Clinicians now have five oral antifungal therapeutic agents to choose from when assessing the risk–benefits associated with a particular treatment for onychomycosis (OM): griseofulvin, itraconazole, terbinafine, ketoconazole, and fluconazole. ...
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The risk of acute liver injury among 69830 patients treated with oral antifungal agents was determined in a cohort study in which patients with prior liver disease were excluded (
Garcia Rodriguez et al 1999). The incidence rates of acute liver injury were found to be 134.1 per 100 000 person-months; (95% confidence interval [CI]: 36.8, 488.0) for ketoconazole, 10.4 (95% CI: 2.9, 38.1) for itraconazole, and 2.5 (95% CI: 0.4, 13.9) for terbinafine. Ketoconazole was associated with the highest relative risk with 228.0 (95% CI: 33.9, 933.0), when compared with the risk among non-users, followed by itraconazole (relative risk [RR] 17.7; 95% CI: 2.6, 72.6) and terbinafine (RR 4.2; 95% CI: 0.2, 24.9). This cohort study confirms the finding that most case reports of liver injury after administration of oral antifungal agents occur with ketoconazole and itraconazole, and argues against using these agents as initial treatment for uncomplicated fungal infections. While the Rodriguez study (
Garcia Rodriguez et al 1999) highlights low incidence of liver injury for terbinafine, the higher rates of hepatotoxicity seen with azole antifungals has adversely affected the perception of terbinafine-induced liver enzyme elevation.
The incidence of terbinafine-related hepatobiliary dysfunction in the same studies are even lower at 1 in 45 000–120 000 patients (Hay 1993). To put this finding further into context, the low risk of hepatic injury observed with terbinafine may be comparable to that seen with paracetamol, a medication widely used for pain relief, and perceived as safe by the general population (Friis and Andreasen 1992; Skorepova 2004).
The risk of hepatotoxicity with terbinafine should not be exaggerated, but should be taken into account, together with any other relevant factors. Patients with chronic or active liver diseases should not be treated with terbinafine, and baseline (pretreatment) liver transaminase testing is recommended. While some physicians continue to monitor liver enzymes during the course of terbinafine treatment, this is no longer recommended by the revised current labeling. After many years of experience with terbinafine, the FDA subsequently removed the LFT monitoring recommendation from the terbinafine label (
MedWatch 2001). This is in line with early safety data reported for 1508 patients with toenail onychomycosis, with a mean age of 50 years, and extensive intractable disease, averaging over 11 years in duration (
Pollak and Billstein 1997). The incidence of hepatic or biliary disorders was 2.8%, of which the most common was abnormal liver function tests (2.4%). A recent study of 504 patients, in which patients with baseline abnormal liver enzymes were excluded, showed no clinically significant alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation in plasma levels when tested 6 weeks into the treatment (250 mg/day) (
Pollak et al 2004). For griseofulvin, there is a clear dosage-dependent association with hepatic toxicity, particularly in patients with prior liver damage (
Skorepova 2004).
