These Highlights Do Not Include All The Information Needed To Use Naftifine Hydrochloride Gel Safely And Effectively. See Full Prescribing Information For Naftifine Hydrochloride Gel.

How Supplied

Naftifine Hydrochloride Gel USP, 2% is a colorless to yellow gel supplied in collapsible tubes in the following size:

45g – NDC 51672-1376-6

60g – NDC 51672-1376-3

Risk Summary

There are no available data on naftifine hydrochloride gel use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, no adverse effects on embryofetal development were seen at oral doses administered during the period of organogenesis up to 37 times the maximum recommended human dose (MRHD) in pregnant rats or subcutaneous doses administered during the period of organogenesis up to 4 times the MRHD in pregnant rats or 7 times the MRHD in pregnant rabbits ( see Data ).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Storage

Store at 20° to 25°C (68° to 77°F);[see USP Controlled Room Temperature].

Naftifine Hydrochloride Gel USP, 2% is a clear to yellow gel for topical use only. Each gram of naftifine hydrochloride gel contains 20 mg of naftifine hydrochloride, a synthetic allylamine antifungal compound.

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

The molecular formula is C ₂₁H ₂₁N∙HCl with a molecular weight of 323.86.

The structural formula of naftifine hydrochloride is:

Naftifine Hydrochloride Gel USP, 2% contains the following inactive ingredients: alcohol (95% v/v), benzyl alcohol, edetate disodium, hydroxyethyl cellulose, polysorbate 20, propylene glycol, purified water and trolamine.

The safety and effectiveness of naftifine hydrochloride gel have been established in the age group 12 to 18 years of age with interdigital tinea pedis. Use of naftifine hydrochloride 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 naftifine hydrochloride 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.

During clinical trials, 99 subjects (9%) aged 65 years and over were exposed to naftifine hydrochloride gel. Safety and effectiveness were similar to those reported by younger subjects.

Naftifine hydrochloride gel has been evaluated for efficacy in two randomized, double-blind, vehicle-controlled, multicenter trials that included 1175 subjects with symptomatic and dermatophyte culture-positive interdigital tinea pedis. Subjects were randomized to receive naftifine hydrochloride gel or vehicle. Subjects applied naftifine hydrochloride gel 2% or vehicle to the affected area of the foot once daily for 2 weeks. Signs and symptoms of interdigital tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed and potassium hydroxide (KOH) examination and dermatophyte culture were performed 6 weeks after the first treatment.

The mean age of the study population was 45 years; 77% were male; and 60% were Caucasian, 35% were Black or African American, and 26% were Hispanic or Latino. 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 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.

None.

The pharmacodynamics of naftifine hydrochloride gel have not been established.

In vitroand in vivobioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of dermatophytes.

Pharmacokinetic analysis of plasma samples from 32 subjects with tinea pedis treated with a mean dose of 3.9 grams naftifine hydrochloride gel applied once daily to both feet for 14 days showed increased exposure over the treatment period, with a geometric mean (CV%) AUC _0-24(area under plasma concentration-versus-time curve from time 0 to 24 hours) of 10.5 (118) ng∙hr/mL on Day 1 and an AUC _0-24of 70 (59) ng∙hr/mL on Day 14. The accumulation ratio based on AUC was approximately 6.

Maximum concentration (C _max) also increased over the treatment period; geometric mean (CV%) C _maxafter a single dose was 0.9 (92) ng/mL on Day 1; C _maxon Day 14 was 3.7 (64) ng/mL. Median T _maxwas 20 hours (range: 8, 20 hours) after a single application on Day 1 and 8 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 naftifine hydrochloride gel was evaluated in 22 pediatric subjects 12 to 17 years of age with tinea pedis. Subjects were treated with a mean dose of 4.1 grams naftifine hydrochloride 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%) AUC _0-24was 15.9 (212) ng∙hr/mL on Day 1 and 60 (131) ng∙hr/mL on Day 14. Geometric mean (CV%) C _maxafter 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.

Naftifine hydrochloride gel USP, 2% is indicated for the treatment of interdigital tinea pedis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.

