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 practice.

In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with LUZU Cream, 1%, the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity.

A post-approval clinical trial was conducted in 75 subjects age 2 to <18 years old with tinea corporis. The adverse reactions in the LUZU Cream, 1% treated population were similar to the vehicle treated population.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. 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.

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information available on the presence of luliconazole 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 LUZU Cream, 1% to women who are breastfeeding. LUZU Cream, 1% has low systemic absorption. The lack of clinical data during lactation precludes a clear determination of the risk of LUZU Cream, 1% to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUZU Cream, 1% and any potential adverse effects on the breastfed infant from LUZU Cream, 1% or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of LUZU Cream, 1% in pediatric patients 12 to <18 years of age with tinea pedis and tinea cruris have been established by evidence from well-controlled trials in adult and pediatric subjects and a pharmacokinetic (PK) study in pediatric subjects [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of LUZU Cream, 1% in pediatric patients 2 to <18 years of age with tinea corporis have been established by evidence from a well-controlled trial in pediatric subjects [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.5 Geriatric Use

Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8% were 65 and over, while 1.4% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action

LUZU Cream, 1% is an azole antifungal [seeMicrobiology (12.4)].

12.2 Pharmacodynamics

At therapeutic doses, LUZU Cream, 1% is not expected to prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics

Luliconazole is the R enantiomer of a chiral molecule. The potential for interconversion between R and S enantiomers in humans has not been assessed. Information on the pharmacokinetics of luliconazole presented below refers to both R enantiomer and S enantiomer, if any, combined.

Luliconazole is >99% protein bound in plasma.

In a PK trial, 12 subjects with moderate to severe tinea pedis and 8 subjects with moderate to severe tinea cruris applied a mean daily amount of approximately 3.5 grams of LUZU Cream, 1% to the affected and surrounding areas once daily for 15 days. Plasma concentrations of luliconazole on Day 15 were measurable in all subjects and fluctuated little during the 24-hour interval. In subjects with tinea pedis, the mean ± SD of the maximum concentration (Cmax) was 0.40 ± 0.76 ng/mL after the first dose and 0.93 ± 1.23 ng/mL after the final dose. The mean time to reach Cmax (Tmax) was 16.9 ± 9.39 hours after the first dose and 5.8 ± 7.61 hours after the final dose. Exposure to luliconazole, as expressed by area under the concentration time curve (AUC0–24), was 6.88 ± 14.50 ng*hr/mL after the first dose and 18.74 ± 27.05 ng*hr/mL after the final dose. In subjects with tinea cruris, the mean ± SD Cmax was 4.91 ± 2.51 ng/mL after the first dose and 7.36 ± 2.66 ng/mL after the final dose. The mean Tmax was 21.0 ± 5.55 hours after the first dose and 6.5 ± 8.25 hours after the final dose. Exposure to luliconazole, as expressed by AUC0–24, was 85.1 ± 43.69 ng*hr/mL after the first dose and 121.74 ± 53.36 ng*hr/mL after the final dose.

PK data of luliconazole measured in adolescent subjects (12 to <18 years of age) with moderate to severe interdigital tinea pedis or moderate to severe tinea cruris as well as in subjects 2 to <18 years of age with tinea corporis are described in Specific Populations below.

Specific Populations

PK of luliconazole was assessed in 30 adolescent subjects 12 to <18 years of age with moderate to severe interdigital tinea pedis (N=15) or moderate to severe tinea cruris (N=15). Subjects with tinea pedis applied approximately 3 grams of LUZU Cream, 1% once daily to the affected area and adjacent skin for 15 days, while subjects with tinea cruris applied LUZU Cream, 1% once daily to the affected and adjacent skin for 8 days.

Generally, the systemic exposure of luliconazole was greater in the subjects with tinea cruris than tinea pedis. In subjects with tinea pedis, the systemic concentrations of luliconazole were quantifiable in all the subjects on Day 8 and Day 15. The mean ± SD Cmax was 1.80 ± 1.86 ng/mL after the first dose on Day 1, and 3.93 ± 1.67 ng/mL and 3.27 ± 1.71 ng/mL on Days 8 and 15, respectively. The mean ± SD AUC0-24 was 20.47 ± 14.47 ng*hr/mL after the first dose on Day 1, and 64.94 ± 32.47 ng*hr/mL and 60.38 ± 37.92 ng*hr/mL on Days 8 and Day 15, respectively. Like in adult subjects, the mean plasma concentrations of luliconazole in adolescent subjects on Days 8 and 15 were similar and fluctuated little during a 24-hour interval.

