CAUTION:   Federal (USA) law prohibits dispensing without a prescription.

Mentax® Cream, 1%, contains the synthetic antifungal agent, butenafine hydrochloride. Butenafine is a member of the class of antifungal compounds known as benzylamines which are structurally related to the allylamines.

Butenafine HCl is designated chemically as N -4- tert -butylbenzyl- N -methyl-1-naphthalenemethylamine hydrochloride. The compound has the empirical formula C ₂₃ H ₂₇ N·HCl, a molecular weight of 353.93, and the following structural formula:

Butenafine HCl is a white, odorless, crystalline powder. It is freely soluble in methanol, ethanol, and chloroform, and slightly soluble in water. Each gram of Mentax® Cream, 1%, contains 10 mg of butenafine HCl in a white cream base of purified water USP, propylene glycol dicaprylate, glycerin USP, cetyl alcohol NF, glyceryl monostearate SE, white petrolatum USP, stearic acid NF, polyoxyethylene (23) cetyl ether, benzyl alcohol NF, diethanolamine NF, and sodium benzoate NF.

Mechanism of Action

Butenafine HCl is a benzylamine derivative with a mode of action similar to that of the allylamine class of antifungal drugs. Butenafine HCl is hypothesized to act by inhibiting the epoxidation of squalene, thus blocking the biosynthesis of ergosterol, an essential component of fungal cell membranes. The benzylamine derivatives, like the allylamines, act at an earlier step in the ergosterol biosynthesis pathway than the azole class of antifungal drugs. Depending on the concentration of the drug and the fungal species tested, butenafine HCl may be fungicidal in vitro . However, the clinical significance of these in vitro data is unknown.

In one study conducted in healthy subjects for 14 days, 6 grams of Mentax® Cream, 1%, was applied once daily to the dorsal skin (3,000 cm ² ) of 7 subjects, and 20 grams of the cream was applied once daily to the arms, trunk and groin areas (10,000 cm ² ) 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, Mentax® 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, Mentax® 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.

Microbiology

Butenafine HCl has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the section:

Epidermophyton floccosum

Trichophyton mentagrophytes

Trichophyton rubrum

Trichophyton tonsurans

CLINICAL STUDIES

Interdigital Tinea Pedis

Once Daily Four Week Dosing

In the following data presentations, patients with interdigital tinea pedis in the absence of moccasin-type tinea pedis and onychomycosis were studied. The term "Mycological Cure" is defined as both negative KOH and culture. The term "Effective Treatment" refers to patients who had a "Mycological Cure" and an Investigator's Global of either "Excellent" (80% to 99% improvement) or "Cleared" (100% improvement). The term "Overall Cure" refers to patients who had both a "Mycological Cure" and an Investigator's Global Assessment of "Cleared" (100% improvement).

Data from the two controlled studies in which Mentax® Cream, 1%, was used once daily for 4 weeks have been combined in the table below. Patients were treated for 4 weeks and evaluated 4 weeks post-treatment. In the "per protocol" analysis shown in the table below, statistical significance (Mentax® vs. vehicle) was assessed 4 weeks post-treatment.

Twice Daily One Week Dosing

In the following data presentations, patients with interdigital tinea pedis in the absence of moccasin-type tinea pedis were studied. Patients with concurrent onychomycosis were not excluded. The term "Mycological Cure" is defined as both negative KOH and culture. The term "Effective Treatment" refers to patients who had a "Mycological Cure" and an Investigator's Global of either "Excellent" (90% to 99% improvement) or "Cleared" (100% improvement). The term "Overall Cure" refers to patients who had both a "Mycological Cure" and an Investigator's Global Assessment of "Cleared" (100% improvement).

Data from the two controlled studies in which Mentax® Cream, 1%, was used twice daily for 1 week have been combined in the table below. Patients were treated for 1 week and evaluated 5 weeks post-treatment. In the "modified-intent-to-treat" analysis shown in the table below, statistical significance (Mentax® vs. vehicle) was assessed 5 weeks post-treatment.

Tinea Corporis and Tinea Cruris

In the following data presentations, patients with tinea corporis or tinea cruris were studied. The term "Mycological Cure" is defined as both negative KOH and culture. The term "Effective Treatment" refers to patients who had a "Mycological Cure" and an Investigator's Global of either "Excellent" (90% to 99% improvement) or "Cleared" (100% improvement). The term "Overall Cure" refers to patients who had both a "Mycological Cure" and an Investigator's Global Assessment of "Cleared" (100% improvement).

