Efficacy and safety of topical terbinafine 10% solution (MOB-015) in the treatment of mild to moderate distal subungual onychomycosis: A randomized, multicenter, double-blind, vehicle-controlled phase 3 study.

BACKGROUND: Onychomycosis is a recalcitrant fungal nail infection. Topical antifungal agents may be preferred over systemic agents due to lack of systemic adverse effects. OBJECTIVE: To investigate the efficacy and safety of topical terbinafine 10% solution (MOB-015) for the treatment of distal and lateral subungual onychomycosis. METHODS: In a multicenter, double-blind, phase III, North American study, patients with mild to moderate distal and lateral subungual onychomycosis involving 20% to 60% of at least 1 great toenail were randomized to once daily application of MOB-015 or matching vehicle for 48 weeks. The primary efficacy variable was complete cure, while the secondary efficacy variables were mycological cure and treatment success. Safety evaluations were also performed. RESULTS: At week 52, the mycological cure (negative culture and potassium hydroxide microscopy) rate in the MOB-015 and vehicle groups was 69.9% and 27.7%, respectively (P < .001), and complete cure (0% clinical disease involvement and mycological cure) was achieved in 4.5% and 0% of patients, respectively (P = .0195). At least 1 adverse event leading to discontinuation of treatment occurred in 2.8% of patients in the MOB-015 group and in 4.2% in the vehicle group. LIMITATION: The follow-up period after end of treatment may not be sufficient to accurately reflect cure in distal and lateral subungual onychomycosis. CONCLUSIONS: MOB-015 is a treatment option for onychomycosis with an adverse event profile similar to vehicle.

A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis.

BACKGROUND: Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared with placebo in women with recurrent vulvovaginal candidiasis, which was defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period. STUDY DESIGN: Two hundred fifteen women with a documented history of recurrent vulvovaginal candidiasis and who, at screening, were experiencing an episode of acute vulvovaginal candidiasis (acute vulvovaginal candidiasis; composite vulvovaginal signs and symptoms score of ≥3 and a positive potassium hydroxide test for yeast) were enrolled. After treatment of the acute infection with fluconazole, subjects were assigned randomly to 1 of 5 treatment regimens: (1) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (2) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (3) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 23 weeks; (4) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 23 weeks; or (5) a matching placebo regimen for 24 weeks. The primary efficacy outcome was the proportion of subjects with ≥1 culture-verified acute vulvovaginal candidiasis episodes through week 48. RESULTS: In the intent-to-treat population, the proportion of subjects with ≥1 acute vulvovaginal candidiasis episodes ranged from 0-7% across the 4 VT-1161 arms vs 52% in the placebo arm, with all arms achieving statistical significance vs placebo. VT-1161 was well-tolerated with a favorable safety profile, and the incidence of adverse events was lower in all VT-1161 arms compared with placebo. In addition, no patient in any VT-1161 arm discontinued the study early because of an adverse event or laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or electrocardiogram recordings. CONCLUSION: In this study, VT-1161 was shown to be efficacious and safe in the treatment of patients with recurrent vulvovaginal candidiasis. These data strongly support further clinical investigation of VT-1161 for the treatment of recurrent vulvovaginal candidiasis.

Luliconazole demonstrates potent in vitro activity against dermatophytes recovered from patients with onychomycosis.

The in vitro activities of luliconazole, amorolfine, ciclopirox, and terbinafine were determined against 320 dermatophyte isolates from large toenails of onychomycosis patients enrolled into an ongoing phase 2b/3 clinical study. The geometric mean MIC for luliconazole was 0.00022 µg/ml against all isolates, compared to 0.0194 to 0.3107 µg/ml for the three other agents. The in vitro potency of luliconazole was maintained regardless of the dermatophyte species.

Luliconazole: a review of a new antifungal agent for the topical treatment of onychomycosis.

Luliconazole is a novel, broad-spectrum, imidazole antifungal under development in the USA as a treatment for dermatophytic skin and nail infections. In vitro, luliconazole is one of the most potent antifungal agents against filamentous fungi including dermatophytes. Luliconazole has been formulated in a 10% solution with unique molecular properties, which allow it to penetrate the nail plate and rapidly achieve fungicidal levels in the nail unit. These properties make luliconazole a potent compound in the treatment of onychomycosis. This article reviews the development of luliconazole solution, 10% its molecular properties, preclinical and clinical data and its future perspectives for the treatment of fungal infections.

