Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Table 1 MedDRA preferred terms used to retrieve liver events in FAERS

PT	Liver injury	Acute hepatic failure
Acute hepatic failure		X
Alanine aminotransferase abnormal	X
Alanine aminotransferase increased	X
Ammonia increased	X
Aspartate aminotransferase abnormal	X
Aspartate aminotransferase increased	X
Bilirubin conjugated increased	X
Bilirubin urine	X
Blood bilirubin abnormal	X
Blood bilirubin increased	X
Blood bilirubin unconjugated increased	X
Cholestasis	X
Coma hepatic		X
Cytolytic hepatitis	X
Hepatic encephalopathy		X
Hepatic enzyme abnormal	X
Hepatic enzyme increased	X
Hepatic failure		X
Hepatic function abnormal	X
Hepatic necrosis	X
Hepatitis	X
Hepatitis acute	X
Hepatitis cholestatic	X
Hepatitis fulminant		X
Hepatitis toxic	X
Hepatocellular damage	X
Hepatotoxicity	X
Hyperammonaemia	X
Hyperbilirubinaemia	X
Jaundice	X
Jaundice cholestatic	X
Jaundice hepatocellular	X
Liver function test abnormal	X
Liver injury	X
Liver transplant		X
Mixed hepatocellular-cholestatic injury	X
Subacute hepatic failure	X
Transaminases abnormal	X
Transaminases increased	X
Urine bilirubin increased	X

PT: Preferred term of the MedDRA terminology. “X” indicates that the PT was used to define the liver event; MedDRA: Medical Dictionary for Regulatory Activities.

Table 2 Top-10 drugs ranked in FAERS according to their reporting frequency for overall liver injury

ATC code	Active substance	Cases LI	Cases ALF	Cases OLI	ROR (95%CI) LI	ROR (95%CI) ALF	ROR (95%CI) OLI
N02BE01	Paracetamol	2780	645	3425	3.69 (3.54-3.84)1	9.58 (8.82-10.41)1	4.31 (4.16-4.48)1
C10AA05	Atorvastatin	1763	131	1894	3.46 (3.29-3.64)1	2.62 (2.20-3.12)1	3.43 (3.27-3.60)1
C10AA01	Simvastatin	1516	80	1596	2.62 (2.49-2.77)1	1.44 (1.15-1.80)1	2.54 (2.41-2.67)1
N06AX21	Duloxetine	1456	59	1515	3.34 (3.15-3.53)1	1.42 (1.10-1.83)1	3.32 (3.14-3.50)1
L03AB07	Interferon beta-1	1377	46	1423	0.73 (0.70-0.78)	0.27 (0.20-0.36)	0.69 (0.66-0.73)
J05AF05	Lamivudine	1162	130	1292	4.68 (4.40-4.98)1	5.22 (4.38-6.22)1	4.86 (4.57-5.16)1
L01BA01	Methotrexate	1200	86	1286	2.89 (2.72-3.07)1	2.15 (1.74-2.66)1	2.85 (2.69-3.02)1
J01CR02	Amoxicillin/clavulanic acid	1164	94	1258	5.86 (5.49-11.36)1	4.50 (3.67-5.53)1	5.89 (5.54-6.27)1
C02KX01	Bosentan	1177	49	1226	9.53 (8.91-10.19)1	3.35 (3.53-4.45)1	9.20 (8.61-9.83)1
L01XE05	Sorafenib	920	271	1191	4.98 (4.64-5.35)1	15.39 (13.58-17.44)1	6.22 (5.83-6.63)1

¹Statistically significant disproportionality (Lower limit 95%CI > 1). ATC: Anatomical therapeutic chemical classification; ALF: Acute liver failure; LI: Liver injury; OLI: Overall liver injury; ROR: Reporting odds ratio.

Table 3 Key results of drug-induced liver injury associated with antimycotics: Number of cases with relevant disproportionality analyses

