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Topical Efinaconazole in the Management of Toenail Onychomycosis

Gurbir Dhadwal, MD, FRCPC, FAAD
St. Paul's Hospital, Vancouver, BC, Canada

Introduction

Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, or non-dermatophyte molds. Results from a large international study show that onychomycosis affects up to 23% of the population.1 The rates of onychomycosis in people older than 40 is even higher, and has been reported to be greater than 50%.1 Risk factors for onychomycosis include increasing age, atopy, sports, diabetes, obesity, peripheral arterial disease, immunosuppression, and pre-existing nail disease.1

Diagnostic Features

  • The clinical diagnosis of onychomycosis can be challenging given that inflammatory disorders of the nails can mimic onychomycosis.
    • The differential diagnosis of onychomycosis includes psoriasis of the nails, idiopathic onychodystrophy, traumatic onychodystrophy, lichen planus, and alopecia areata.
    • Onychomycosis accounts for approximately 50% of nail disorders.2
  • In patients with mycologically proven onychomycosis the most common clinical findings are:
    • Discoloration of the nail (85%), hyperkeratosis (80%) and onycholysis (43%).
    • The rates of damaged nail (13%) and paronychia (7%) were lower.1
  • To confirm a diagnosis of onychomycosis, clippings can be obtained from the distal nail, curettings can be obtained from below the nail plate with a 1mm curette, or a scalpel can be used to pare down the overlying normal nail plate to get to the debris beneath the nail for KOH and/or culture.3
  • Curetting beneath the nail plate increases the sensitivity of KOH and culture when done in conjunction with either clipping or paring alone.3

Treatment Rationale

  • Onychomycosis impacts patients' psychosocial functioning.
  • In a survey on how adults with onychomycosis are perceived by others, survey respondents said they would:4
    • Perceive those with onychomycosis as less likely to be able to form good relationships.
    • Be more likely to exclude those with onychomycosis from social activities.
    • Feel uncomfortable sitting or standing beside an infected person.
  • Many patients with onychomycosis have associated pain, which can be underestimated by physicians.5
  • Onychomycosis in diabetic patients may be associated with serious consequences.
    • Diabetic patients with onychomycosis have higher rates of infections and of foot ulcers6 compared to diabetic patients without onychomycosis.
    • The presence of onychomycosis in a patient increases the risk of diabetic foot complications from moderate to high risk.7

    Treatment/Management Options

    Systemic Therapies

    • Terbinafine
      • Terbinafine is currently the most efficacious systemic agent for treating onychomycosis.
        • Mycological cure - 74%
        • Complete cure - 38%
        • Assessed at week 48, after a 12 week treatment course.8
        • Mycological cure is defined as a negative KOH and negative fungal culture.
      • Complete cure is defined as mycological cure with 0% clinical nail involvement. There is a Health Canada Black box warning stating “Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of terbinafine tablets; Treatment with terbinafine tablets should be discontinued if biochemical or clinical evidence of liver injury develops.” The actual rates of idiosyncratic hepatobiliary dysfunction have been reported to range between 1 : 45 000 to 1 : 120 000.9,10
      • The typical dosing for toenail onychomycosis is 250mg once daily for 12 weeks.
    • Azoles
      • Ketoconazole
        • In 2013, the FDA issued a safety announcement that oral ketoconazole tablets should not be a first-line treatment for any fungal infection due to hepatotoxicity, adrenal insufficiency and drug interactions. The US label for ketoconazole now carries an FDA black box warning that systemic ketoconazole should only be used when other effective antifungals are not available or tolerated, due to hepatotoxicity and drug interactions leading to QT prolongation.11
      • Itraconazole
        • Mycological cure - 54%
        • Complete cure - 14%
        • Black box warning: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.12
        • 200mg once daily for 3 months or pulse dosing: 3 pulses of 200mg bid for 7 days, with 3 week drug free intervals between pulses.

    Topical Therapies

    • Ciclopirox 8% nail solution13
      • The cure rates for ciclopirox in two double blinded Phase III trials were:
        • Mycological cure - 29-35%
        • Complete cure - 6%-9%
      • The treatment protocol for Ciclopirox 8% nail solution involves once daily application, with removal of the ciclopirox solution every 7 days with isopropyl alcohol, with removal of the unattached, infected nail as frequently as monthly for up to 48 weeks.
    • Efinaconazole 10% solution
      • Mycological cure - 55.2% and 53.4%
      • Complete cure - 17.8% and 15.2%
      • 48 weeks of treatment

    Efinaconazole 10% Solution

    Background

    • Efinaconazole is a topical azole antifungal that inhibits ergosterol, a structural component of fungal cell membranes, leading to the loss of cell membrane integrity.14,15
    • In vitro efinaconazole has been found to be active against dermatophytes, non-dermatophytes, and yeasts.16
    • It has low keratin affinity which allows enhanced penetration through the nail compared to ciclopirox, this presumably allows the topical to better treat fungus within and under the nail plate.17
    • Efinaconazole 10% solution has been shown to penetrate through nail polish, so that patients do not need to remove their nail polish to treat on a daily basis.18
    • The treatment course for efinaconazole 10% solution is once daily for 48 weeks, applied to the affected toenail, underside of the nail plate, and to the surrounding skin. Debridement or removal of previously applied efinaconazole 10% solution is not necessary as there is no buildup from daily application.19

