Sergen

Sergen® (butenafine HCl cream), 1%, is indicated for the topical treatment of the following dermatologic infections: tinea (pityriasis) versicolor due to M. furfur (formerly P. orbiculare), interdigital tinea pedis (athlete's foot), tinea corporis (ringworm) and tinea cruris (jock itch) due to E. floccosum, T. mentagrophytes, T. rubrum, and T. tonsurans. Butenafine HCl cream was not studied in immunocompromised patients. (See DOSAGE AND ADMINISTRATION Section).

Patients with tinea (pityriasis) versicolor should apply Sergen® (butenafine) once daily for two weeks. In the treatment of interdigital tinea pedis, Sergen® (butenafine) should be applied twice daily for 7 days OR once daily for 4 weeks (NOTE: in separate clinical trials, the 7-day dosing regimen was less efficacious than the 4-week regimen (see Clinical Studies Section). While the clinical significance of this difference is unknown, these data should be carefully considered before selecting the dosage regiment for patients at risk for the development of bacterial cellulitis of the lower extremity associated with interdigital cracking/fissuring).

Patients with tinea corporis or tinea cruris should apply Sergen® (butenafine) once daily for two weeks.

Sufficient Sergen® (butenafine) Cream should be applied to cover affected areas and immediately surrounding skin of patients with tinea versicolor, interdigital tinea pedis, tinea corporis, and tinea cruris. If a patient shows no clinical improvement after the treatment period, the diagnosis and therapy should be reviewed.

Sergen® (butenafine HCl cream) Cream, 1%, is contraindicated in individuals who have known or suspected sensitivity to Sergen® (butenafine) Cream, 1%, or any of its components.

WARNINGS

Sergen® (butenafine HCl cream) Cream, 1%, is not for ophthalmic, oral, or intravaginal use.

PRECAUTIONS

General

Sergen® (butenafine) Cream, 1%, is for external use only. If irritation or sensitivity develops with the use of Sergen® (butenafine) Cream, 1%, treatment should be discontinued and appropriate therapy instituted. Diagnosis of the disease should be confirmed either by culture on an appropriate medium, [except M. furfur (formerly P. orbiculare)] or by direct microscopic examination of infected superficial epidermal tissue in a solution of potassium hydroxide.

Patients who are known to be sensitive to allylamine antifungals should use Sergen® (butenafine HCl cream) Cream, 1%, with caution, since cross-reactivity may occur.

Use Sergen® (butenafine) Cream, 1%, as directed by the physician, and avoid contact with the eyes, nose, and mouth, and other mucous membranes.

Carcinogenesis, Mutagenesis, Impairment of Fertlity

Long-term studies to evaluate the carcinogenic potential of Sergen® (butenafine) Cream 1% have not been conducted. Two in vitro assays (bacterial reverse mutation test and chromosome aberration test in Chinese hamster lymphocytes) and one in vivo study (rat micronucleus bioassay) revealed no mutagenic or clastogenic potential for butenafine.

In subcutaneous reproductive studies in rats at 25 mg/kg/day (6 times the maximum possible systemic dose) in humans based on a mg/m² comparison) dose level, butenafine did not produce any adverse effects on male or female fertility.

Pregnancy

Teratogenic effects: Pregnancy Category B

Subcutaneous or topical doses of butenafine (25 to 50 mg/kg/day) (equivalent to 5 to 20 times the maximum possible systemic dose in humans based on a mg/m² comparison) were not teratogenic in rats and rabbits. In an oral teratogenicity study in rabbits (80, 200, and 400 mg butenafine HCl/kg/day) (equivalent to 3 to 16 times the maximum possible systemic dose in humans based on a mg/m² comparison), no treatment-related external, visceral, or skeletal malformations or variations were observed. There are, however, no adequate and well-controlled studies that have been conducted with topically applied butenafine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known if butenafine HCl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised in prescribing Sergen® (butenafine) Cream, 1%, to a nursing woman. Nursing mothers should avoid application of Sergen® (butenafine) Cream, 1%, to the breast.