Pharmacological class	Activesubstance	Cases LI	CasesALF	CasesOLI	ROR (95%CI) LI	ROR (95%CI)ALF	ROR (95%CI)OLI
Antibiotics	Amphotericin B	251	14	265	5.33 (4.65-6.10)1	2.86 (1.69-4.84)1	5.20 (4.55-5.94)1
Imidazole derivatives	Miconazole2	16	-	16	0.33 (0.20-0.54)	-	0.30 (0.18-0.50)
	Ketoconazole2	88	6	94	6.68 (5.28-8.44)1	4.22 (1.88-9.45)1	6.64 (5.28-8.34)1
Triazole derivatives	Fluconazole	381	31	412	4.25 (3.81-4.74)1	3.46 (2.42-4.93)1	4.26 (3.83-4.73)1
	Itraconazole	178	4	182	3.73 (3.19-4.37)1	0.84 (0.32-2.25)	3.50 (2.99-4.09)1
	Voriconazole	342	19	361	5.61 (4.99-6.31)1	2.97 (1.89-4.67)1	5.48 (4.89-6.14)1
	Posaconazole	65	5	70	5.39 (4.12-7.04)1	4.00 (1.65-9.66)1	5.39 (4.16-6.99)1
Other antimycotics for systemic use	Flucytosine	6	-	6	3.06 (1.31-7.13)1	-	2.80 (1.20-6.52)1
	Caspofungin	161	7	168	7.03 (5.90-7.37)1	2.79 (1.32-5.87)1	6.78 (5.71-8.05)1
	Micafungin	48	2	50	6.90 (5.02-9.49)1	-	6.64 (4.86-9.09)1
	Anidulafungin	13	1	14	4.97 (2.75-9.00)1	-	4.97 (2.79-8.84)1
Antimycotics used for topical indications (dermatological use) with systemic absorption	Griseofulvin3	3	-	3	2.00 (0.62-6.47)	-	1.83 (0.57-5.92)
	Terbinafine3	395	27	422	5.11 (4.58-5.69)1	3.39 (2.32-4.96)1	5.06 (4.55-5.62)1
Antimycotics for topical use with potential systemic absorption (e.g., gynecological and intestinal use)	Nystatin	12	-	12	2.01 (1.12-3.62)1	-	1.84 (1.02-3.31)1
	Econazole	6	-	6	3.25 (1.39-7.60)1	-	2.97 (1.27-6.94)1
	Ciclopirox	3	-	3	3.39 (1.02-11.30)1	-	3.10 (0.93-10.33)

Only agents with at least three cases for the event of interest are shown (i.e., those for which disproportionality can be calculated).

¹Statistically significant disproportionality (Lower limit 95%CI > 1);

²Frequent topical use;

³Also topical use. ALF: Acute liver failure; LI: Liver injury; OLI: Overall liver injury; ROR: Reporting odds ratio.

Table 4 Clinical, pharmacological and regulatory aspects of antimycotics for systemic use currently on the market (ketoconazole not shown)

Drug	Approval (EMA-FDA)	Indication(s)	Main hepatic issues	Drug interactions
Amphotericin B	1995 (FDA)1	Empirical therapy for presumed fungal infection in febrile, neutropenic patients Cryptococcal Meningitis in HIV infected patients Visceral leishmaniasis	No detailed information provided (general statement in the section on side effects)	Unclear from the label (metabolic pathway unknown)
Miconazole	No centralized approval	Onychomycosis (topical) Local candida infections (topical and systemic)	Not reported	CYP3A4 and CYP2C9 inhibitor (when administered systemically)
Fluconazole	1990 (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
Itraconazole	1992 (FDA)	Onychomycosis of the toenail caused by Trichophyton rubrum or T. mentagrophytes (FDA)	Hepatic injury (FDA)	Potent CYP3A4 inhibitor (drug interactions in warnings)
Voriconazole	2002 (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)
Posaconazole	2006 (FDA) 2005 (EMA)	Refractory IFI/Patients with IFI intolerant to first line therapy Oropharyngeal candidiasis Prophylaxis of IFI	Hepatic toxicity and monitoring of hepatic function (EMA and FDA)	Potent CYP3A4 inhibitor (drug interactions in contraindications)
Caspofungin	2001(EMA and FDA)	Empirical therapy for presumed fungal infections in febrile, neutropenic patients Invasive candidiasis Invasive aspergillosis (patients refractory or intolerant)	Hepatic effects	No CYP3A4 inhibition; No P-gp induction and poor substrate
Micafungin	2005 (only FDA)	Treatment of invasive candidiasis Treatment of esophageal candidiasis Prophylaxis of Candida infection	Hepatic effects	No P-gp induction or substrate
Anidulafungin	2006 (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
Terbinafine	19952	Fingernail onychomycosis Toenail onychomycosis	Hepatotoxicity	CYP2D6 inhibitor
Griseofulvin	1975 (FDA)	Various forms of tineas (corporis, pedis, cruris, barbae, capitis, unguium)	Hepatotoxicity	Unclear from the label

Information are derived from relevant summary of product characteristic (EMA) or product information (FDA), as of March 26^th, 2013. When no information could be obtained from EMA and FDA documents, the Italian label was used.

¹On 28 August 2006, orphan designation (EU/3/06/391) was granted by the European Commission to Nektar Therapeutics United Kingdom Ltd, United Kingdom, for amphotericin B (for inhalation use) for the prevention of pulmonary fungal infections in patients deemed at risk;

²Pediatric investigation plan agreed with EMA. EMA: European Medicines Agency; FDA: Food and Drug Administration; IFI: Invasive fungal infections.