Naftifine Hydrochloride (Page 2 of 3)

11 DESCRIPTION

Naftifine hydrochloride cream, USP is a white to off-white cream for topical use only. Each gram contains 20 mg of naftifine hydrochloride, USP, (2%), a synthetic allylamine antifungal compound.

Chemically, naftifine HCl is (E)-N-Cinnamyl-N-methyl-1-napthalenemethylamine hydrochloride.

The molecular formula is C₂₁ H₂₁ N•HCl with a molecular weight of 323.86.

The structural formula of naftifine hydrochloride, USP is:

Naftifine hydrochloride cream, USP contains the following inactive ingredients: benzyl alcohol, cetyl alcohol, cetyl esters wax, isopropyl myristate, polysorbate 60, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol. Hydrochloric acid may be added to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Naftifine hydrochloride cream is a topical antifungal drug [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

The pharmacodynamics of naftifine hydrochloride cream have not been established.

12.3 Pharmacokinetics

In vitro and in vivo bioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of dermatophytes.

The pharmacokinetics of naftifine hydrochloride cream was evaluated following once-daily topical application for 2 weeks to 21 adult subjects, both males and females, with both tinea pedis and tinea cruris. The median total amount of cream applied was 6.4 g (range 5.3 g to 7.5 g) per day. The results showed that the systemic exposure (i.e., maximum concentration (C_max ) and area under the curve from time 0 to 24 hours (AUC_0-24 ) to naftifine increased over the 2 week treatment period in all the 21 subjects. Geometric mean (coefficient of variation or CV%) AUC_0-24 was 117 (41.2) ng*hr/mL on Day 1, and 204 (28.5) ng*hr/mL on Day 14. Geometric mean (CV %) C_max was 7 ng/mL (55.6) on Day 1 and 11 ng/mL (29.3) on day 14. Median time to C_max (T_max ) was 8 hours (range 4 to 24 hours) on Day 1 and 6 hours (range 0 to 16 hours) on Day 14. Accumulation after 14 days of topical application was less than two fold. Trough concentrations generally increased throughout the 14 day study period. Naftifine continued to be detected in plasma in 13/21 (62%) subjects on day 28, the mean (standard deviation or SD) plasma concentrations were 1.6 ± 0.5 ng/mL (range below limit of quantitation (BLQ) to 3 ng/mL). In the same pharmacokinetic trial conducted in patients with tinea pedis and tinea cruris, median fraction of the dose excreted in urine during the treatment period was 0.0016% on Day 1 versus 0.0020% on Day 14.

In a second trial that enrolled 22 subjects, the pharmacokinetics of naftifine hydrochloride cream was evaluated in 20 pediatric subjects 13 to less than 18 years of age with both tinea pedis and tinea cruris. Subjects were treated with a median dose of 8.1 g (range 6.6 g to 10.1 g) applied to the affected areas once daily for 2 weeks. The results showed that the systemic exposure increased over the treatment period. Geometric mean (CV%) AUC_0-24 was 138 (50.2) ng*hr/mL on Day 1, and 192 (74.9) ng*hr/mL on Day 14. Geometric mean (CV %) C_max was 9.21 ng/mL (48.4) on Day 1 and 12.7 ng/mL (67.2) on day 14. Median fraction of the dose excreted in urine during the treatment period was 0.0030% on Day 1 and 0.0033% on Day 14.