Pediatric Use

Safety and efficacy in pediatric patients below the age of 12 years have not been studied. Use of Sergen® (butenafine) Cream, 1%, in pediatric patients 12 to 16 years of age is supported by evidence from adequate and well-controlled studies of Sergen® (butenafine) Cream, 1%, in adults.

In controlled clinical trials, 9 (approximately 1%) of 815 patients treated with Sergen® (butenafine) Cream, 1%, reported adverse events related to the skin. These included burning/stinging, itching, and worsening of the condition. No patient treated with Sergen® (butenafine) Cream, 1%, discontinued treatment due to an adverse event. In the vehicle-treated patients, two of 718 patients discontinued because of treatment-site adverse events, one of which was severe burning/stinging and itching at the site of application.

In uncontrolled clinical trials, the most frequently reported adverse events in patients treated with Sergen® (butenafine) Cream, 1%, were: contact dermatitis, erythema, irritation, and itching, each occurring in less than 2% of patients.

In provocative testing in over 200 subjects, there was no evidence of allergic contact sensitization for either the cream or the vehicle base for Sergen® (butenafine) Cream, 1%.

Overdosage of butenafine HCl in humans has not been reported to date.

In one study conducted in healthy subjects for 14 days, 6 grams of Sergen® (butenafine) Cream, 1%, was applied once daily to the dorsal skin (3,000 cm²) of 7 subjects, and 20 grams of the cream was applied once daily to the arms, trunk and groin areas (10,000 cm²) of another 12 subjects. After 14 days of topical applications, the 6-gram dose group yielded a mean peak plasma butenafine HCl concentration, Cmax, of 1.4 ± 0.8 ng/mL, occurring at a mean time to the peak plasma concentration, Tmax, of 15 ± 8 hours, and a mean area under the plasma concentration-time curve, AUC_{0-24 hrs} of 23.9 ± 11.3 ng-hr/mL. For the 20-gram dose group, the mean Cmax was 5.0 ± 2.0 ng/mL, occurring at a mean Tmax of 6 ± 6 hours, and the mean AUC_{0-24 hrs} was 87.8 ± 45.3 ng-hr/mL. A biphasic decline of plasma butenafine HCl concentrations was observed with the half-lives estimated to be 35 hours and > 150 hours, respectively.

At 72 hours after the last dose application, the mean plasma concentrations decreased to 0.3 ± 0.2 ng/mL for the 6-gram dose group and 1.1 ± 0.9 ng/mL for the 20-gram dose group. Low levels of butenafine HCl remained in the plasma 7 days after the last dose application (mean: 0.1 ± 0.2 ng/mL for the 6-gram dose group, and 0.7 ± 0.5 ng/mL for the 20-gram dose group). The total amount (or % dose) of butenafine HCl absorbed through the skin into the systemic circulation has not been quantitated. It was determined that the primary metabolite in urine was formed through hydroxylation at the terminal t-butyl side-chain.

In 11 patients with tinea pedis, Sergen® (butenafine) Cream, 1%, was applied by the patients to cover the affected and immediately surrounding skin area once daily for 4 weeks and a single blood sample was collected between 10 and 20 hours following dosing at 1, 2 and 4 weeks after treatment. The plasma butenafine HCl concentration ranged from undetectable to 0.3 ng/mL.

In 24 patients with tinea cruris, Sergen® (butenafine) Cream, 1%, was applied by the patients to cover the affected and immediately surrounding skin area once daily for 2 weeks (mean average daily dose: 1.3 ± 0.2 g). A single blood sample was collected between 0.5 and 65 hours after the last dose, and the plasma butenafine HCl concentration ranged from undetectable to 2.52 ng/mL (mean ± SD: 0.91 ± 0.15 ng/mL). Four weeks after cessation of treatment, the plasma butenafine HCl concentration ranged from undetectable to 0.28 ng/mL.