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

If redness or irritation develops with the use of naftifine hydrochloride gel treatment should be discontinued. ( 5.1)

Apply a thin layer of naftifine hydrochloride gel, 2% once daily to the affected areas plus an approximate ½ inch margin of healthy surrounding skin for 2 weeks.

For topical use only. Naftifine hydrochloride gel, 2% is not for ophthalmic, oral, or intravaginal use.

If irritation or sensitivity develops with the use of naftifine hydrochloride gel, treatment should be discontinued.

Gel, 2%. Each gram contains 20 mg of naftifine hydrochloride in a colorless to yellow gel.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In two randomized, vehicle-controlled trials, 1143 subjects were treated with naftifine hydrochloride gel versus 571 subjects treated with the vehicle. The trial subjects were 12 to 92 years old, were primarily male (76%), and were 59% Caucasian, 38% Black or African American, and 23% Hispanic or Latino. Subjects received doses once daily, topically, for 2 weeks to cover the affected skin areas plus a ½-inch margin of surrounding healthy skin. The most common adverse reactions were application site reactions which occurred at the rate of 2% in naftifine hydrochloride 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 to 17 years of age with interdigital tinea pedis received naftifine hydrochloride 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 naftifine hydrochloride gel to cause irritation. There was no evidence that naftifine hydrochloride gel causes contact sensitization, phototoxicity, or photoallergenicity in healthy skin.

• Inform patients that naftifine hydrochloride gel is for topical use only. Naftifine hydrochloride gel is not intended for ophthalmic, oral, or intravaginal use.
• Patients should be directed to contact their physician if irritation develops with the use of naftifine hydrochloride gel.

NDC 51672-1376-3

60 g

Naftifine Hydrochloride

Gel USP, 2%

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC USE, ORAL OR INTRAVAGINAL USE

Rx only

Keep this and all medications out of the reach of children.

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 mg/kg/day, 20 mg/kg/day, 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 (36 times MRHD based on AUC comparison).

Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitrogenotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivogenotoxicity 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 (12 times MRHD based on mg/m ²comparison).

How Supplied

Naftifine Hydrochloride Gel USP, 2% is a colorless to yellow gel supplied in collapsible tubes in the following size:

45g – NDC 51672-1376-6

60g – NDC 51672-1376-3

Risk Summary

There are no available data on naftifine hydrochloride gel use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, no adverse effects on embryofetal development were seen at oral doses administered during the period of organogenesis up to 37 times the maximum recommended human dose (MRHD) in pregnant rats or subcutaneous doses administered during the period of organogenesis up to 4 times the MRHD in pregnant rats or 7 times the MRHD in pregnant rabbits ( see Data ).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Storage

Store at 20° to 25°C (68° to 77°F);[see USP Controlled Room Temperature].

Naftifine Hydrochloride Gel USP, 2% is a clear to yellow gel for topical use only. Each gram of naftifine hydrochloride gel contains 20 mg of naftifine hydrochloride, a synthetic allylamine antifungal compound.

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

The molecular formula is C ₂₁H ₂₁N∙HCl with a molecular weight of 323.86.

The structural formula of naftifine hydrochloride is:

Naftifine Hydrochloride Gel USP, 2% contains the following inactive ingredients: alcohol (95% v/v), benzyl alcohol, edetate disodium, hydroxyethyl cellulose, polysorbate 20, propylene glycol, purified water and trolamine.

The safety and effectiveness of naftifine hydrochloride gel have been established in the age group 12 to 18 years of age with interdigital tinea pedis. Use of naftifine hydrochloride 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 naftifine hydrochloride 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.

During clinical trials, 99 subjects (9%) aged 65 years and over were exposed to naftifine hydrochloride gel. Safety and effectiveness were similar to those reported by younger subjects.