Luliconazole for the treatment of interdigital tinea pedis: A double-blind, vehicle-controlled study.

Tinea pedis (TP) typically is treated with topical antifungal agents. Luliconazole, a novel imidazole drug, is shown to be as or more effective in vitro and in vivo than bifonazole, terbinafine, and lanoconazole. Two treatment durations with luliconazole cream 1% were evaluated for treatment of TP. Participants with interdigital TP were randomized (N= 147) and treated with either luliconazole or its vehicle for either 2 or 4 weeks. The primary efficacy end point was the proportion of participants achieving complete clearance 2 weeks following completion of treatment. In the 2-week active treatment group, complete clearance was achieved in 26.8% (11/41) of participants versus 9. 1% (2/22) in the 2-week vehicle group at 2-weeks posttreatment. In the 4-week active treatment group, 45.7% (16/35) achieved complete clearance versus 10.0% (2/20) in the 4-week vehicle group at 2-weeks posttreatment. Twenty-three adverse events (AEs) were reported; most were mild (56.5% [13/23]) to moderate (26. 1% [6/23]) in severity. All reported AEs were determined to be unrelated (78.3% [18/23]) or unlikely related (21.7% [5/23]) to the study medication. The results of this study indicate that luliconazole cream 1% applied once daily for either 2 or 4 weeks is safe and effective for treatment of TP. More importantly, the antifungal effects of luliconazole persist for several weeks, resulting in increased rates of mycological cure.

Molecular analysis of dermatophytes suggests spread of infection among household members.

Dermatophyte infection from the same strains may be an important route for transmission of dermatophytoses within a household. In this study, we used molecular methods to identify dermatophytes in members of dermatophyte-infected households and evaluated variables associated with the spread of infection. Fungal species were identified by polymerase chain reaction (PCR) using primers targeting the internal transcribed spacer (ITS) regions (ITS1 and ITS4). For strain differentiation, fungal DNA was probed with a ribosomal DNA-specific probe (containing ITS1, 5.8S ribosomal DNA, and ITS2) to detect restriction fragment length polymorphisms (RFLPs). Associations between the spread of a dermatophyte infection and fungal/host variables were determined using χ² and logistic regression analyses. Among the 50 households enrolled in this study, 18 included multiple infected members (MIMs). Trichophyton rubrum was the most commonly isolated dermatophyte species, followed by Trichophyton mentagrophyts and Epidermophyton floccosum. Sixteen T rubrum strains (TR-A to TR-P) were identified, with spread of infection detected in 8 MIM households. Factors that were significantly (P<.05) associated with the spread of infection included the presence of strains TR-B or TR-D, a history of concomitant tinea pedis and onychomycosis, and plantar scaling and/or nail discoloration. This study is unique in that it used molecular evidence to demonstrate the association of certain strains with the spread of dermatophyte infection among members of the same household.

Determination of posaconazole levels in toenails of adults with onychomycosis following oral treatment with four regimens of posaconazole for 12 or 24 weeks.

Pharmacokinetic data from a randomized, parallel-group, multicenter study are presented. Adults with toenail onychomycosis (n = 146) received posaconazole (100 mg, 200 mg, or 400 mg) once daily (QD) for 24 weeks or 400 mg QD for 12 weeks. The posaconazole concentration in the great toenail exhibited a dose-related increase starting at week 2 for 24 weeks and a mean toenail-to-plasma concentration ratio of approximately 3:1 at the end of treatment for the 400-mg 24-week dose.

Skin concentrations and pharmacokinetics of posaconazole after oral administration.

A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC(90) value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC(90) in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC(90). POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections.

Terbinafine hydrochloride oral granules versus oral griseofulvin suspension in children with tinea capitis: results of two randomized, investigator-blinded, multicenter, international, controlled trials.

