Ciclopirox Nail Lacquer 8% for the Treatment of Onychomycosis: A Canadian Perspective

A. K. Gupta MD, PhD, MBA/HCM, FRCPC^1,2
J. R. Schouten, BSc², L. E. Lynch, HBSc^2
1Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Sciences Centre (Sunnybrook site) and the University of Toronto, Toronto, Canada
²Mediprobe Research Inc., London, Ontario, Canada

ABSTRACT

Onychomycosis is prevalent in the Canadian population, and risk factors, such as old age and diabetes, are increasing. This condition has traditionally been treated using oral antifungal agents with varying degrees of success. Recently, ciclopirox nail lacquer 8% solution became the first topical agent approved in Canada for onychomycosis. Ciclopirox nail lacquer may be safe and effective for the treatment of onychomycosis, and certain candidates may benefit from therapy. Ciclopirox may be implicated for prophylactic use in order to prevent recurrent infection and may be used in combination with oral agents.

Key Words: onychomycosis, ciclopirox nail lacquer

Demographic studies suggest that onychomycosis affects between 6.1% and 6.9% of the Canadian population.¹ Several risk factors are associated with the development of onychomycosis, including male gender, increasing age, diabetes, peripheral vascular disease, and immunosuppression.²
With the increasing age of the Canadian population and the high incidence of diabetes, a set of safe and effective options for the treatment of this condition is needed.

Ciclopirox Nail Lacquer

Ciclopirox (Penlac™, Dermik) 8% solution is the only topical antifungal approved for onychomycosis in Canada. This compound is fungicidal in vitro against proliferating and dormant fungal cells,³ and has a broad spectrum of activity.⁴ Ciclopirox nail lacquer was recently approved in Canada (April 2004) as part of a comprehensive nail management program, in which the lacquer is applied once daily for 48 weeks and nail debridement is performed under the supervision of a medical professional.⁵

Mechanism of Action

Ciclopirox targets a variety of metabolic processes in the fungal cell. It chelates polyvalent cations (Fe+3 and Al+3) that are involved in fungal enzymatic activity, ultimately interrupting intracellular energy production and toxic peroxide degradation.⁶ Ciclopirox may also inhibit fungal nutrient uptake, resulting in a depletion of amino acids and nucleotides and a reduction in protein synthesis.⁶

Pharmacokinetics

Ciclopirox nail lacquer penetrates the nail plate via a transungual delivery system. When the solvent evaporates the concentration of ciclopirox increases from 8% to 34.8%, providing a concentration gradient that facilitates the transfer of the drug through the nail plate.6 This mode of application permits distribution of the active compound throughout the entire nail plate, including the lateral margins and onycholytic portions of the nail.^7-9
In vitro penetration studies in pigskin, cow horn, sheep hoof plates, and human nails6,10 using radiolabelled ciclopirox demonstrated penetration of the active ingredient as deep as 0.4mm into the nail after one application.
Pharmacological studies demonstrate that ciclopirox nail lacquer, applied daily for 7-14 days, penetrates the nail at concentrations that exceed the in vitro minimum inhibitory concentrations (MICs) for most fungal species.⁶

Safety

Drug-Drug Interactions
Ciclopirox has no reported interactions with other systemic drugs.¹¹

Adverse Events

Ciclopirox treatment-emergent adverse events (TEAE) reported in US pivotal trials were localized to the treatment area.¹² Nine percent of patients treated with ciclopirox nail lacquer and 7% of patients treated with vehicle reported TEAEs considered by the investigator to be related to the test material.⁵ The most common TEAE was a mild rash at the application site13 (5% ciclopirox, 1% vehicle).

Other attributable TEAEs included nail disorders such as shape change, irritation, ingrown toenail, and discolouration.

Systemic Absorption

Low levels of ciclopirox are recovered systemically.⁵ The mean systemic absorption of ciclopirox is less than 5% of the applied dose.¹⁰

Efficacy

In Vitro
The efficacy of ciclopirox has been demonstrated in vitro against a broad spectrum of proliferating and dormant fungal strains.3 The MIC (mean ± SEM) for ciclopirox was 0.04±0.02mgml-1 against dermatophytes, 0.05±0.02mgml-1 against yeasts, and 1.04±2.62mgml-1 against other nondermatophytes.⁴

In Vivo
Two double-blind, vehicle-controlled, multicenter pivotal US clinical trials^5,12 assessing the use of ciclopirox nail lacquer for mild-to-moderate onychomycosis (20%-65% surface area involvementof the target toenail) demonstrated significant mycological efficacy of the active compound when compared with the vehicle. The mycological cure (negative KOH and culture) rate for ciclopirox nail lacquer applied once daily for 48 weeks was 29% (ciclopirox) vs. 11% (vehicle) in the first trial and 36% (ciclopirox) vs. 9% (vehicle) in the second trial.¹²

Data from a meta-analysis of 10 trials conducted worldwide showed a mean (±SE) mycological cure rate of 52.6%±4.2% (range: 46.7%-85.7%).12 Although the parameters of these studies were different, these results were consistent with the US results. These studies and US pivotal trials establish the efficacy of ciclopirox nail lacquer for the treatment of onychomycosis.

