Once-Weekly Fluconazole (150, 300, Or 450 Mg) in the Treatment of Distal Subungual Onychomycosis of the Toenail

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 dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, 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 different 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 confirmed 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 success 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 fluconazole groups were significantly superior to placebo (p = 0.0001); there were no significant 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 distal 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; psy- the proximal onychomycotic border, and signs/symp- chiatric or psychological dysfunction that would pre- toms of onychomycosis. The percentage of nail involve- clude compliance with the study protocol; or alcohol or ment was rated on a scale of 0 to 5 (0 = 0%; 1 = 1% to illegal substance abuse. In addition, patients who 24%; 2 = 25% to 49%; 3 = 50% to 74%; 4 = 75% to required treatment with any of the following medica- 99%; and 5 = 100%); the onychomycotic border was tions were not allowed to participate: Cimetidine, determined from the distance between the nail fold and hydrochlorothiazide, rifampin, warfarin, phenytoin, a transverse notch cut on the healthy part of the nail cyclosporine, terfenadine, astemizole, or loratadine. immediately proximal to the infection at baseline. This Patients who planned to donate blood, those who were notch was used to measure the distance from the nail not willing to forgo repeated pedicures or cosmetic toe- fold to the proximal onychomycotic border at subse- nail treatments, those who were judged by the investi- quent evaluations unless the infection advanced proxi- gator to be uncooperative or noncompliant, and those mally, in which case the nail was renotched at the new unwilling or unable to give informed consent were onychomycotic border. Clinical signs and symptoms of excluded. onychomycosis, hyperkeratosis, and discoloration were rated by the investigator as either absent or present. Treatment procedures Mycologic evaluations of the target nail were per- The study included four phases: Screening, baseline formed at screening, during treatment at months 3 assessment, double-blind therapy, and blinded post- through 12, and during follow-up at 2, 4, and 6 months treatment follow-up (Fig. 1). At screening, the most after the end of treatment. Subungual debris and nail severely involved large toenail, which was at least 25% specimens from the target nail were examined for fungal affected by onychomycosis and had at least a 2 mm hyphae (KOH direct microscopy) and submitted for a proximal border of healthy nail, was designated as the fungal culture at a central laboratory (The Fungus target toenail. Specimens for mycologic evaluation Testing Laboratory, The University of Texas Health were taken from this nail, and a global visual evaluation Science Center, San Antonio, TX). Culture plates were of all toenails was performed. Patients who met all held for 3 weeks before they were deemed to be negative. inclusion and exclusion criteria (including positive Clinical response. The investigators compared clin- KOH and culture for dermatophytes) returned for their ical response at the end of therapy with baseline status baseline visit, at which time safety and efficacy assess- and categorized the response as follows: (1) Cure – the ments were performed and study drug was dispensed. target toenail was clinically normal, and healthy nail During double-blind therapy, monthly visits were regrowth was complete; (2) improvement – there was scheduled for evaluating safety and efficacy and for dis- evidence of clinical improvement in the target toenail pensing the study drug; safety assessments were also with more healthy nail plate present than observed at performed at weeks 2 and 6. The double-blind treat- baseline, but healthy nail regrowth was incomplete; (3) ment phase of the study was considered to be complete failure – the target toenail showed no clinical improve- when either the target toenail was clinically normal and ment or required two successive new notches during the pathogen eradicated for two consecutive monthly months 3 through 12 of treatment. The clinical response visits or the full 12 months of therapy had been admin- during the follow-up period (months 2, 4, and 6 after istered, whichever occurred first. Therapy could also be the end of treatment) was compared with the status at Journal of the American Academy of Dermatology S80 Scher et al. June 1998

Fig. 2. Clinical response: Possible treatment outcomes.

