (1.27-6.94)1
Ciclopirox3-33.39 (1.02-11.30)1-3.10 (0.93-10.33)
Table 4 Clinical, pharmacological and regulatory aspects of antimycotics for systemic use currently on the market (ketoconazole not shown)
DrugApproval (EMA-FDA)Indication(s)Main hepatic issuesDrug interactions
Amphotericin B1995 (FDA)1Empirical therapy for presumed fungal infection in febrile, neutropenic patients Cryptococcal Meningitis in HIV infected patients Visceral leishmaniasisNo detailed information provided (general statement in the section on side effects)Unclear from the label (metabolic pathway unknown)
MiconazoleNo centralized approvalOnychomycosis (topical) Local candida infections (topical and systemic)Not reportedCYP3A4 and CYP2C9 inhibitor (when administered systemically)
Fluconazole1990 (FDA)Acute vaginal candidiasis when local therapy is not appropriate Candidal balanitis when local therapy is not appropriate Mucosal and invasive candidiasis, genital candidiasis (trush), cryptococcal meningitis, dermatomycosis, coccidiodomycosis and onychomycosis (EMA revision in 2011)Hepatic injury (warning FDA and EMA)Potent CYP2C9 inhibitor; moderate CYP3A4 inhibitor; CYP2C19 inhibitor
Itraconazole1992 (FDA)Onychomycosis of the toenail caused by Trichophyton rubrum or T. mentagrophytes (FDA)Hepatic injury (FDA)Potent CYP3A4 inhibitor (drug interactions in warnings)
Voriconazole2002 (EMA and FDA)Invasive aspergillosis Candidemia in non-neutropenic patients Esophageal candidiasis (FDA) Fluconazole-resistant serious invasive Candida infections (including C. krusei) (EMA) Serious fungal infections caused by Scedosporium spp. and Fusarium spp.Hepatic toxicity and monitoring of hepatic function (EMA and FDA)CYP2C9, 2C19 and 3A4 inhibitor (several contraindicated drugs)
Posaconazole2006 (FDA) 2005 (EMA)Refractory IFI/Patients with IFI intolerant to first line therapy Oropharyngeal candidiasis Prophylaxis of IFIHepatic toxicity and monitoring of hepatic function (EMA and FDA)Potent CYP3A4 inhibitor (drug interactions in contraindications)
Caspofungin2001(EMA and FDA)Empirical therapy for presumed fungal infections in febrile, neutropenic patients Invasive candidiasis Invasive aspergillosis (patients refractory or intolerant)Hepatic effectsNo CYP3A4 inhibition; No P-gp induction and poor substrate
Micafungin2005 (only FDA)Treatment of invasive candidiasis Treatment of esophageal candidiasis Prophylaxis of Candida infectionHepatic effectsNo P-gp induction or substrate
Anidulafungin2006 (FDA) 2007 (EMA)Invasive candidiasis in adult non-neutropenic patients (EMA) Esophageal candidiasis (FDA)Hepatic effects (warning FDA and EMA)No CYP substrate, inhibitor or inducer
Terbinafine19952Fingernail onychomycosis Toenail onychomycosisHepatotoxicityCYP2D6 inhibitor
Griseofulvin1975 (FDA)Various forms of tineas (corporis, pedis, cruris, barbae, capitis, unguium)HepatotoxicityUnclear from the label