Naftifine hydrochloride gel has been evaluated for efficacy in two randomized, double-blind, vehicle-controlled, multicenter trials that included 1175 subjects with symptomatic and dermatophyte culture-positive interdigital tinea pedis. Subjects were randomized to receive naftifine hydrochloride gel or vehicle. Subjects applied naftifine hydrochloride gel 2% or vehicle to the affected area of the foot once daily for 2 weeks. Signs and symptoms of interdigital tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed and potassium hydroxide (KOH) examination and dermatophyte culture were performed 6 weeks after the first treatment.

The mean age of the study population was 45 years; 77% were male; and 60% were Caucasian, 35% were Black or African American, and 26% were Hispanic or Latino. 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 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.

None.

The pharmacodynamics of naftifine hydrochloride gel have not been established.

In vitroand in vivobioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of dermatophytes.

Pharmacokinetic analysis of plasma samples from 32 subjects with tinea pedis treated with a mean dose of 3.9 grams naftifine hydrochloride gel applied once daily to both feet for 14 days showed increased exposure over the treatment period, with a geometric mean (CV%) AUC _0-24(area under plasma concentration-versus-time curve from time 0 to 24 hours) of 10.5 (118) ng∙hr/mL on Day 1 and an AUC _0-24of 70 (59) ng∙hr/mL on Day 14. The accumulation ratio based on AUC was approximately 6.

Maximum concentration (C _max) also increased over the treatment period; geometric mean (CV%) C _maxafter a single dose was 0.9 (92) ng/mL on Day 1; C _maxon Day 14 was 3.7 (64) ng/mL. Median T _maxwas 20 hours (range: 8, 20 hours) after a single application on Day 1 and 8 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 naftifine hydrochloride gel was evaluated in 22 pediatric subjects 12 to 17 years of age with tinea pedis. Subjects were treated with a mean dose of 4.1 grams naftifine hydrochloride 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%) AUC _0-24was 15.9 (212) ng∙hr/mL on Day 1 and 60 (131) ng∙hr/mL on Day 14. Geometric mean (CV%) C _maxafter 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.

Naftifine hydrochloride gel USP, 2% is indicated for the treatment of interdigital tinea pedis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.

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

If redness or irritation develops with the use of naftifine hydrochloride gel treatment should be discontinued. ( 5.1)

Apply a thin layer of naftifine hydrochloride gel, 2% once daily to the affected areas plus an approximate ½ inch margin of healthy surrounding skin for 2 weeks.

For topical use only. Naftifine hydrochloride gel, 2% is not for ophthalmic, oral, or intravaginal use.

If irritation or sensitivity develops with the use of naftifine hydrochloride gel, treatment should be discontinued.

Gel, 2%. Each gram contains 20 mg of naftifine hydrochloride in a colorless to yellow gel.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In two randomized, vehicle-controlled trials, 1143 subjects were treated with naftifine hydrochloride gel versus 571 subjects treated with the vehicle. The trial subjects were 12 to 92 years old, were primarily male (76%), and were 59% Caucasian, 38% Black or African American, and 23% Hispanic or Latino. Subjects received doses once daily, topically, for 2 weeks to cover the affected skin areas plus a ½-inch margin of surrounding healthy skin. The most common adverse reactions were application site reactions which occurred at the rate of 2% in naftifine hydrochloride 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 to 17 years of age with interdigital tinea pedis received naftifine hydrochloride 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 naftifine hydrochloride gel to cause irritation. There was no evidence that naftifine hydrochloride gel causes contact sensitization, phototoxicity, or photoallergenicity in healthy skin.

• Inform patients that naftifine hydrochloride gel is for topical use only. Naftifine hydrochloride gel is not intended for ophthalmic, oral, or intravaginal use.
• Patients should be directed to contact their physician if irritation develops with the use of naftifine hydrochloride gel.

NDC 51672-1376-3

60 g

Naftifine Hydrochloride

Gel USP, 2%

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC USE, ORAL OR INTRAVAGINAL USE

Rx only

Keep this and all medications out of the reach of children.

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 mg/kg/day, 20 mg/kg/day, 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 (36 times MRHD based on AUC comparison).

Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitrogenotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivogenotoxicity 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 (12 times MRHD based on mg/m ²comparison).