Adverse events the end of therapy but could be categorized only as cure At each visit, adverse events observed by the inves- or failure (Fig. 2). tigator or volunteered by the patient were recorded. Mycologic response. Mycologic response at the end Adverse events were recorded as to onset, duration, of therapy and at follow-up visits was categorized as severity (mild, moderate, or severe), causality (study follows: (1) Eradication – KOH wet mount and fungal drug, concomitant treatment, onychomycosis, other ill- culture results were both negative for dermatophytes; ness, or other), action taken (no action, change in and (2) persistence – KOH wet mount or fungal culture dosage, medical treatment, or other), and status (cleared results were positive for dermatophytes. or ongoing). Any abnormal laboratory result that result- Clinical success. After all clinical responses were ed in an interruption or permanent discontinuation of gathered from the investigators, the sponsor recatego- drug therapy was also recorded as an adverse event. rized the responses to determine “clinical success” Blood and urine specimens were obtained for laborato- based on the percentage of target nail involvement. ry testing (hematology, blood chemistry, and urinalysis) Clinical success was defined as a target nail involve- at screening, baseline, weeks 2 and 6 and months 1 ment of 0% (clear nail) or 1% to 24% (minimally through 12 during therapy, and at the 2-month follow- involved nail), and was determined for the end of ther- up visit. In addition, a serum pregnancy test was per- apy and the 6-month follow-up visit. formed for women of childbearing potential (except at Posttherapy cure and clinical relapse. Two addi- weeks 2, 6, and follow-up). Other safety evaluations tional evaluations were calculated by the sponsor to included vital signs, body weight, and recording of the summarize changes during the follow-up period. use of concomitant medications. Posttherapy cure was defined as clinical improvement at the end of therapy with subsequent clinical cure at the Statistical analysis 6-month follow-up visit. Clinical relapse was defined as the patients who were cured (0% target nail affected) at Overall difference among treatment groups in clini- the end of therapy but were categorized as clinical fail- cal response was determined by means of the Mantel- ures at the 6-month follow-up visit. Haenszel statistic with three degrees of freedom; pair- Global clinical response. A global nail evaluation wise comparisons were made by means of the same sta- was performed at screening, baseline, end of therapy, tistic. The percentage of clinical successes, mycologic and during follow-up by a visual inspection of all toe- response, and clinical response at the 6-month follow- nails for the absence (healthy nail) or presence (affect- up visit were compared among treatment groups by ed nail) of onychomycosis. No other clinical or myco- means of the Pearson chi-square statistic; pairwise com- logic assessments were performed on the nontarget parisons were made by means of Fisher exact test. The nails. time (months) on therapy to clinical success and to Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Scher et al. S81

Table I. Patient evaluation subgroups

Fluconazole

150 mg 300 mg 450 mg Placebo Total

Received treatment 89 88 92 92 361 End of therapy ITT 88 86 89 92 355 Evaluable 79 75 80 79 313 Follow-up ITT 77 75 81 83 316 Evaluable 73 72 77 78 300 Analyzed for safety 89 88 92 92 361 ITT, Intent to treat.

