5.1 Local Adverse Reactions

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

6.1 Clinical Trials Experience

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.

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.

8.1 Pregnancy

There are no adequate and well-controlled trials of naftifine hydrochloride gel in pregnant women. Because animal reproduction studies are not always predictive of human response, naftifine hydrochloride gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The animal multiples of human exposure calculations were based on daily dose body surface area comparison (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 4 g 2% gel per day (1.33 mg/kg/day for a 60 kg individual).

Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 to 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at doses up to 300 mg/kg/day (36.5× MRHD). Subcutaneous doses of 10 mg/kg/day and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 to 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (3.7× MRHD). Subcutaneous doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 to 18) to pregnant female rabbits. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (7.3× MRHD).

A peri- and post-natal development study was conducted in rats. Oral doses of 30 mg/kg/day, 100 mg/kg/day, 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 (36.5× MRHD). No developmental toxicity was noted at 100 mg/kg/day (12.2× MRHD).

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naftifine hydrochloride gel is administered to a nursing woman.

8.4 Pediatric Use

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

Use of naftifine hydrochloride gel in this age group is supported by evidence from adequate and well controlled studies 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.

8.5 Geriatric Use

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.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The pharmacodynamics of naftifine hydrochloride gel 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.

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%) AUC0-24 (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 AUC0-24 of 70 (59) ng∙hr/mL on Day 14. The accumulation ratio based on AUC was approximately 6.

Maximum concentration (Cmax) also increased over the treatment period; geometric mean (CV%) Cmax after a single dose was 0.9 (92) ng/mL on Day 1; Cmax on Day 14 was 3.7 (64) ng/mL. Median Tmax was 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%) AUC0-24 was 15.9 (212) ng∙hr/mL on Day 1 and 60 (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

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 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 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 (12 times MRHD based on mg/m2 comparison).

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

Storage

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