SUPPORTED BY AN EDUCATIONAL GRANT FROM U.S. PHARMACEUTICALS, PFIZER INC. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail Richard K. Scher, MD, Debra Breneman, MD, Phoebe Rich, MD, Ronald C. Savin, MD, David Stuart Feingold, MD, Nellie Konnikov, MD, Jerome L. Shupack, MD, Sheldon Pinnell, MD, Norman Levine, MD, Nicholas J. Lowe, MD, Raza Aly, PhD, Richard B. Odom, MD, Donald L. Greer, PhD, Manuel R. Morman, PhD, MD, Alicia D. Bucko, DO, Eduardo H. Tschen, MD, Boni E. Elewski, MD, and Edgar B. Smith, MD New York, New York; Cincinnati and Cleveland, Ohio; Portland, Oregon; New Haven, Connecticut; Boston, Massachusetts; Durham, North Carolina; Tucson, Arizona; Santa Monica and San Francisco, California; New Orleans, Louisiana; Rutherford, New Jersey; Albuquerque, New Mexico; and Galveston, Texas Background: Onychomycosis is a prevalent infection of the nail caused primarily by der- matophytes. Fluconazole is active in vitro against the most common pathogens of ony- chomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. Objective: The purpose of this study was to compare the efficacy and safety of three differ- ent doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Methods: In this multicenter, double-blind study, 362 patients with mycologically con- firmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical suc- cess of the target nail was defined as reduction of the affected area to less than 25% or cure. Results: At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole- treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the flu- conazole groups were significantly superior to placebo (p = 0.0001); there were no signifi- cant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. Conclusion: The results of this study support the use of fluconazole in the treatment of dis- tal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated. (J Am Acad Dermatol 1998;38:S77-86.) From the Department of Dermatology, Columbia-Presbyterian Onychomycosis, a common and persistent fun- Medical Center, New York. Reprint requests: Richard K. Scher, MD, Clinical Research/ gal infection of the fingernails and toenails, can be Department of Dermatology, Columbia-Presbyterian Medical quite distressing to the patient.1-4 In more than 90% Center, 161 Fort Washington Ave., Room 750, New York, NY of cases, the causative pathogen is a dermatophyte, 10032. Copyright © 1998 by the American Academy of Dermatology, Inc. most commonly Trichophyton rubrum but also T. 0190-9622/98/$5.00 + 0 16/0/90457 mentagrophytes, T. tonsurans, and Epidermophyton S77 Journal of the American Academy of Dermatology S78 Scher et al. June 1998 Fig. 1. Study design. floccosum5-7; less common pathogens are yeasts pare the efficacy and safety of oral fluconazole, and nondermatophyte moulds.4,6,8 Fungal infec- administered for up to 12 months in doses of 150, tions of the nail are very difficult to treat, sponta- 300, or 450 mg once weekly, to that of placebo in neous remission is rare, and recurrence after treat- the treatment of onychomycosis of the toenail ment with traditional therapy has been common.3 caused by dermatophytes.18,19 The once-weekly Griseofulvin has a long history of use; however, dosage regimen was based on the documented its limited spectrum of activity, low clinical and rapid diffusion of fluconazole into skin and nail, mycologic cure rates,9,10 high relapse rates, and with persistence of high concentrations.18,19 prolonged duration of therapy have restricted its clinical usefulness in the management of ony- PATIENTS AND METHODS chomycosis.3,11-13 Ketoconazole produced higher Study design clinical cure rates than griseofulvin,10 but pro- This study followed a randomized, double-blind, longed therapy (12 to 18 months) was still required fixed-dose, parallel-group, placebo-controlled multi- to clear toenails; the associated relapse rate was center design (Fig. 1). The study protocol was approved still high; and the risk of therapy-limiting adverse by the institutional review boards at the participating effects, especially hepatotoxicity, and drug inter- treatment facilities. Patients were randomly assigned to actions was greater. Because of these disadvan- one of the following four treatment regimens: 150 mg tages with griseofulvin and ketoconazole therapy, fluconazole (one 150 mg tablet plus two matching the usefulness of oral antimycotic treatment with placebo tablets); 300 mg fluconazole (two 150 mg fungal infection of the toenail was in question.8,11 tablets plus one matching placebo tablet); 450 mg flu- Fluconazole is a broad-spectrum antifungal conazole (three 150 mg tablets); or placebo (three agent with demonstrated in vitro activity against matching placebo tablets). Patients were instructed to take three tablets as a single dose on the same day each dermatophytes, including Trichophyton and oth- week. ers, as well as against Candida species.14 The in Patients were between 18 and 70 years of age and vivo activities against dermatophytes and Candida had the clinical diagnosis of distal subungual ony- have been confirmed by high efficacy rates in clin- chomycosis of one of the large toenails confirmed ical trials evaluating the use of fluconazole in mycologically by potassium hydroxide (KOH) wet 15,16 treating superficial mycotic skin infections. In mount and a positive culture for dermatophytes. The addition, successful outcomes with fluconazole in target toenail had to be at least 25% affected and have patients with onychomycosis have been recently at least 2 mm of healthy nail along the proximal nail described in case reports17,18 and open-label inves- fold. Excluded from the trial were pregnant or lactating tigations involving small numbers of patients.19-22 women and women who intended to become pregnant The purpose of this investigation was to com- during study treatment or within 3 months of discontin- Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Scher et al. S79 uing treatment. Also excluded were patients with terminated if, in the opinion of the investigator, the hypersensitivity to the azole class of compounds; patient was not responding adequately (clinically or patients with significant systemic disease that would mycologically) and further treatment was deemed to be affect compliance or interpretation of study results; and of no benefit. Patients who were clinically cured or those who had been treated with systemic or topical improved at the end of therapy entered a 6-month blind- prescription-strength corticosteroids or topical antifun- ed follow-up period and were assessed at 2, 4, and 6 gals within 2 weeks, systemic oral antifungal drugs months after treatment. Patients who were listed as within 3 months, or any investigational drug within 1 treatment failures at the end of therapy did not enter the month before enrolling in the study. Patients with any of follow-up period. the following were also excluded: Diabetes mellitus requiring treatment with medication (including sulfony- Method of assessment lureas and other oral hypoglycemic agents); immuno- Efficacy was assessed on the basis of clinical (visu- suppression; renal, hematologic, or hepatic dysfunc- al) and mycologic (microscopic and microbiologic) tion; fungal culture positive for the nondermatophytes evaluations during treatment (months 1 through 12) and Scopulariopsis, Hendersonula, or Scytalidium; suspect- during the follow-up period (months 2, 4, and 6 after ed chronic mucocutaneous candidiasis; psoriasis of the treatment). Clinical evaluations included the percentage skin or nail; lichen planus; nail or anatomic abnormali- of target nail involvement, distance from the nail fold to ties of the toe resulting in an abnormal appearance;