mycologic eradication was compared among treatment with a minimum duration of less than 1 year and a groups by means of the log-rank test; pairwise compar- maximum of 50 years. Most patients (overall: isons were made with the same statistic. The change in 69%; fluconazole: 66%; and placebo: 78%) had at the percentage of target nail affected and the rate of least 50% target nail involvement with onychomy- change in the distance to the onychomycotic border cosis. The infecting dermatophyte was T. rubrum among treatment groups were compared by means of a in all patients except for 20 in whom T. tonsurans one-way ANCOVA; pairwise comparisons of adjusted (10 patients), T. mentagrophytes (nine patients), treatment means were made by means of the two-sided t-statistic. Statistical significance was declared at the and E. floccosum (one patient) were the causative p ≤ 0.05 level. pathogens. Twenty-five patients had mixed infections, with both dermatophyte and nondermato- RESULTS phyte fungal organisms isolated from baseline cul- Study patients tures. The mean duration of therapy for safety- A total of 362 patients were randomized to the evaluable patients ranged from 9.5 to 10.2 months four treatment groups (150, 300, or 450 mg flu- in the fluconazole groups and was 7.3 months in conazole or placebo), of whom 361 received at the placebo group. least one dose of study medication and were included in the safety analysis (Table I). Of the 362 Clinical efficacy randomized patients, 313 were evaluable for effica- Fluconazole was superior to placebo in all clin- cy at the end of therapy. Two patients were exclud- ical efficacy evaluations (Table II). At the end of ed because their target nails were less than 25% therapy and 6-month follow-up evaluations, clini- involved at baseline; the other 47 excluded patients cal success rates were significantly higher (p = discontinued therapy prematurely for reasons not 0.0001) in all three fluconazole groups (150, 300, related to efficacy such as loss from follow-up, and 450 mg) compared with placebo (Table II). adverse events, withdrawal of consent, and proto- The clinical success rates (defined as cure or col violations. At the end of the 6-month follow-up, improvement sufficient to reduce the involved area 300 patients were evaluable for efficacy. of the target nail to less than 25%) at the end of Demographic characteristics and baseline dis- therapy were very high in all fluconazole groups: ease severity were not significantly different 86% at 150 mg, 87% at 300 mg, and 89% at 450 among the treatment groups (p ≥ 0.666). Most mg. By contrast, only 8% of the placebo group patients enrolled were white (91%), and most were were clinical successes. The differences in clinical men (73%). The mean age of patients was 48.5 success between the three fluconazole dose groups years for those receiving placebo and 47.8 years were not statistically significant. for those receiving fluconazole. The mean dura- At the end of therapy, a complete clinical cure tion of the dermatophyte infection in the combined was achieved in 31% of fluconazole-treated study population was between 11 and 12 years, patients compared with only 3% of placebo-treat- Journal of the American Academy of Dermatology S82 Scher et al. June 1998

Table II. Summary of efficacy results

Fluconazole

150 mg 300 mg 450 mg Placebo

End of therapy Clinical success* 86% (68/79) 87% (65/75) 89% (71/80) 8% (6/79) Clinical cure† 28% (22/79) 29% (22/75) 36% (29/80) 3% (2/79) Mycologic eradication 47% (37/79) 59% (44/75) 62% (49/79) 14% (11/78) 6-month follow-up Clinical success* 77% (56/73) 79% (57/72) 86% (66/77) 9% (7/78) Clinical cure† 37% (27/73) 46% (33/72) 48% (37/77) 3% (2/78) Mycologic eradication 53% (38/72) 59% (42/71) 61% (47/77) 16% (12/77) Clinical relapse‡ 0% (0/20) 5% (1/21) 7% (2/27) 0% Posttherapy cure§ 13% (7/53) 25% (13/51) 24% (12/50) 0% *Clinical success was defined as clinical cure or improvement sufficient to reduce the affected area of the target nail to < 25%. †Clinical cure was defined as a clinically normal target nail with complete regrowth of healthy tissue. ‡Clinical relapse refers to patients who were clinically cured at end of therapy but not at the 6-month follow-up visit. §Posttherapy cure refers to patients who were clinically improved relative to baseline but not cured at end of therapy, and who then were clinically cured at the 6-month follow-up visit.

