Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality

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. Only the first three are approved by the FDA for this indication. Griseofulvin is fungistatic and inhibits nucleic acid synthesis, arresting cell division at metaphase, and impairing fungal wall synthesis. Due to its low cure rates and high relapse, it is rarely used for treatment of onychomycosis. Itraconazole is a broad spectrum drug and is effective against dermatophytes, candida, and some nondermatophytic molds. Itraconazole works by inhibiting ergosterol synthesis via cytochrome P-450 (CYP450)-dependent demethylation step. This azole antifungal agent is metabolized in the liver by cytochrome P-450 3A4 (CYP3A4), and therefore has the potential to interact with drugs metabolized through this pathway. Terbinafine, an allylamine, is fungicidal and remains at therapeutic levels in keratinized tissues, but with a short plasma half-life of 36 hours. Terbinafine has the advantage in that it does not inhibit CYP3A4 isoenzyme during its metabolism where some 50% of all commonly prescribed drugs are metabolized. The only potentially significant drug interaction with terbinafine is with the cytochrome P-450 2D6 (CYP2D6) isoenzyme. The lack of widely reported or published clinically relevant drug interactions, and extensive experience from a large prospective, surveillance study conducted in "real world" setting with no patient exclusions, suggest that this is not a major issue. The high cure rates of terbinafine against dermatophytes, as shown in many studies since its launch in the 1990s, together with lack of clinically significant drug interactions and well established safety record, indicate the use of continuous oral terbinafine as the top choice for the treatment of onychomycosis in most patients.