    Efficacy

    • The efficacy of topical 10% efinaconazole was demonstrated in two Phase III studies with 1655 patients.
    • The cure rates at 52 weeks, 4 weeks after the completion of treatment, in the two Phase III studies were:
      • Mycological cure - 55.2% and 53.4%
      • Complete cure - 17.8% and 15.2%

    Factors Affecting the Efficacy of Topical Efinaconazole 10% Solution

    • Females had higher complete clearance rates than males (27.1% versus 15.8%, p=0.001).20
    • Concomitant tinea pedis21
      • Treatment of concomitant tinea pedis - complete cure 29.4% and mycological cure 56.2%.
      • Without treatment of concomitant tinea pedis - complete cure 16.1% and mycological cure 45.2%.
    • Diabetes22
      • Patients with controlled diabetes (n=69) were compared to non-diabetic patients (n=993).
      • Complete cure rates were 13% and 18.8% respectively, the difference was not statistically significant.
    • Duration of disease - There is a trend that patients with onychomycosis for less than 1 year had higher complete cure rates than those with a longer duration of disease.23
      • < 1 year - 42.6% complete cure versus 16.7% for vehicle - not statistically significantly different from vehicle.
      • 1-5 years - 17.1% complete cure versus 4.4% for vehicle.
      • > 5 years - 16.2% complete cure versus 2.5% for vehicle.
    • Disease severity - Patients with less nail involvement had higher cure rates.24
      • ≤ 25% nail involvement - complete cure rate 25.8%; mycological cure 58.2%.
      • >25% nail involvement - complete cure rate 15.9%; mycological cure 55.5%.

    Clinical Pathway

    • In 2015 a group of Canadian dermatologists developed a clinical pathway for managing toenail onychomycosis (figure 1),25 based on the available data.
    • The clinical pathway provides a guide toward a patient-centred treatment strategy, focusing on prevention, management, and minimizing re-infection of onychomycosis.
    • Treatment stragies are based on severity of disease:
      • >60% of toenail affected: oral terbinafine
      • 20-60% of toenail affected: topical efinaconazole +/- oral terbinafine
      • <20% of toenail affected: topical efinaconazole

    Figure 1

    Figure 1. Pathway to the prevention and treatment of toenail onychomycosis.25


    Summary

    • When making a diagnosis of onychomycosis, curetting beneath the nail plate with a 1mm curette combined with clipping the nail, can increase the sensitivity of clipping the nail alone.
    • Topical therapy appears most effective for patients with early disease and smaller amounts of nail involvement.
    • When treating topically, concurrently treating the concomitant tinea pedis appears to increase the complete cure rate.
    • Treatment with efinaconazole involves once daily application of the 10% solution to the nail plate, under the nail plate, and to the surrounding skin for 48 weeks with penetration through the nail plate, without removing nail polish; there is also no need to remove the solution from the nail plate on a weekly basis.
    • The complete cure rate with efinaconazole 10% solution is between 15.2% and 17.8%.
    • In terms of systemic therapy, terbinafine has a complete cure rate of 35%; ketoconazole has an FDA black box warning against using it first-line for any fungal infections.

    References

    1. Haneke E, Roseeuw D. Int J Dermatol. 1999 Sep;38(S2):7-12.
    2. Faergemann J, Baran R. Br J Dermatol. 2003 Sep;149(65):1-4.
    3. Hull PR. J Am Acad Dermatol. 1998 Dec;39(6):1015-7.
    4. Chan HH, et al. Biopsychosoc Med. 2014 Jul;8(1):15
    5. Drake LA, et al. J Am Acad Dermatol. 1999 Aug;41(2):189-96.
    6. Boyko EJ, et al. Diabetes Care. 2006 Jun;29(6):1202-7.
    7. Ibrahim A. Diabetes Res Clin Pract. 2017 May;127: 285-287.
    8. Novartis. Lamasil (terbinafine hydrochloride tablets). 2013.
    9. Hay RJ. J Am Acad Dermatol. 1993 Jul;29(1):50-4.
    10. Orion E, et al. Clin Dermatol. 2005 Mar-Apr;23(2):182-92.
    11. Janssen Pharmaceuticals. Nizoral (ketoconazole) tablets. 2014.
    12. Janssen Pharmaceuticals. Sporanox (Itraconazole) tablets. 2017.
    13. Sterimax Inc. Ciclopirox topical solution. 2013.
    14. Rodriguez RJ, et al. Biochim Biophys Acta. 1985 Dec 4;837(3):336-43.
    15. Parks LW, et al. Lipids. 1995 Mar;30(3):227-30.
    16. Jo Siu WJ, et al. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
    17. Sugiura K, et al. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
    18. Zeichner JA, et al. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
    19. Valeant Pharmaceuticals. Jublia (efinaconazole) topical solution, 10%. 2014.
    20. Gupta AK, et al. J Drugs Dermatol. 2014 Jul;13(7):815-20.
    21. Markinson B, Caldwell B. J Am Podiatr Med Assoc. 2015 Sep;105(5):407-11
    22. Vlahovic TC, Joseph WS. J Drugs Dermatol. 2014 Oct;13(10):1186-90.
    23. Rich P. J Drugs Dermatol. 2015 Jan;14(1):58-62.
    24. Rodriguez DA. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-29.
    25. Gupta AK, et al. J Cutan Med Surg. 2015 Sep-Oct;19(5):440-9.

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