ed patients (Table II): 28% in the 150 mg flucona- improved patients at the end of therapy who were zole group; 29% in the 300 mg group; and 36% in clinically cured at the 6-month follow-up visit), the 450 mg group (p = 0.0001 vs. placebo for each the clinical cure rate in each fluconazole dosage group). Only 7% of fluconazole-treated patients group increased at the 6-month follow-up, to 37% failed to improve (6% at 150 mg, 11% at 300 mg, at 150 mg, 46% at 300 mg, and 48% at 450 mg. and 4% at 450 mg) compared with 78% of place- Only 3 of 68 (4%) patients in the combined flu- bo-treated patients. conazole treatment groups experienced a clinical Over the 12-month treatment period, a consis- relapse, i.e., as failure at 6 months posttherapy in tent improvement in the percentage of target nail patients who had been clinically cured at the end involvement occurred for all of the fluconazole of therapy. treatment groups compared with a minimal change For those patients who were classified as clini- over time with placebo. All treatment groups aver- cal successes at the end of therapy or at the end of aged approximately 50% to 74% involvement at the follow-up period, the time to success was baseline. The rating for the placebo group was defined as the months from the start of treatment only slightly less at the end of therapy, whereas the until either the first of two consecutive visits with three fluconazole groups had significant reduction less than 25% involvement, or the achievement of of involvement at the end of therapy. A statistical- clinical success at the end of therapy or the end of ly significant reduction (p ≤ 0.05 vs. placebo) in follow-up. The mean time to clinical success for the percentage of target nail affected was first the fluconazole treatment groups was 6.6 months observed after 3 months of treatment in each of the at 150 mg, 6.2 months at 300 mg, and 6.7 months fluconazole dosage groups, and the reduction in at 450 mg. the percentage of target nail involvement became progressively greater over subsequent months. Mycologic efficacy Fluconazole treatment remained significantly As with clinical success, mycologic response superior at the end of the 6-month posttherapy fol- rates, at both the end of therapy and 6-month follow-up (Table II). The high rates of clinical suc- low-up, were significantly higher (p = 0.0001) in cess achieved at the end of therapy in patients all three fluconazole dosage groups (150, 300, and treated with fluconazole were largely maintained 450 mg per week) compared with placebo (Table at the 6-month posttreatment assessment: 77% at II). Although the eradication rates among the flu- 150 mg, 79% at 300 mg, and 86% at 450 mg. As a conazole treatment groups were not significantly result of posttherapy cures (defined as clinically different, the percentage of patients with an eradi- Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Scher et al. S83

Table III. Summary of adverse events

Fluconazole

150 mg 300 mg 450 mg Placebo

Patients evaluable 89 88 92 92 Patients experiencing an AE 74 (83%) 74 (84%) 79 (86%) 72 (78%) Patients experiencing a serious AE 2 (2%) 4 (5%) 7 (8%)* 2 (2%) Patients discontinuing because of AE 3 (3%) 7 (8%) 4 (4%) 5 (5%) Patients discontinuing because of laboratory abnormality 1 (1%) 2 (2%) 1 (1%) 1 (1%) Most common treatment-related AEs† Headache 7 (8%) 4 (5%) 5 (5%) 2 (2%) Abdominal pain 3 (3%) 2 (2%) 5 (5%) 3 (3%) Respiratory disorder 4 (4%) 3 (3%) 4 (4%) 3 (3%) Diarrhea 2 (2%) 3 (3%) 2 (2%) 2 (2%) Rash 4 (4%) 3 (3%) 1 (1%) 2 (2%) Nausea 2 (2%) 3 (3%) 1 (1%) 3 (3%) AE, Adverse event. *Includes one death during treatment phase. †Most common events are those with incidence ≥ 3% in any treatment group; “treatment-related” includes unknown causality.

