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

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.