Butenafine: An Update of Its Use in Superficial Mycoses

A. K. Gupta MD, PhD, FRCPC
Division of Dermatology, Department of Medicine, Sunnybrook and Womens’ College Health Sciences Center (Sunnybrook site), and the University of Toronto, Toronto, Canada.

ABSTRACT

Butenafine is a synthetic benzylamine antifungal agent that may be fungicidal against susceptible organisms, e.g., dermatophytes. Butenafine may be effective and safe in the treatment of interdigital tinea pedis (apply twice daily for 1 week or once daily for 4 weeks), tinea corporis/ tinea cruris (apply twice daily for 2 weeks), and pityriasis versicolor (apply once daily for two weeks). The effectiveness of the drug persists for at least 4 weeks following the discontinuation of therapy suggesting that there is some retention of the drug in the skin following termination of active therapy.

Key Words: butenafine, tinea, fungal

Topical butenafine (Mentax®, Bertek Pharmaceuticals) is approved in the US for the treatment of tinea pedis interdigitalis, tinea corporis, tinea cruris, and in August 2001, this drug was approved by the US FDA for the treatment of pityriasis versicolor, a superficial fungal infection caused by Malassezia spp.

Mechanism of Action

Butenafine hydrochloride is a synthetic benzylamine derivative with a mode of action similar to that of the allylamine class of antifungal drugs. Like the allylamines, butenafine inhibits the fungal enzyme squalene epoxidase, thereby blocking the biosynthesis of ergosterol, which is an essential component of fungal cell membranes.

In Vitro Activity

In certain concentrations and against susceptible organisms, such as dermatophytes, butenafine is thought to be fungicidal.¹ Butenafine hydrochloride is active in vitro against many species of fungi, including Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Epidermophyton floccosum, Microsporum canis, and yeasts including C. parapsilosis, C. albicans, and Malassezia spp.

Therapeutic Efficacy

Tinea Pedis ^2-4

Butenafine applied once daily for 4 weeks or twice daily for 1 week is effective in the treatment of interdigital tinea pedis. In a multicenter, randomized, double-blind, placebocontrolled study the effectiveness of a once-daily application of butenafine for 4 weeks in the management of interdigital tinea pedis was evaluated.² At week 4, the mycologic cure rates (negative light microscopy and culture) in the butenafine and vehicle groups were 91% and 63%, respectively (P<0.01). Four weeks following the discontinuation of therapy, the mycologic cure rates in the two groups were 83% and 38%, respectively (P<0.001).

A second study³ using the same regimen reports that the differences in cure rates between the butenafine and vehicle groups was greatest at 4 weeks post-treatment. This continued increase in the efficacy rate of butenafine until the 4-week follow-up is consistent with data from animal studies that indicate that butenafine persists in the stratum corneum for some time following discontinuation of active therapy.^4-6

A multicenter, double-blind, randomized, controlled trial evaluated the efficacy of one-week, twice-daily treatment with butenafine in patients with tinea pedis.⁷ Efficacy analysis was performed on 271 patients who were culture positive for tinea pedis (butenafine group: 132, vehicle group: 139). In the butenafine group there was a significantly higher mycologic cure at day 8 compared to the vehicle group (43% vs. 25%, P=0.002).

Similarly, the mycologic cure rates at the 5-week follow-up were 74% vs. 22%, respectively (P<0.0001). Both mycological and clinical cures were found in 23% of patients receiving butenafine, compared to 3% in the vehicle group (P<0.0001). Both mycological and clinical cures were found in 23% of patients receiving butenafine, compared to 3% in the vehicle group (P<0.0001).

Tinea Corporis

A multicenter, randomized, vehicle controlled, doubleblind trial evaluated the efficacy of butenafine 1% cream applied once daily for 2 weeks in the treatment of tinea corporis.⁸ Efficacy was evaluated in 78 patients (42 butenafine, 36 vehicle). The mycologic cure (negative KOH and culture) was higher in the butenafine group compared to the vehicle group on day 7 (64% vs. 9%, P<0.001) and day 14 (88% compared to 28% of the vehicle group (P<0.0001). At week 4, following completion of therapy, the butenafine group continued to demonstrate a high mycologic cure rate (88%) compared to a decrease in cure rate in the vehicle group to 17% (P<0.0001). At day 14, the overall cure (mycological cure plus 100% clinical remission) in the butenafine group was 31% compared to 3% in the vehicle group (P=0.001). At the week 4 followup point, the overall cure in the butenafine and vehicle groups was 67% and 14%, respectively (P<0.0001).

Tinea Cruris

In a multicenter, randomized, vehicle-controlled, doubleblind trial, butenafine 1% cream was applied once daily for 2 weeks.⁹ The mycologic cure (negative KOH and culture) was higher in the butenafine group compared to placebo as early as day 7. The higher efficacy rate in the allylamine group increased during the 2-week period of active treatment. At the 4-week follow-up point, the mycologic cure rate in the butenafine group was 81% compared to 13% in the vehicle group (P<0.0001). At the end of treatment, the overall cure rate (negative mycology and clinical cure) was 32% in the butenafine group compared to 8% in the vehicle group (P<0.01). At 4 weeks post-treatment, overall cure was achieved in 62% of the butenafine, versus a decrease to 3% for the vehicle group (P< 0.0001).