Separate studies compared Mentax® Cream to vehicle applied once daily for 2 weeks in the treatment of tinea corporis and tinea cruris. Patients were treated for 2 weeks and evaluated 4 weeks post-treatment. All subjects with a positive baseline exam (including positive culture and KOH) and who were dispensed medication were included in the "modified intent-to-treat" analysis shown in the table below. Statistical significance (Mentax® vs. vehicle) was achieved for all patient outcome categories at Week 2 (end of treatment) and Week 6 (4 weeks post-treatment).

Mentax® (butenafine HCl cream) Cream, 1%, is indicated for the topical treatment of the following superficial dermatophytoses: 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 ).

CONTRAINDICATIONS

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

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

PRECAUTIONS

General

Mentax® Cream, 1%, is for external use only. If irritation or sensitivity develops with the use of Mentax® Cream, 1%, treatment should be discontinued and appropriate therapy instituted. Diagnosis of the disease should be confirmed either by direct microscopic examination of infected superficial epidermal tissue in a solution of potassium hydroxide or by culture on an appropriate medium.

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

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

Information for Patients

The patient should be instructed to:

1. Use Mentax® Cream, 1%, as directed by the physician. The hands should be washed after applying the medication to the affected area(s). Avoid contact with the eyes, nose, mouth, and other mucous membranes. Mentax® Cream, 1%, is for external use only.
2. Dry the affected area(s) thoroughly before application, if you wish to apply Mentax® Cream, 1%, after bathing.
3. Use the medication for the full treatment time recommended by the physician, even though symptoms may have improved. Notify the physician if there is no improvement after the end of the prescribed treatment period, or sooner, if the condition worsens (see below).
4. Inform the physician if the area of application shows signs of increased irritation, redness, itching, burning, blistering, swelling, or oozing.
5. Avoid the use of occlusive dressings unless otherwise directed by the physician.
6. Do not use this medication for any disorder other than that for which it was prescribed.

Drug Interactions

Potential drug interactions between Mentax® (butenafine HCl cream) Cream, 1%, and other drugs have not been systematically evaluated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of Mentax® 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. Reproductive studies were conducted in which approximately 150 mg/m ² /day (25 mg/kg/day) of butenafine was administered subcutaneously, which is 5 times higher than the maximum recommended human topical dose (30 mg/m ² /day) for the treatment of tinea pedis, and six times higher than the anticipated maximum human topical dose (24 mg/m ² /day) for the treatment of tinea corporis or tinea cruris. At this dose in animals no adverse effects on male or female fertility were demonstrated.

Pregnancy

Teratogenic Effects:  Pregnancy Category B

Subcutaneous or topical doses of butenafine at 150 to 300 mg/m ² /day (25 to 50 mg/kg/day) (equivalent to 5 to 10 times the maximum potential exposure at the recommended human topical dose for the treatment of tinea pedis, or 6 to 12 times the anticipated maximum exposure at the human topical dose for the treatment of tinea corporis or tinea cruris) during organogenesis in rats and rabbits were not teratogenic. There are, however, no adequate and well-controlled studies that have been conducted of 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 Mentax® Cream, 1%, to a nursing women.

Pediatric Use

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

ADVERSE REACTIONS

In controlled clinical trials, 8 (approximately 1%) of 644 patients treated with Mentax® Cream, 1%, reported adverse events related to the skin. These included burning/stinging and worsening of the condition. No patient treated with Mentax® Cream, 1%, discontinued treatment due to an adverse event. In the vehicle-treated patients, two of 624 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 Mentax® Cream, 1%, were: contact dermatitis, erythema, irritation, and itching, each occurring in less than 2% of patients.

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

In the treatment of interdigital tinea pedis , Mentax® 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 . While the clinical significance of this difference is unknown, these data should be carefully considered before selecting the dosage regimen 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 Mentax® once daily for two weeks.

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

HOW SUPPLIED

Mentax® (butenafine HCl cream) Cream, 1%, is supplied in tubes in the following sizes:

 15-gram tube (NDC 62794-151-02) 30-gram tube (NDC 62794-151-03)

STORE BETWEEN 5°C and 30°C (41° and 86°F).

Manufactured By: DPT Laboratories

San Antonio, Texas 78215

Distributed By: BERTEK PHARMACEUTICALS INC.

Morgantown WV 26505

July 1999

PN341.02H

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