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Naftin Cream

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Naftin Cream

CLINICAL PHARMACOLOGY

Mechanism Of Action

NAFTIN Cream is a topical antifungal drug [see Microbiology]

Pharmacodynamics

The pharmacodynamics of NAFTIN Cream have not been established.

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 NAFTIN Cream was evaluated following once-daily topical application for 2 weeks to twenty one 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 5.3-7.5 g) per day. The results showed that the systemic exposure (i.e., maximum concentration (Cmax) and area under the curve (AUC)) to naftifine increased over the 2 week treatment period in all the 21 subjects. Geometric Mean (CV%) AUC0-24 was 117 (41.2) ng*hr/mL on Day 1, and 204 (28.5) ng*hr/mL on Day 14. Geometric Mean (CV %) Cmax was 7 ng/mL (55.6) on Day 1 and 11 ng/mL (29.3) on day 14. Median Tmax was 8.0 hours on Day 1 (range: 4 to 24) and 6.0 hours on Day 14 (range: 0 to 16). 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 (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 NAFTIN Cream was evaluated in 20 pediatric subjects 13 – 17 years of age with both tinea pedis and tinea cruris. Subjects were treated with a median dose of 8.1 g (range 6.6-10.1 g) applied to the affected areas once daily for 14 days. The results showed that the systemic exposure increased over the treatment period. Geometric Mean (CV%) AUC0-24 was 138 (50.2) ng*hr/mL on Day 1, and 192 (74.9) ng*hr/mL on Day 14. Geometric Mean (CV %) Cmax 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.

Microbiology

Although the exact mechanism of action against fungi is not known, naftifine hydrochloride appears to interfere with sterol biosynthesis by inhibiting the enzyme squalene 2, 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

Clinical Studies

Tinea Cruris

NAFTIN Cream has been investigated for safety and efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 146 subjects with symptomatic and dermatophyte culture positive tinea cruris. Subjects were randomized to receive (naftifine hydrochloride) Cream or vehicle. Subjects applied the study agent (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 study 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-totreat 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 NAFTIN (naftifine hydrochloride) Cream, 2%
N=75
Vehicle
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 Myco logical cure is defined as negative KOH and dermatophyte culture.

Interdigital Tinea Pedis

NAFTIN Cream has been investigated for efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 217 subjects with symptomatic and dermatophyte culture positive interdigital tinea pedis. Subjects were randomized to receive NAFTIN Cream or vehicle. Subjects applied the study agent (naftifine hydrochloride) Cream or vehicle to the affected area of the foot plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs and symptoms of interdigital tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed and KOH examination and dermatophyte culture was performed at the primary efficacy endpoint at week 6.

The mean age of the study population was 42 years and 71% were male and 57% were white. At baseline, subjects were confirmed to have signs and symptoms of interdigital tinea pedis, positive KOH exam, and confirmed dermatophyte culture. The primary efficacy endpoint was the proportions of subjects with a complete cure at the week 6 visit (see Table 2). Complete cure was defined as both a clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture).

The efficacy results at week 6, four weeks following the end of treatment, are presented in Table 2 below. Naftin Cream demonstrated complete cure in subjects with interdigital tinea pedis, but complete cure in subjects with only moccasin type tinea pedis was not demonstrated.

Table 2 : Efficacy Results for Pivotal Interdigital Tinea Pedis Trial (Week 6 Assessment)

Endpoint NAFTIN (naftifine hydrochloride) Cream, 2%
N=147
Vehicle
N=70
Complete Curea 26 (18%) 5 (7%)
Effective Treatmentb 83 (57%) 14 (20%)
Mycological Curec 99 (67%) 15 (21%)
a Complete cure is a composite endpoint of both mycological cure and clinical cure. Clinical cure is defined as 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 near absent).
c Mycological cure is defined as negative KOH and dermatophyte culture.

Last reviewed on RxList: 12/2/2014
This monograph has been modified to include the generic and brand name in many instances.

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