cation response tended to increase with increasing headache (6% among fluconazole-treated patients dose. The effect of the 450 mg dose compared with vs. 2% among placebo-treated patients), abdomi- that of the 150 mg dose approached, but did not nal pain (4% vs. 3%), respiratory disorders (4% vs. achieve, statistical significance (p = 0.079). 3%), diarrhea (3% vs. 2%), rash (3% vs. 2%), and For those patients whose dermatophyte had nausea (2% vs. 3%). been mycologically eradicated at the end of thera- Most of the adverse events were mild or moder- py or the end of the 6-month follow-up, the time to ate in severity. As shown in Table III, the percent- eradication was defined as the months from the age of patients in whom study medication was per- start of treatment until either the first of two con- manently discontinued because of an adverse secutive visits with negative mycologic evaluation event or laboratory abnormality was the same for (both KOH wet mount and fungal culture for der- the active fluconazole treatment groups combined matophytes), or the negative mycologic evaluation (18 of 269, 6.7%) and the placebo group (6 of 92, at the end of therapy or end of follow-up. The 6.5%). One patient, a 53-year-old male who mean time to mycologic eradication for three flu- received fluconazole 450 mg/week for 8 months, conazole treatment groups was 10.1 months at 150 died during the treatment phase of the study. The mg, 8.8 months at 300 mg, and 9.6 months at 450 death was attributed to AIDS-related pneumonia mg. and was not considered to be related to the study drug. Safety For laboratory test values, the median changes Adverse events of all causalities occurred in were generally similar among treatment groups 84% of fluconazole-treated and 78% of placebo- and not clinically meaningful. Five patients (four treated patients (Table III). Forty-three percent of receiving fluconazole and one in the placebo all fluconazole-treated patients reported a poten- group) were withdrawn from the study because of tially treatment-related adverse event as compared liver function test abnormalities (elevated SGOT with 29% in the placebo group; this difference was or SGPT). In two of the fluconazole-treated not significant. The incidence of treatment-related patients (one at 150 mg, one at 300 mg) and the adverse events was the same for the 300 and 450 one placebo-treated patient, the abnormality was mg treatment groups (42%) and very similar considered to be related to the study drug. No clin- (44%) for the 150 mg group. The most common ical symptoms associated with the abnormal lab- treatment-related adverse events (Table III) were oratory tests were reported. In four patients, the Journal of the American Academy of Dermatology S84 Scher et al. June 1998 liver enzymes returned to normal after study drug bed epithelium and incorporate into the nail plate; was discontinued. In the fifth patient, SGPT and the ability to achieve high clinical and mycologic SGOT levels were already high before fluconazole cure rates, together with a low relapse rate; a low (300 mg/week) was started and remained elevated incidence of adverse effects; few drug interactions; during treatment and after study drug was stopped; and low cost.12,13 An intermittent dosing regimen however, the investigator did not consider this out- using once-weekly therapy was also perceived come to be related to the study drug. favorably by patients in this study. With these criteria in mind, the potential advantages and disad- DISCUSSION vantages of each drug must be considered when Recurrence of symptoms after discontinuing selecting therapy. treatment has been a universal problem in the Fluconazole has a chemical structure distinct treatment of patients with fungal nail infections. In from other oral antifungal drugs and unique phar- this study, however, clinical success rates were macologic properties and pharmacokinetics.29 It largely maintained after fluconazole therapy was has a broad spectrum of antifungal activity against discontinued. The clinical relapse rate among dermatophytes, Candida species, and some non- cured patients over 6 months of follow-up was dermatophyte moulds identified as causal patho- very low (4%). Indeed, clinical cure rates contin- gens in onychomycosis. In contrast to ketocona- ued to increase during the follow-up period after zole and itraconazole, oral absorption of flucona- therapy discontinuation. Continued effectiveness zole is independent of food or gastric pH, and it of fluconazole during follow-up was also evident has high oral bioavailability (> 90%).30 As a result on the basis of eradication rates 6 months after flu- of its low lipophilicity and low affinity for plasma conazole was stopped that were comparable to proteins, fluconazole is widely distributed and those at the end of therapy. penetrates well into body tissues, including skin Until recently, only three treatment options and nails.30-32 