A third trial evaluated the pharmacokinetics of naftifine hydrochloride cream in 27 pediatric subjects 2 to less than 12 years of age with at least moderate tinea corporis. Subjects were divided into younger (ages 2 to less than 6 years, 17 subjects) and older (6 to less than 12 years, 10 subjects) groups. Median doses of 1.3 g (range 1 g to 3.1 g) and 2.3 g (range 2.2 g to 4.2 g) were applied once-daily for 2 weeks in the younger and older groups, respectively, to the affected area plus a ½ inch margin. Plasma and urine pharmacokinetic assessments were conducted on Day 1 in the older group only and on Day 14 in both groups. All subjects showed measurable levels of naftifine in plasma after topical application of naftifine hydrochloride cream. Following a single dose on Day 1 in subjects 6 to less than 12 years of age, the geometric mean (CV%) values of C_max and AUC_0-24 were 3.60 (76.6) ng/mL and 49.8 (64.4) ng*h/mL, respectively. On Day 14 in this group, the C_max and AUC_0-24 were 3.31 (51.2) ng/mL and 52.4 (49.2) ng*h/mL, respectively. In subjects 2 to less than 6 years of age on Day 14, the C_max and AUC_0-24 were 3.98 (186) ng/mL and 54.8 (150) ng*h/mL, respectively. In the older group of subjects 6 to 12 years of age, the systemic exposures (both C_max and AUC_0-24 ) on Days 1 and 14 were comparable. The median fraction of the dose excreted into urine over 24 hours following drug applications on Day 1 and Day 14 was 0.0029% and 0.0014%, respectively.

12.4 Microbiology

Although the exact mechanism of action against fungi is not known, naftifine hydrochloride appears to interfere with sterol biosynthesis by inhibiting the enzyme squalene2, 3-epoxidase.This inhibition of enzyme activity results in decreased amounts of sterols,especially ergosterol, and a corresponding accumulation of squalene in the cells.

Mechanism of Resistance

To date, a mechanism of resistance to naftifine has not been identified.

Naftifine has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section:

Trichophyton rubrum

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year dermal carcinogenicity study, naftifine hydrochloride cream was administered to Sprague-Dawley rats at topical doses of 1%, 2% and 3% (10, 20, and 30 mg/kg/day naftifine hydrochloride). No drug-related tumors were noted in this study up to the highest dose evaluated in this study of 30 mg/kg/day (12 times MRHD based on AUC comparison).

Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay).

Oral administration of naftifine hydrochloride to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 100 mg/kg/day (6 times MRHD).

14 CLINICAL STUDIES

14.1 Tinea Cruris

Naftifine hydrochloride cream has been investigated for safety and efficacy in a randomized, double-blind, vehicle-controlled, multi-center trial in 146 subjects with symptomatic and dermatophyte culture positive tinea cruris. Subjects were randomized to receive naftifine hydrochloride cream or vehicle. Subjects applied naftifine hydrochloride cream or vehicle to the affected area plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs and symptoms of tinea cruris (presence or absence of erythema, pruritus, and scaling) were assessed, and KOH examination and dermatophyte culture were performed at the primary efficacy endpoint at week 4.

The mean age of the trial population was 47 years and 87% were male and 43% were white. At baseline, subjects were confirmed to have signs and symptoms of tinea cruris, positive KOH exam, and confirmed dermatophyte presence based on culture results from a central mycology laboratory. The analysis of the intent-to-treat population was a comparison of the proportions of subjects with a complete cure at the week 4 visit (see Table 1). Complete cure was defined as both clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture).

The percentage of subjects experiencing clinical cure and the percentage of subjects experiencing mycological cure at week 4 are presented individually in Table 1 below.

Table 1 Efficacy Results for Pivotal Tinea Cruris Trial (Week 4 Assessment)

Endpoint	Naftifine Hydrochloride Cream, 2%	Vehicle
	N=75	N=71
Complete Curea	19 (25%)	2 (3%)
Effective Treatmentb	45 (60%)	7 (10%)
Mycological Curec	54 (72%)	11 (16%)
a. Complete cure is a composite endpoint of both mycological cure and clinical cure. Clinical cure is defined as the absence of erythema, pruritus, and scaling (grade of 0).
b. Effective treatment is a negative KOH preparation and negative dermatophyte culture, erythema, scaling, and pruritus grades of 0 or 1 (absent or nearly absent).
c. Mycological cure is defined as negative KOH and dermatophyte culture.