Pityriasis Versicolor

While Malassezia yeasts are normal skin commensals, in some individuals the yeasts transform to a pathogenic, hyphal form, resulting in pityriasis versicolor. In two randomized, controlled trials butenafine and vehicle were applied once daily for two weeks in patients with pityriasis versicolor. In the first study, at 6 weeks post-treatment, 55% of patients receiving butenafine were mycologically cured and 51% were completely cured (i.e., negative mycology and no erythema, scaling or pruritus.). The corresponding numbers for the vehicle group were 36% and 36%, respectively. In the second study, "effective treatment" was defined as negative mycology plus a score of one or less on a 4 point scale (0 to 3) for erythema, pruritus and scaling. At 6 weeks follow-up, 43% of butenafine patients were considered to be effectively treated, versus 26% of the vehicle group.¹⁰

In addition to the evidence for butenafine’s efficacy in pityriasis versicolor, butenafine has in vivo activity against Malassezia yeasts.¹¹ Butenafine applied twice-daily for 1 week is effective for treating patients with seborrheic dermatitis, which is also caused by Malassezia spp. This agent is, however, not approved for seborrheic dermatitis.

Tolerability

In controlled clinical trials, 9 of 815 patients (approx. 1%) treated with butenafine cream 1% reported adverse reactions related to the skin.¹⁰ These reactions included burning/stinging of the skin and worsening of the dermatosis. No patients discontinued therapy due to an adverse event. Two of 624 patients receiving the vehicle discontinued therapy because of treatment site related events including severe burning/stinging and itching.¹⁰ In uncontrolled trials, the adverse events most commonly associated with the use of butenafine 1% cream included contact dermatitis, erythema, irritation, and itching, with each occurring in less than 2% of patients.¹⁰

Dosage and Administration

Butenafine cream 1% is indicated in the US for the topical treatment of interdigital tinea pedis, tinea corporis, and tinea cruris due to T. rubrum, T. tonsurans, T. mentagrophytes, and E. floccosum. In tinea pedis interdigitalis, butenafine cream 1% may be applied twice daily for 7 days or once daily for 4 weeks. In patients with tinea corporis and tinea cruris, it is indicated for once daily application for 2 weeks. For the treatment of pityriasis versicolor, butenafine cream 1% should be applied once daily for 2 weeks.

Butenafine is FDA Pregnancy Category B. In December 2001, butenafine cream 1% was approved by the US FDA as a nonprescription treatment (Lotrimin Ultra®, Schering-Plough).

Acknowledgement

Dr. Gupta wishes to thank Colin Rule, HBSc for his help with this manuscript.

References

1. Butenafine Hydrocholoride. In: AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists Inc., pp. 3332-3 (2001).
2. Reyes B, Beutner KR, Cullen SI, Rosen T, Shupack JL, Weinstein MB. Butenafine, a fungicidal benzylamine derivative, used once daily for the treatment of interdigital tinea pedis. Int J Dermatol 37(6):450-3 (1998 Jun).
3. Tschen E, Elewski B, Gorsulowsky DC, Pariser DM. Treatment of interdigital tinea pedis with a 4-week once-daily regimen of butenafine hydrochloride 1% cream. J Am Acad Dermatol 36(2 Pt 1):S9-14 (1997 Feb).
4. Arika T, Yokoo M, Hase T, Maeda T, Amemiya K, Yamaguchi H. Effects of butenafine hydrochloride, a new benzylamine derivative, on experimental dermatophytosis in guinea pigs. Antimicrob Agents Chemother 34(11):2250-3 (1990 Nov).
5. Arika T, Yokoo M, Yamaguchi H. Topical treatment with butenafine significantly lowers relapse rate in an interdigital tinea pedis model in guinea pigs. Antimicrob Agents Chemother 36(11):2523-5 (1992 Nov).
6. Arika T, Hase T, Yokoo M. Anti-Trichophyton mentagrophytes activity and percutaneous permeation of butenafine in guinea pigs. Antimicrob Agents Chemother 37(2):363-5 (1993 Feb).
7. Savin R, De villez RL, Elewski B, et al. One-week therapy with twice-daily butenafine 1% cream versus vehicle in the treatment of tinea pedis: Amulticenter, double-blind trial. J Am Acad Dermatol 36(2 Pt 1):S15-9 (1997 Feb).
8. Greer DL, Weiss J, Rodriguez DA, Hebert AA, Swinehart JM. Arandomized trial to assess once-daily topical treatment of tinea corporis with butenafine, a new antifungal agent. J Am Acad Dermatol 37(2 Pt 1):231-5.
9. Lesher J, Babel D, Stewart D, et al. Butenafine 1% cream in the treatment of tinea cruris: A multicenter, vehicle controlled, double-blind trial. J Am Acad Dermatol 36(2 Pt 1):S20-4 (1997 Feb).
10. Butenafine HCl cream, 1%, Mentax®‚ package insert. Bertek Pharmaceuticals, Inc., NC, USA. June 2001.
11. Gupta AK, Yokou M, Arika T, et al. Evaluation of the in vitro and in vivo efficacy of butenafine hydrochloride cream against Malassezia furfur species and seborrheic dermatitis. J Dermatol Treat 11:79-83 (2000).

In this issue:

1. Butenafine: An Update of Its Use in Superficial Mycoses
2. Prevention of Polymorphous Light Eruption and Solar Urticaria
3. Update on Drugs and Drug News - September 2002