adverse reactions were application site reactions which occurred at the rate of 2% in naftin gel arm versus 1% in vehicle arm. most adverse reactions were mild in severity. in an open-label pediatric pharmacokinetics and safety trial 22 pediatric subjects 12-17 years of age with interdigital tinea pedis received naftin ® gel. the incidence of adverse reactions in the pediatric population was similar to that observed in adult population. cumulative irritancy testing revealed the potential for naftin ® gel to cause irritation. there was no evidence that naftin ® gel causes contact sensitization, phototoxicity, or photoallergenicity in healthy skin. 6.2 postmarketing experience because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the following adverse reactions have been identified during post-approval use of naftifine hydrochloride: blisters, burning sensation, crusting, dryness, erythema/redness, inflammation, irritation, maceration, pain, pruritus [mild]/itching, rash and swelling.

data animal data systemic embryofetal development studies were conducted in rats and rabbits. for the comparison of animal to human doses, the mrhd is set at 4 g 2% gel per day (1.33 mg/kg/day for a 60 kg individual). oral doses of 30, 100, and 300 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis to pregnant female rats. no treatment-related effects on embryofetal toxicity were noted at doses up to 300 mg/kg/day (37 times the mrhd based on mg/m 2 comparison). subcutaneous doses of 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis to pregnant female rats. no treatment-related effects on embryofetal toxicity were noted at 30 mg/kg/day (4 times the mrhd based on mg/m 2 comparison). subcutaneous doses of 3, 10, and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis to pregnant female rabbits. no treatment-related effects on embryofetal toxicity were noted at 30 mg/kg/day (7 times the mrhd based on mg/m 2 comparison). a peri-and post-natal development study was conducted in rats. oral doses of 30, 100, and 300 mg/kg/day naftifine hydrochloride were administered to female rats from gestational day 14 to lactation day 21. reduced body weight gain of females during gestation and of the offspring during lactation was noted at 300 mg/kg/day (37 times the mrhd based on mg/m 2 comparison). no developmental toxicity was noted at 100 mg/kg/day (12 times the mrhd based on mg/m 2 comparison). 8.2 lactation risk summary there is no information available on the presence of naftifine hydrochloride in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production after topical application of naftin gel to women who are breastfeeding. it is not known whether naftifine hydrochloride is excreted in human milk. because many drugs are excreted in human milk, caution should be exercised when naftifine hydrochloride is administered to a nursing woman. the lack of clinical data during lactation precludes a clear determination of the risk naftin gel to an infant during lactation. therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naftin gel and any potential adverse effects on the breastfed infant from naftin gel or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of naftin® gel have been established in the age group 12 to 18 years of age with interdigital tinea pedis. use of naftin® gel in this age group is supported by evidence from adequate and well controlled trials in adults with additional safety and pk data from an open label trial, conducted in 22 adolescents ≥12 years of age who were exposed to naftin® gel at a dose of approximately 4 g/day [see clinical pharmacology (12.3) ] . safety and effectiveness in pediatric patients <12 years of age have not been established. 8.5 geriatric use during clinical trials, 99 subjects (9%) aged 65 years and over were exposed to naftin ® gel. safety and effectiveness were similar to those reported by younger subjects.

ryofetal development studies were conducted in rats and rabbits. for the comparison of animal to human doses, the mrhd is set at 4 g 2% gel per day (1.33 mg/kg/day for a 60 kg individual). oral doses of 30, 100, and 300 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis to pregnant female rats. no treatment-related effects on embryofetal toxicity were noted at doses up to 300 mg/kg/day (37 times the mrhd based on mg/m 2 comparison). subcutaneous doses of 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis to pregnant female rats. no treatment-related effects on embryofetal toxicity were noted at 30 mg/kg/day (4 times the mrhd based on mg/m 2 comparison). subcutaneous doses of 3, 10, and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis to pregnant female rabbits. no treatment-related effects on embryofetal toxicity were noted at 30 mg/kg/day (7 times the mrhd based on mg/m 2 comparison). a peri-and post-natal development study was conducted in rats. oral doses of 30, 100, and 300 mg/kg/day naftifine hydrochloride were administered to female rats from gestational day 14 to lactation day 21. reduced body weight gain of females during gestation and of the offspring during lactation was noted at 300 mg/kg/day (37 times the mrhd based on mg/m 2 comparison). no developmental toxicity was noted at 100 mg/kg/day (12 times the mrhd based on mg/m 2 comparison).

%) c max after a single dose was 0.9 (92) ng/ml on day 1; c max on day 14 was 3.7 (64) ng/ml. median t max was 20.0 hours (range: 8, 20 hours) after a single application on day 1 and 8.0 hours (range: 0, 24 hours) on day 14. trough plasma concentrations increased during the trial period and reached steady state after 11 days. in the same pharmacokinetic trial the fraction of dose excreted in urine during the treatment period was less than or equal to 0.01% of the applied dose. in a second trial, the pharmacokinetics of naftin ® gel was evaluated in 22 pediatric subjects 12-17 years of age with tinea pedis. subjects were treated with a mean dose of 4.1 grams naftin ® gel applied to the affected area once daily for 14 days. the results showed that the systemic exposure increased over the treatment period. geometric mean (cv%) auc0-24 was 15.9 (212) ng∙hr/ml on day 1 and 60.0 (131) ng∙hr/ml on day 14. geometric mean (cv%) cmax after a single dose was 1.40 (154) ng/ml on day 1 and 3.81 (154) ng/ml on day 14. the fraction of dose excreted in urine during the treatment period was less than or equal to 0.003% of the applied dose. 12.4 microbiology mechanism of action naftifine is an antifungal that belongs to the allylamine class. 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. the inhibition of enzyme activity by this allylamine 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 trichophyton mentagrophytes epidermophyton floccosum

. trough plasma concentrations increased during the trial period and reached steady state after 11 days. in the same pharmacokinetic trial the fraction of dose excreted in urine during the treatment period was less than or equal to 0.01% of the applied dose. in a second trial, the pharmacokinetics of naftin ® gel was evaluated in 22 pediatric subjects 12-17 years of age with tinea pedis. subjects were treated with a mean dose of 4.1 grams naftin ® gel applied to the affected area once daily for 14 days. the results showed that the systemic exposure increased over the treatment period. geometric mean (cv%) auc0-24 was 15.9 (212) ng∙hr/ml on day 1 and 60.0 (131) ng∙hr/ml on day 14. geometric mean (cv%) cmax after a single dose was 1.40 (154) ng/ml on day 1 and 3.81 (154) ng/ml on day 14. the fraction of dose excreted in urine during the treatment period was less than or equal to 0.003% of the applied dose.

endpoint was the proportion of subjects with a complete cure at 6 weeks after the start of treatment (4 weeks after the last treatment). 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 1 below. table 1 interdigital tinea pedis: number (%) of subjects with complete cure, effective treatment, and mycological cure at week 6 following treatment with naftin ® gel (full analysis set, missing values treated as treatment failure) trial 1 trial 2 endpoint naftin ® gel, 2% n=382 n (%) vehicle n=179 n (%) naftin ® gel, 2% n=400 n (%) vehicle n=213 n (%) complete cure 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). 64 (17%) 3 (2%) 104 (26%) 7 (3%) treatment effectiveness effective treatment is a negative koh preparation and negative dermatophyte culture, erythema, scaling, and pruritus grades of 0 or 1 (absent or nearly absent). 207 (54%) 11 (6%) 203 (51%) 15 (7%) mycological cure mycological cure is defined as negative koh and dermatophyte culture. 250 (65%) 25 (14%) 235 (59%) 22 (10%)