BACKGROUND: Although griseofulvin is currently considered the primary antifungal agent used to treat tinea capitis in many countries, increasingly higher doses and longer durations of treatment are becoming necessary to achieve effective treatment. Alternative antifungal therapies with shorter/simpler treatment regimens may be important to develop for this indication. OBJECTIVE: To compare the efficacy and safety of a new pediatric formulation of terbinafine hydrochloride oral granules with griseofulvin oral suspension in the treatment of tinea capitis. METHOD: Children (4-12 years of age) with clinically diagnosed and potassium hydroxide microscopy-confirmed tinea capitis were randomized in two identical studies (trial 1, trial 2) to once-daily treatment with terbinafine (5-8 mg/kg; n = 1040) or griseofulvin administered per label (10-20 mg/kg; n = 509) for a period of 6 weeks followed by 4 weeks of follow-up. End-of-study complete cure (negative fungal culture and microscopy with Total Signs and Symptoms Score [TSSS] = 0), and mycologic (negative culture and microscopy) and clinical cure (TSSS = 0) were primary and secondary efficacy variables, respectively. Efficacy analysis was based on pooled data using modified intent-to-treat population (those who received at least one dose of study drug and had positive baseline fungal culture, N = 1286). Safety assessments included monitoring of the frequency and severity of adverse events (AEs). RESULTS: Rates of complete cure and mycologic cure were significantly higher for terbinafine than for griseofulvin (45.1% vs 39.2% and 61.5% vs 55.5%, respectively; P < .05). A majority (86.7%) of patients received griseofulvin, 10 to 19.9 mg/kg per day; complete cure rate was not found to be higher among patients who received griseofulvin more than 20 mg/kg per day compared with those who received less than 20 mg/kg per day. Complete cure rate was statistically significantly greater for terbinafine compared to griseofulvin in trial 1 (46.23% vs 34.01%) but not in trial 2 (43.99% vs 43.46%). On the basis of pooled data, clinical cure was higher for terbinafine than for griseofulvin, but the difference was not found to be statistically significant (P = .10). Subgroup analyses revealed that terbinafine was significantly better than griseofulvin for all cure rates--mycologic, clinical, and complete--among patients with Trichophyton tonsurans but not Microsporum canis (P < .001). For M. canis, mycologic and clinical cure rates were significantly better with griseofulvin than with terbinafine (P < .05). Approximately 50% of patients in each group reported an AE; almost all were mild or moderate in severity. Nasopharyngitis, headache, and pyrexia were most common in both groups. There were no drug-related serious AEs, no deaths, and no significant effects on weight or laboratory parameters, including liver transaminases. LIMITATIONS: In retrospect, a difference in the distribution of infecting microorganisms between the two trials was a limitation. Stringent adherence to griseofulvin doses recommended by prescribing information but smaller than those used in current clinical practice, and exclusion of adjuvant therapies such as shampoos or topical agents, which are routinely used in practice, are other limitations. CONCLUSIONS: Data from this largest pediatric trial of terbinafine to date indicate that terbinafine is efficacious and well tolerated in the treatment of tinea capitis. Terbinafine is an effective alternative to griseofulvin against T. tonsurans tinea capitis.

The impact of aggressive debridement used as an adjunct therapy with terbinafine on perceptions of patients undergoing treatment for toenail onychomycosis.

OBJECTIVE: To determine whether adding aggressive debridement to oral terbinafine for treating toenail onychomycosis impacts patient-reported outcomes (PROs). MATERIALS AND METHODS: A total of 504 patients were randomized to receive 12 weeks of terbinafine 250 mg/day with or without debridement, with an additional 36-week follow-up. The OnyCOE-t, a validated disease-specific PRO questionnaire, was completed at baseline and weeks 6, 12, 24, and 48. It included six multi-item scales (symptom frequency, appearance problems, physical activities problems, stigma, and treatment satisfaction), and one single-item scale: overall problem. Longitudinal analysis of change was conducted to assess treatment effect. Repeated-measures models adjusted for visit, age, sex, baseline scores, severity and duration of infection; treatment interactions were also tested. RESULTS: Symptom frequency and treatment satisfaction significantly improved in the terbinafine + debridement group compared with terbinafine alone (p = 0.0395 and p = 0.0077, respectively). Age and sex were often significant explanatory variables, and further analysis of change scores at 12 weeks revealed that females treated with terbinafine + debridement reported significantly less improvement in the physical activities problems (p = 0.0021) and overall problem (p = 0.0112) scores. CONCLUSIONS: Aggressive debridement, when used as an adjunct therapy with oral terbinafine, improved treatment satisfaction and reduced symptom frequency. The observed sex differences warrant further investigation.