In a study in which fluconazole 50 were available for the management of onychomy- mg/day was administered to nine men for 14 days, cosis: Topical antifungal therapy, nail removal, or measurement of plasma and nail concentrations prolonged oral therapy with either griseofulvin or revealed rapid diffusion of drug into nails after the ketoconazole. All these approaches were associat- first dose.31 Plasma concentrations of fluconazole ed with significant drawbacks, the most important increased over the 14-day study period from 0.76 of which was the inability of these therapies to to 2.21 µg/ml, and nail concentrations increased provide sustained clinical or mycologic cure. The from 1.31 to 1.8 µg/ml. advent of newer and more effective oral antifungal In the present study, fluconazole, administered drugs, such as fluconazole,23 itraconazole,24-26 in doses of 150, 300, or 450 mg once weekly for and terbinafine,27,28 has marked a turning point in up to 12 months, was highly successful in curing the management of onychomycosis, and has or improving the clinical signs of onychomycosis offered patients hope for treating this formerly of the toenail and in eradicating the infecting der- recalcitrant infection. With the availability of these matophyte. Among patients who achieved clinical newer agents, clinicians are faced with challenging success, the mean time to clinical success in the decisions regarding the best antifungal therapy for fluconazole treatment groups was approximately 6 individual patients. There are currently no pub- to 7 months, with significant clinical success noted lished studies comparing fluconazole with any as early as 3 months after starting therapy. other antimycotic agent in the treatment of ony- Clinicians may want to use this timeframe as a chomycosis. However, the results obtained in this guideline for fluconazole treatment duration, keep- study of fluconazole compare favorably with the ing in mind that therapeutic levels persist several results obtained in studies of other antimycotic months thereafter. In addition, significant differ- agents. ences in eradication rates between fluconazole and The ideal characteristics of an oral antifungal placebo were seen as early as the 6-month visit. medication used to treat patients with nail infec- These early clinical and mycologic response rates tions include the following: A spectrum of activity are similar to those reported previously in small that includes all possible mould and yeast open-label fluconazole studies.19-22,33 The fact pathogens; the capacity to diffuse through the nail that clinical/mycologic improvement is made early Journal of the American Academy of Dermatology Volume 38, Number 6, Part 2 Scher et al. S85 in therapy assures both clinicians and patients that 7. Hay RJ. Onychomycosis. Agents of choice. Dermatol the therapy is effective. This has clear advantages Clin 1993;11:161-9. 8. Barranco V. New approaches to the diagnosis and man- in situations where treatment is initiated before agement of onychomycosis. Int J Dermatol 1994;33:292- mycologic verification of infection. In these cir- 9. cumstances, patients whose dystrophic nails are 9. Davies RR, Everall JD, Hamilton E. Mycological and clinical evaluation of griseofulvin for chronic ony- not fungal may avoid a full course of therapy. chomycosis. Br Med J 1967;3:464-8. Over the course of the 12-month treatment peri- 10. Hay RJ, Clayton YM, Griffiths WAD, Dowd PM. A com- od, very few adverse effects resulted in discontin- parative double blind study of ketoconazole and griseofulvin in dermatophytosis. Br J Dermatol 1985;112:691- uation of therapy. In addition, the frequency and 6. severity of adverse effects were similar in the flu- 11. Korting HC, Schäfer-Korting M. Is tinea unguium still conazole and placebo treatment groups, even widely incurable? Arch Dermatol 1992;128:243-8. 12. Odom RB. New therapies for onychomycosis. J Am though the mean duration of therapy with flucona- Acad Dermatol 1996;35:S26-30. zole was 2 months longer than with placebo. 13. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an Unlike ketoconazole, the newer antifungal agents overview. Part II. J Am Acad Dermatol 1994;30:911-33. 34 14. Wildfeuer A, Seidl HP. Comparison of the in vitro activ- are rarely associated with hepatic injury. ity of fluconazole against Candida albicans and der- Because of their greater specificity for fungal matophytes. Arzneimittelforschung Drug Res cytochrome P-450 enzymes, clinically significant 1995;45:819-21. 15. Fischbein A, Haneke E, Lacner K, Male O, Mohn R, drug interactions also occur less frequently with Muller H, et al. Comparative evaluation of oral flucona- the newer azole compounds, fluconazole and itra- zole and oral ketoconazole in the treatment of fungal conazole, as compared with ketoconazole.13 infections of the skin. Int J Dermatol 1992;31(suppl 2):12-6. 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