Successful treatment of onychomycosis caused by nondermatophyte molds with ciclopirox nail lacquer has been reported.¹³ These results demonstrate the broad spectrum of activity of ciclopirox nail lacquer in vivo.

Combination Therapy

Ciclopirox has demonstrated synergy in vitro when combined with oral agents. Synergy between ciclopirox and terbinafine was demonstrated in vitro4 against 5 of 6 nondermatophyte species tested. Synergy, additivism, and indifference were observed between ciclopirox and itraconazole.⁴ No antagonism was observed for either combination.

Mycological cure rates in patients receiving 8 weeks of terbinafine (250mg/day) plus ciclopirox nail lacquer (once daily for 48 weeks) compared with patients receiving 12 weeks of terbinafine monotherapy (250mg/day) suggest that combination therapy of ciclopirox nail lacquer with lower doses of terbinafine may be effective. At the end of 48 weeks, mycological cure was reported in 66.7% of patients treated for 8 weeks with terbinafine and ciclopirox, 70.4% of patients receiving 12 weeks terbinafine and ciclopirox, and 56.0% for those treated with 12 weeks of terbinafine alone (p>0.05).¹⁴

Candidates for Treatment

Patients not eligible for systemic treatment due to safety issues (i.e., the elderly and patients with hepatic dysfunction), those using multiple medications, or patients unwilling to use systemic treatment are candidates for topical antifungal therapy using ciclopirox nail lacquer.
In patients with onycholysis, the lacquer may penetrate to onycholytic regions that may not receive adequate drug from conventional oral therapy. In cases of dermatophytoma, a subungual mass of densely packed thick-walled fungal hyphae, a combined approach of oral/topical/mechanical therapies may increase efficacy rates. In lateral onychomycosis, the concentration of the oral antifungal agent is lower in the lateral portion of the nail plate, and combining it with ciclopirox nail lacquer may help improve efficacy by providing drug to this area of the nail.¹⁵

Patients may benefit from the use of ciclopirox nail lacquer applied twice weekly^7,11 as a means of preventing recurrence. However, the benefit of prophylactic treatment needs to be confirmed in controlled trials.

Cost

Pharmaco-economic analysis¹⁶ suggests that ciclopirox nail lacquer may be a cost-effective option for the management of dermatophyte onychomycosis.
The wholesale price of the lacquer in Canada is $89.95/6g bottle, which offers more than 1,000 applications.¹⁷

Conclusion

Ciclopirox nail lacquer is the only approved topical agent for the treatment of mild-to-moderate onychomycosis. The choice of antifungal therapy depends on several factors: efficacy, spectrum of activity, convenience, cost, and patient/physician preference. Combination therapy using ciclopirox nail lacquer and terbinafine may be a consideration in moderate-to-severe cases of onychomycosis.

References

1. Gupta AK, Jain HC, Lynde CW, Macdonald P,Cooper EA, Summerbell RC. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol 43(2 Pt 1):244-8 (2000 Aug).
2. Gupta AK, Konnikov N, Macdonald P, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol 139(4):665-71 (1998 Oct).
3. Seebacher C. Action mechanisms of modern antifungal agents and resulting problems in the management of onychomycosis. Mycoses 46(11- 12):506-10 (2003 Dec).
4. Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol 149(2):296-305 (2003 Aug).
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7. Baran R, De Doncker P. Lateral edge nail involvement indicates poor prognosis for treating onychomycosis with the new systemic antifungals. Acta Derm Venereol 76(1):82-3 (1996 Jan).
8. Gupta AK, Daniel CR. Onychomycosis: strategies to reduce failure and recurrence. Cutis 62(4):189- 91 (1998 Oct).
9. Gupta AK, Lynch LE. Onychomycosis: review of recurrence rates, poor prognostic factors, and strategies to prevent disease recurrence. Cutis 74(1 Suppl):10-5 (2004 Jul).
10. Gupta AK, Ryder JE, Baran R. The use of topical therapies to treat onychomycosis. Dermatol Clin 21(3):481-9 (2003 Jul).
11. Gupta AK. Ciclopirox nail lacquer: a brush with onychomycosis. Cutis 68(2 Suppl):13-6 (2001 Aug).
12. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol 43(4 Suppl):S70-80 (2000 Oct).
13. Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 42(2 Pt 1):217-24 (2000 Feb).
14. Gupta AK, and the Onychomycosis Combination Therapy Study Group. Ciclopirox topical solution, 8% combined with oral terbinafine to treat onychomycosis: a randomized, evalutor-blinded study. J Drugs Dermatol 4(4):481-5 (2005 Aug).
15. Gupta AK, Baran R. Ciclopirox nail lacquer solution 8% in the 21st century. J Am Acad Dermatol 43(4 Suppl):S96-102 (2000 Oct).
16. Gupta AK. Pharmacoeconomic analysis of ciclopirox nail lacquer solution 8% and the new oral antifungal agents used to treat dermatophyte toe onychomycosis in the United States. J Am Acad Dermatol 43(4 Suppl):S81-95 (2000 Oct).
17. PPS Pharma Buyers Guide. Moncton, NB: Total Pricing Systems Inc. P.174 (2005 July).

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