Onychomycosis: diagnosis and definition of cure.

Until now, there has been no agreement on criteria defining resolution of onychomycosis. Most published reports use clinical and mycological cure, which comprises a completely normal-appearing nail plate, and negative nail culture and microscopy results, as the end point for defining success of therapeutic intervention. Reported here is the definition of onychomycosis, which delineates both primary and secondary criteria for diagnosis of onychomycosis and identifies clinical and laboratory parameters to define a resolved fungal nail infection. Onychomycosis cure is defined by the absence of clinical signs or the presence of negative nail culture and/or microscopy results with one or more of the following minor clinical signs: (1) minimal distal subungual hyperkeratosis; and (2) nail-plate thickening. Clinical signs indicative of persistent onychomycosis at the end of the observation period include (1) white/yellow or orange/brown streaks or patches in or beneath the nail plate; and (2) lateral onycholysis with subungual debris. Although nail appearance will usually continue to improve after cessation of therapy, the nails may have a persistent abnormal appearance even in cases where treatment has been effective.

Toenail assessment tool for quantitation of visibly infected mycotic nail plate in onychomycosis.

Typically, the amount of mycotic nail involvement in onychomycosis (fungal infection of the nail) before and after drug therapy is determined visually. Because there is an inherent element of subjectivity, it is difficult to accurately measure and compare results across clinical trials or to assess how much improvement has been achieved in response to therapy. We developed a simple tool for measuring mycotic nail involvement. This novel tool consists of a large grid containing 5 toenail templates of varying nail morphologies that are derived from the actual shape of the toenail of the great toe in several males and females, and one standardized computer-generated nail shape. The toenail templates are presented in 7 different sizes to match different nail sizes. Each toenail template is further divided into 8 segments, each comprising approximately 12.5% of the total nail surface. Measurement of the percentage of mycotic nail involvement is accomplished by the following procedure: (1) placing tracing film over the target toenail; (2) tracing the outline of the entire toenail, followed by tracing the affected portion of the toenail on the same film; (3) placing the tracing film over a nail template on the grid that best fits the shape of the toenail; and (4) counting the number of grid segments that correspond to 50% or more involvement. To assess feasibility, the tool was used in a large randomized trial involving over 30 sites and 500 subjects with onychomycosis. This tool is a more accurate and less biased alternative to visual assessment for measuring nail involvement or progression of nail clearing.

Treatment of toenail onychomycosis with oral terbinafine plus aggressive debridement: IRON-CLAD, a large, randomized, open-label, multicenter trial.

This study was conducted to investigate the efficacy of oral terbinafine with and without aggressive debridement for the treatment of toenail onychomycosis. Onychomycosis patients aged 18 to 75 years received 12 weeks of terbinafine, 250 mg/day, alone (n = 255) or with aggressive debridement (n = 249). Both groups showed marked improvement from baseline at all time points. At week 48, complete, mycologic, and clinical cure rates were higher in the terbinafine plus debridement group compared with the terbinafine alone group, although significance was reached only for clinical cure (59.8% versus 51.4%; P = .023). Although approximately 39% of the patients received at least one antidiabetic, antihypertensive, or cholesterol-lowering agent concomitantly, including statins, the incidence of treatment-emergent adverse events was low and the adverse events were generally mild to moderate in severity. No clinically significant changes in liver transaminase levels were observed 6 weeks after treatment or after 12 weeks in those tested. These results support the well-established safety and efficacy of terbinafine for treatment of onychomycosis.

The OnyCOE-t questionnaire: responsiveness and clinical meaningfulness of a patient-reported outcomes questionnaire for toenail onychomycosis.

