Ciclopirox treats onychomycosis

April 2002

Onychomycosis is a superficial fungal infection of the nail. It has been suggested that 50% of the population may be affected by the age of 70. The treatment of onychomycosis is challenging and may be complicated by relapse or reinfection. Selecting appropriate pharmacologic treatment for onychomycosis involves several factors, including the efficacy of the agent, potential side effects, drug interactions, cost and the patient’s preference for a formulation. Ciclopirox 8% nail lacquer solution (Penlac, Aventis Pharmaceuticals) is the first topical therapy approved by the FDA for the treatment of dermatophyte onychomycosis. It offers an innovative approach to the treatment of onychomycosis.

Spectrum of activity

Ciclopirox olamine is a synthetic hydroxypryridone anti-mycotic. It is structurally and mechanistically unrelated to other antifungal agents. Its broad spectrum of activity includes yeasts, dermatophytes and mold strains. In addition, it demonstrates activity against gram-positive and gram-negative bacteria, including Staphylococcus aureus resistant to methicillin, ofloxacin and vancomycin, and it exhibits fungicidal activity in vivo against Trichophyton mentagrophytes, T. rubrum and Epidermophyton floccosum.

Mechanism of action

---Onychomycosis due to Trychophyton rubrum.
Source: CDC/Dr. Edwin P. Ewing Jr.

Ciclopirox has a novel mechanism of action targeting multiple fungal cell processes. The major pathway involves the chelation of polyvalent cations such as Fe³⁺. Inhibition of these cations results in inhibition of metal-dependent enzymes and impairment of energy production in the fungal cell. Ciclopirox has also been shown to affect the degradation of toxic peroxides in the fungal cell, decrease uptake of nutrients into the cell and disrupt the fungal cell membrane. It is believed that the multifaceted mechanism of action of ciclopirox may help slow the development of resistance. However, studies evaluating the development of fungal resistance with ciclopirox have not been conducted. The effect of ciclopirox treatment on cross-resistance of oral antifungal therapy is unknown.

After topical application to the affected nail, solvents in the lacquer evaporate, leaving a high concentration of ciclopirox in the remaining film. As a result of the high concentration, ciclopirox is able to penetrate through the nail plate to the site of fungal infection. Substantial penetration of the nail plate has been demonstrated after one application of ciclopirox. However, fungicidal concentrations are not achieved throughout the nail until seven to 14 days of topical application. Mean absorption of the topical dose over six months is <5%. In human studies, serum and urine levels were below the level of detection one month after treatment cessation.

Efficacy

The safety and efficacy of ciclopirox were evaluated in two unpublished double-blind, placebo-controlled studies. Patients with onychomycosis of the great toenail without lunula involvement were enrolled in these trials. Patients were treated with ciclopirox 8% topical solution daily for 48 weeks. Intention-to-treat analysis showed a statistical difference in both studies for the endpoint “almost clear” (defined as 10% nail involvement or less and negative mycology). In the first study, at 48 weeks, this endpoint was achieved in seven of 107 (6.5%) and one of 108 (0.9%) of the ciclopirox and placebo groups, respectively. In the second study, this endpoint was reached by 14 of 116 (12%) and one of 115 (0.9%) in the ciclopirox and placebo groups, respectively.

Complete cure (defined as clear nail and negative mycology) was achieved by six of 110 (5.5%) in the ciclopirox group, one of 109 (0.9%) in the placebo group in the first study and 10 of 118 (8.5%) in the ciclopirox group and zero of 117 (0%) in the placebo group in the second study. Results for this endpoint in the second study were statistically significant. At 48 weeks, six of 112 (5%) patients in the first study and 10 of 119 (8%) in the second study were completely cured.

The safety and efficacy of ciclopirox was evaluated in a multicenter, open-label uncontrolled, observational study in 3,666 patients. Patients with onychomycosis were treated with ciclopirox 8% nail lacquer daily for six months. The primary outcome measure was the decrease from baseline of the affected area of the nail. Results of a subset of 215 patients with diabetes showed that ciclopirox reduced mean nail area involvement from 64.3% at baseline to 41.2% at three months and to 25.7% at six months.

Safety

Adverse events in the clinical trials conducted by the manufacturer were generally similar to the placebo group.

Skin reactions including rash, periungual erythema and erythema of the proximal nail fold were more common in the ciclopirox group than in the placebo group. Application site reactions, nail shape changes and nail discoloration were also more frequent in the ciclopirox group. Although ciclopirox has been rated pregnancy category B, no long-term controlled clinical trials have evaluated its use in pregnant women. It is not known whether ciclopirox is excreted in breast milk. The safety and efficacy of ciclopirox has not been evaluated in pediatric populations.

Dosage and administration

Ciclopirox topical solution should be applied evenly to clean dry nails and 5 mm of the surrounding skin with the applicator brush daily at bedtime. Contact with surrounding skin other than that immediately adjacent to the affected nail may result in transient burning, redness and irritation and should be avoided. If possible, the solution should be applied to the nail bed, hyponychium (point where nail plate separates from the nail bed) and under surface of the nail plate. The solution should dry for at least 30 seconds after application. It is recommended by the manufacturer to wait eight hours after application before bathing or showering. Once a week, previous applications of the lacquer should be removed from the nail using rubbing alcohol. At that time, any loose nail or skin may be filed or trimmed before new application of the lacquer.

The assistance of a health care professional may be necessary for monthly removal of the unattached infected nail. Therapy may be continued for up to 48 weeks. To maintain its antifungal activity, ciclopirox should be protected from light and stored in a cool dry place.

Indication

Ciclopirox is indicated for the treatment of mild to moderate onychomycosis in immunocompetent patients with onychomycosis caused by T. rubrum of the fingernails and toenails without lunula involvement. Safety and efficacy have not been evaluated beyond 48 weeks, and efficacy in severe onychomycotic infections has not been evaluated. Therefore, if onychomycosis is treated, systemic antifungal agents should remain first-line therapy. Clinical trials have not included a significant number of immunocompromised or geriatric patients; therefore, efficacy in these populations is unknown. The effects of ciclopirox on systemic antifungal therapy for the treatment of onychomycosis have not been studied, and it is not known whether ciclopirox may reduce the effectiveness of these agents. Therefore, the manufacturer does not recommend the concomitant administration of these agents.

Summary

Ciclopirox is the first topical therapy approved for the treatment of onychomycosis. It offers a unique therapeutic option for the treatment of mild to moderate nail fungal infections. Advantages over conventional treatments include lack of drug interactions and monitoring requirements, an improved safety profile and the lowest cost. Future clinical studies are needed to compare the efficacy of topical ciclopirox with systemic oral agents, to evaluate the utility of combination therapy and to determine effects on fungal resistance.

For more information:

• Baran R. Ciclopirox nail lacquer: The first prescription topical therapy for onychomycosis –Introduction. J Am Acad Dermat. 2000;43:S55-S56.
• Bohn M, Kraemer K. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Derm. 2000;43:S57-S69.
• Gupta AK, Baran R. Ciclopirox nail lacquer solution 8% in the 21st century. J Am Acad Derm. 2000;43:S96-S102.
• Product information: Penlac, Aventis, Frankfurt am Mein, Germany, 2000.
• Data on file, Aventis 2000.
• Seebacher C, Nietsch KH, Ulbricht HM. A multicenter, open-label study of the efficacy and safety of ciclopirox nail lacquer solution 8% for the treatment of onychomycosis in patients with diabetes. Cutis. 2001;68(2 Suppl):17-22.