Individual Article: Updated Review of Topical Pharmaceuticals and Complementary and Alternative Medications for the Treatment of Onychomycosis in Both General and Special Populations in the United States

In a subsequent phase 4, long-term, single center, open-labeled follow-up study in 23 adult subjects who completed 48 weeks of efinaconazole 10% solution once-daily treatment, there was a continued reduction in disease severity post-treatment.30 At week 48 there were no complete cures, but 9% achieved complete cure at 72 weeks despite being off treatment. Similarly, treatment success was achieved by 39.1% and 56.5%, respectively. Furthermore, median percent affected target toenail were 40% and 25%, respectively. A long-term 72-week single-arm study in 605 participants by Iozumi et al. further found a complete cure rate of 31.1% and treatment success rate of 56.6% at week 72.71  These studies suggest that longer post-treatment follow-up would illuminate better efficacy results beyond those reported in the traditional phase 3 studies that end at week 52. This is also an important consideration as a post hoc analysis of the phase 3 data noted that, compared with younger patients, older patients have slower toenail growth and greater disease severity and duration that may require treatment beyond the standard 48-week regimen currently employed in trials.³¹ In addition, the post-treatment study for efinaconazole is significantly longer than the post-treatment follow-up study for tavaborole, which was only 8 weeks after discontinuation of treatment and was a pooled analysis from the prior phase 3 studies rather than a phase 4 study.²² Although 28.6% of participants treated with tavaborole achieved complete cure at post-treatment week 8 vs 9% of efinaconazole-treated patients, the 2 studies cannot be compared because the 2 studies were developed with different initial primary endpoints (phase 3 pooled analysis vs prospective phase 4 trial, respectively) and the sample sizes are low. In another study assessing participant characteristics resulting in complete cure at week 24, younger age (<65 years) and female gender were found to be major contributors.³² The greater efficacy seen in females has also been recapitulated by Rosen.³³

Utility of efinaconazole in the presence of nail polish was also assessed. Del Rosso remarked that nail plate penetration is not affected by nail polish.³⁴ Canavan et al performed a single-center, blinded study in 11 subjects comparing the efficacy of efinaconazole 10% solution daily for onychomycosis in nails with and without concurrent nail polish.³⁵ After 48 weeks of treatment, efficacy of efinaconazole did not diminish in the presence of nail polish and was comparable between the 2 groups. However, subjects noted undesirable cosmetic changes to the quality of the polish with continued use over time. This is in contrast with tavaborole, which did not alter nail polish appearance in an ex vivo study of human fingernails.³⁶  However, the efficacy of tavaborole, as well as ciclopirox, in the presence of nail polish has not yet been evaluated.

Effect of daily efinaconazole 10% solution for pediatric onychomycosis was also assessed in a phase 4, open-label study in 62 children aged 6 to 16 years after 48 weeks of treatment.³⁷ At week 52, 40.0% of participants achieved complete cure. Mycologic cure rate was 65.0% with 36.7% achieving mycologic cure as early as week 12. Pharmacokinetic analysis also revealed low systemic exposure to efinaconazole.

Complementary and Alternative Therapies for Onychomycosis
Several at-home remedies and essential oils have been popularized as treatments for onychomycosis. The first paper reviewing such over-the-counter natural remedies was published by Halteh et al in 2015.38 A more recent update has been published in 2022 by Nickels et al.³⁹ 

 

Vicks VapoRub, an over-the-counter topical cough suppressant, contains 3 active ingredients with in vitro antifungal activity: camphor, eucalyptus oil, and menthol.40 Efficacy of Vicks VapoRub topical monotherapy for onychomycosis over 48 weeks is noted in 2 small, single-arm, open-label trials with reported clinical cure rates of 11% to 27.8%, partial cure rates of 55.6% to 83%, and mycologic cure rates of ~28%.^41,42 Propolis extract, a resin compound produced by honeybees, has shown efficacy in a single open-label, single-arm trial of 16 patients with complete cure rate of 56.3%.⁴³ Tea tree oil exhibits broad-spectrum antimicrobial properties and studies assessing twice daily application for onychomycosis for 6 months reported clinical cure rates of 27% to 78.5% and mycologic cure rates of 82% to 89%. Impressively, a head-to-head, double-blind, randomized, controlled trial of 177 patients with DLSO treated with tea tree oil twice daily vs 1% clotrimazole twice daily over 6 months exhibited similar clinical cure rates.⁴⁴ 

 

Spirulina (Arthrospira maxima) also exhibits antifungal activity in vitro. Calmagen^® lotion, which contains spirulina and is sold in Australia, has been studied in a few small trials. One notable trial was a double-blind, randomized, controlled clinical trial comparing Calmagen lotion with placebo over 12 weeks, which found Calmagen to achieve a 100% mycological cure rate and a statistically significant improvement over placebo.⁴⁵ 

Ageratina pinchinchensis, a traditional Mexican plant medicine, also demonstrates in vitro antifungal activity against dermatophytes.⁴⁶ Two small double-blind, randomized, controlled trials compared Ageratina pichinchensis extract in nail lacquer with 8% ciclopirox.^46,48 Mycological cure rates were 59.1% and 63.8%, respectively, and clinical cure rates were 71.4% and 80.9%, respectively.⁴⁸ Topical ozonized sunflower oil (OLEOZON®) twice daily has also shown superiority to ketoconazole 2% cream twice daily for 3 months in a head-to-head single-blinded, randomized, controlled trial of 400 participants, with mycologic cure rates of 90.5% and 13.5%, respectively.⁴⁹

While complementary and alternative therapies may have an adjunctive role for onychomycosis with existing preliminary support, the data are currently limited. Large-scale, randomized, controlled trials are lacking, especially comparing these therapies with current FDA-approved topical antifungals (ciclopirox, tavaborole, efinaconazole). At this time, the evidence is not sufficient to recommend such therapies to patients with onychomycosis.

Given the ever-increasing prevalence of onychomycosis and the multitude of potential patient co-morbidities, the choice of therapeutic anti-fungal agents must be both economical, effective, and safe. An updated consensus guideline for onychomycosis diagnosis and treatment in the US was recently published in 2021.⁵⁰ Prior to that document, national guidelines were last published in 2014 and 2015 in Britain⁵¹ and Canada,⁵² respectively.