BACKGROUND: This research was conducted to confirm the validity and reliability and to assess the responsiveness and clinical meaningfulness of the OnyCOE-t, a questionnaire specifically designed to measure patient-reported outcomes (PRO) associated with toenail onychomycosis. METHODS: 504 patients with toenail onychomycosis randomized to receive 12 weeks of terbinafine 250 mg/day with or without target toenail debridement in the IRON-CLAD trial completed the OnyCOE-t at baseline, weeks 6, 12, 24, and 48. The OnyCOE-t is composed of 6 multi-item scales and 1 single-item scale. These include a 7-item Toenail Symptom assessment, which comprises both Symptom Frequency and Symptom Bothersomeness scales; an 8-item Appearance Problems scale; a 7-item Physical Activities Problems scale; a 1-item Overall Problem scale; a 7-item Stigma scale; and a 3-item Treatment Satisfaction scale. In total, 33 toenail onychomycosis-specific items are included in the OnyCOE-t. Clinical data, in particular the percent clearing of mycotic involvement in the target toenail, and OnyCOE-t responses were used to evaluate the questionnaire's reliability, validity, responsiveness, and the minimally clinical important difference (MCID). RESULTS: The OnyCOE-t was shown to be reliable and valid. Construct validity and known groups validity were acceptable. Internal consistency reliability of multi-item scales was demonstrated by Cronbach's alpha > .84. Responsiveness was good, with the Treatment Satisfaction, Symptom Frequency, Overall Problem, and Appearance Problem scales demonstrating the most responsiveness (Guyatt's statistic of 1.72, 1.31, 1.13, and 1.11, respectively). MCID was evaluated for three different clinical measures, and indicated that approximately an 8.5-point change (on a 0 to 100 scale) was clinically meaningful based on a 25% improvement in target nail clearing. CONCLUSION: The OnyCOE-t questionnaire is a unique, toenail-specific PRO questionnaire that can be used with confidence in future studies of toenail onychomycosis. MCID was evaluated for three different clinical measures, and indicated that approximately a 7-point change (on a 0 to 100 scale) was clinically meaningful based on a 12.5% improvement in target nail clearing.

Safety and efficacy of oral terbinafine in the treatment of onychomycosis: analysis of the elderly subgroup in Improving Results in ONychomycosis-Concomitant Lamisil and Debridement (IRON-CLAD), an open-label, randomized trial.

OBJECTIVES: The primary objective of this subanalysis was to examine the safety, tolerability, and efficacy of terbinafine in the treatment of toenail onychomycosis in the patients aged > or = 65 years in the Improving Results in Onychomycosis Concomitant Lamisil And Debridement (IRON-CLAD) trial. (Lamisil and IRON-CLAD are trademarks of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.) The secondary objective was to determine if toenail debridement would provide additional efficacy benefits in this subgroup. METHODS: The IRON-CLAD trial was an open-label, randomized, multicenter study of adults who underwent 4 weeks of screening and received terbinafine 250 mg/d for 12 weeks with or without aggressive toenail debridement (at baseline and weeks 6, 12, and 24). Clinic visits occurred at weeks 6, 12, 24, and 48. Safety and tolerability were assessed by adverse event (AE) rates based on changes in laboratory values, patient-volunteered information, answers to investigator questions, and physical examinations. Efficacy was evaluated by mycologic cure (negative microscopy of potassium hydroxide samples and negative culture), clinical cure (> or = 87.5% nail clearing), and complete cure (mycologic cure and complete toenail clearing) at week 48. The present subanalysis of IRON-CLAD results assessed participants aged > or = 65 years (older subgroup). RESULTS: A total of 504 patients were randomized, of whom 75 were aged > or = 65 years. In the older subgroup, the mean (SD) age was 68.9 (3.04), 86.7% (65/75) were white, and 66.7% (50/75) were male. Incidence of AEs reported during the treatment period or within 30 days after treatment discontinuation (treatment-emergent AEs [TEAEs]) was 28.0% in the older subgroup and 23.0% in the overall study population. Most TEAEs were mild (73.7%) to moderate (23.7%) in severity, and most (86.8%) were not suspected by the investigators to be related to study treatment. The most frequently occurring TEAEs in the older subgroup were nausea (4.0%), sinusitis (4.0%) arthralgia (2.7%), and hypercholesterolemia (2.7%). The proportion of participants who withdrew from the trial due to TEAEs was 4.0% (3/75) in the older group and 2.8% (14/504) in the overall population. Only 3 of 11 discontinuations in the older subgroup were due to a TEAE suspected by the investigator to be related to study treatment. Sixty-four percent of the older subgroup took antihypertensive medications, 25% took antidiabetics, and 47% took antilipemic medications. There were no clinical signs of drug interactions in the older subgroup. Clinical efficacy outcomes in the older subgroup were generally good and appeared to be comparable with those in the younger subgroup. At week 48, mycologic cure had occurred in 64.0% (95% CI, 53.1%-74.9%) of the older subgroup, clinical cure in 41.3% (95% CI, 30.2%-52.5%), and complete cure in 28.0% (95% CI, 17.8%-38.2%). Debridement did not appear to affect mycologic outcomes or clinical effectiveness, but rates of clinical and complete cure appeared to be higher among older patients who underwent adjuvant debridement. CONCLUSIONS: The results of this subanalysis suggest that terbinafine was well tolerated and efficacious in these patients aged > or = 65 years with moderate to severe toenail onychomycosis, many of whom were taking antihypertensives, antidiabetics, or lipid-lowering agents concomitantly. There were no reported clinical signs of drug interactions.

