Prescribers must be aware of potential serious side effects, drug interactions, and laboratory monitoring associated with itraconazole. It is contraindicated in patients with current or history of congestive heart failure (CHF) as it exhibits negative inotropic effects. Additionally, rare cases of anaphylaxis, hepatotoxicity, and neuropathy (eg, transient or permanent hearing loss) have been reported.6 Itraconazole is a potent inhibitor of the cytochrome P450 system and may affect the metabolism of other drugs. Cisapride, pimoxide, levacetylmethadol, methadone, and quinidine should be avoided because of the risk of serious cardiac adverse events such as QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death.6 Additionally, calcium channel blocks should be avoided because of the additive risk for CHF exacerbation. All patients should have liver enzymes checked at baseline and periodically during therapy because of the risk of hepatotoxicity.6 Finally, itraconazole is pregnancy category C, so caution should be exercised in treating female patients of childbearing potential.
The potential for serious adverse effects and drug interactions makes topical onychomycosis treatment preferable notwithstanding low efficacy of topical treatments and hence decreased adherence by patients. While ciclopirox 8% nail lacquer is FDA approved for the topical treatment of onychomycosis, its cure rate ranges from 5.5-8.5%4 and requires frequent concurrent nail debridement. Other topical therapies are currently in development and may offer higher cure rates for patients. In October 2013, efinaconazole 10% topical solution became the first topical triazole antifungal solution approved by the Canadian regulatory authority, Health Canada, for the treatment of mild to moderate onychomycosis.
Efinaconazole has not yet received US FDA approval. Two phase 3 clinical trials have been conducted in the US to evaluate the safety and efficacy of efinaconazole 10% topical solution for onychomycosis. Efinaconazole had a complete cure rate approximately 5 times greater than placebo (P<0.001) (Figure 1). The mycological cure rate from efinaconazole was 53-55% compared to 16% from placebo (P<0.001).7 Mild local skin reactions included application site dermatitis and vesicles. Systemic absorption of efinaconazole 10% solution topically applied to the nail is below the threshold for clinical drug-drug interactions, suggesting that it has limited or no potential for drug interactions8. Consequently, lab monitoring is not recommended.
Efinaconazole is a triazole antifungal, which inhibits sterol 14α-demethylase in the ergosterol biosynthesis pathway, thereby disrupting fungal cell membrane function.9 Efinaconazole has a broad spectrum antifungal activity against dermatophytes, nondermatophyte molds, and yeast.10 It has broad spectrum antifungal activity, with particular effectiveness
against T. rubrum and T. mentagrophytes and C. albicans.11 Additionally, efinaconazole has exhibited in-vitro antifungal activity against Trichophyton, Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces, Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon, and Candida.9
Efinaconazole 10% solution has several unique properties that explain its efficacy. Its non-lacquer, alcohol-based vehicle does not require debridement between applications and creates a low surface tension that provides easy access to the nail bed.10,12 Moreover, efinaconazole possesses a low binding affinity to keratin, allowing for favorable nail plate penetration and quick drug release in its free, active form into the nail plate.10,12 It is designed to be applied to a clean, dry nail plate surface, lateral and proximal nail folds, hyponychium, and undersurface of the nail plate once daily for 48 weeks.
Another new topical therapy for onychomycosis is tavaborole 5% solution. As of October 2013, the New Drug Application (NDA) for tavaborole 5% solution was accepted by the US FDA for review. This drug is in a new class of broad-spectrum antifungals, called benzoxaboroles, which inhibits fungal leucyl transfer RNA synthetase (LeuRS), an enzyme essential for protein synthesis.13 Tavaborole demonstrates broad-spectrum antifungal activity against yeast, molds, dermatophytes, and filamentous fungi.14 The degree of nail penetration of tavaborole 5% solution is 250 times greater than that of ciclopirox,15 penetrating the lower ventral and intermediate layers of the nail plate 72 hours after application.16 Additionally, tavaborole drug load that penetrated the lower layers of the nail plate was 5 times greater than ciclopirox.17 Tavaborole 5% solution is safe; The most common side effects are local application reactions and no treatment-related systemic side effects were observed.14 Tavaborole represents a new boron-based class of anti-fungals, which have a totally different mechanism of action than other anti-fungals on the market. Phase 3 clinical study results for this product are expected to be published soon.