The use of terbinafine in the treatment of onychomycosis in adults and special populations: a review of the evidence.

Terbinafine is an allylamine with fungicidal activity, first approved for the treatment of onychomycosis in the United Kingdom in the early 1990s, and in the US in 1996. Terbinafine is the most frequently prescribed oral antifungal agent in the US and Canada for onychomycosis. Its efficacy and safety in dermatophyte toenail onychomycosis in adults has been established in many studies. In fact, 18 randomized controlled trials have shown terbinafine to be highly effective, with a meta-average for mycological cure of 76% +/- 3% (mean +/- standard error). In large surveillance studies, terbinafine exhibited excellent safety profiles consistent with results obtained in pivotal studies. Additionally, terbinafine has been reported to be superior to both itraconazole and fluconazole in comparative studies in the treatment of dermatophyte toenail onychomycosis. Recent studies have reported terbinafine to be more cost effective than griseofulvin, fluconazole, or itraconazole. Terbinafine has also been used to treat onychomycosis effectively and safely in special patient populations, such as children, the elderly, immunocompromised patients, diabetics, and those with Down syndrome. Terbinafine should therefore be considered for the management of onychomycosis in adults based on its effectiveness, broad spectrum, fungicidal nature, established safety profile, and very low occurrence of drug interactions. Furthermore, the data support the use of terbinafine to treat dermatophyte onychomycosis in children and the elderly.

Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality.

Clinicians now have five oral antifungal therapeutic agents to choose from when assessing the risk-benefits associated with a particular treatment for onychomycosis (OM): griseofulvin, itraconazole, terbinafine, ketoconazole, and fluconazole. Only the first three are approved by the FDA for this indication. Griseofulvin is fungistatic and inhibits nucleic acid synthesis, arresting cell division at metaphase, and impairing fungal wall synthesis. Due to its low cure rates and high relapse, it is rarely used for treatment of onychomycosis. Itraconazole is a broad spectrum drug and is effective against dermatophytes, candida, and some nondermatophytic molds. Itraconazole works by inhibiting ergosterol synthesis via cytochrome P-450 (CYP450)-dependent demethylation step. This azole antifungal agent is metabolized in the liver by cytochrome P-450 3A4 (CYP3A4), and therefore has the potential to interact with drugs metabolized through this pathway. Terbinafine, an allylamine, is fungicidal and remains at therapeutic levels in keratinized tissues, but with a short plasma half-life of 36 hours. Terbinafine has the advantage in that it does not inhibit CYP3A4 isoenzyme during its metabolism where some 50% of all commonly prescribed drugs are metabolized. The only potentially significant drug interaction with terbinafine is with the cytochrome P-450 2D6 (CYP2D6) isoenzyme. The lack of widely reported or published clinically relevant drug interactions, and extensive experience from a large prospective, surveillance study conducted in "real world" setting with no patient exclusions, suggest that this is not a major issue. The high cure rates of terbinafine against dermatophytes, as shown in many studies since its launch in the 1990s, together with lack of clinically significant drug interactions and well established safety record, indicate the use of continuous oral terbinafine as the top choice for the treatment of onychomycosis in most patients.