In subjects with moderate to severe tinea cruris, the systemic concentrations of luliconazole were quantifiable in all the subjects on Day 8. The mean ± SD Cmax was 9.80 ± 5.94 ng/mL after the first dose (Day 1) and 15.40 ± 13.62 ng/mL after the last dose (Day 8). The mean ± SD AUC0-24 was 157.07 ± 92.18 ng*hr/mL and 266.06 ± 236.07 ng*hr/mL, after the first dose (Day 1) and the last dose (Day 8).

In subjects with tinea corporis, the systemic concentrations of luliconazole were assessed at pre-dose and at 6 hours post-dose on the last day of treatment following once daily treatment with LUZU Cream, 1% for 7 days. The systemic concentrations were quantifiable in all the 12 subjects and the mean ± SD daily dose of LUZU Cream, 1% was 2.84 ± 1.82 g. The mean ± SD concentrations of luliconazole at 15 minutes prior to dosing and at 6 hours post-dose on Day 7 were 4.63 ± 2.93 ng/mL and 4.84 ± 3.33 ng/mL, respectively.

Drug Interactions

Results of in vitro studies indicated that therapeutic doses of LUZU Cream, 1% did not inhibit cytochrome P450 (CYP) enzymes 1A2, 2C9 and 2D6, but can inhibit the activity of CYP2B6, 2C8, 2C19, and 3A4. The most sensitive enzyme, CYP2C19, was further evaluated in an in vivo study using omeprazole as a probe substrate in adult subjects with moderate to severe interdigital tinea pedis and tinea cruris. The results showed that LUZU Cream, 1% applied at a daily amount of approximately 4 grams increased the omeprazole systemic exposure (AUC) by approximately 30% compared to the exposure of omeprazole administered alone. LUZU Cream, 1% is considered a weak inhibitor of CYP2C19. For tinea cruris, extrapolation from both in vitro inhibition studies and in vivo data in adults to the adolescent subjects showed that in some subjects, levels of luliconazole can approach or exceed those required to be a moderate inhibitor of CYP2C19.

Results of in vitro studies indicated that therapeutic doses of LUZU Cream, 1% did not induce CYP1A2, 2B6, and 3A4.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted.

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

In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment-related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment-related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1× MRHD based on BSA comparisons).

14.1 Interdigital Tinea Pedis

The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in two randomized, double-blind, vehicle-controlled, multi-center clinical trials in 423 subjects with a clinical and culture-confirmed diagnosis of interdigital tinea pedis. Subjects were randomized to receive LUZU Cream, 1% or vehicle. Subjects applied either LUZU Cream, 1% or vehicle cream to the entire area of the forefeet including all interdigital web spaces and approximately 2.5 cm (1 in) of the surrounding area of the foot once daily for 14 days.

The mean age of the study population was 41 years (range 13 to 78 years); 82% were male; 53% were White and 40% were Black or African American. Signs and symptoms of tinea pedis (erythema, scaling, and pruritus), KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 14), 2 and 4 weeks post-treatment.

Overall treatment success was defined as complete clearance (clinical cure and mycological cure) at 4 weeks post-treatment. LUZU Cream, 1% demonstrated complete clearance in subjects with interdigital tinea pedis. Treatment outcomes at 4 weeks post-treatment are summarized in Table 1.

14.2 Tinea Cruris

The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in a randomized, double-blind, vehicle-controlled, multi-center clinical trial in 256 subjects with a clinical and culture-confirmed diagnosis of tinea cruris. Subjects were randomized to receive LUZU Cream, 1% or vehicle. Subjects applied either LUZU Cream, 1% or vehicle cream to the affected area and approximately 2.5 cm (1 in) of the surrounding area once daily for 7 days.

The mean age of the study population was 40 years (range 14 to 88 years); 83% were male; 58% were White and 34% were Black or African American. Signs and symptoms of tinea cruris (erythema, scaling, and pruritus), positive KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 7), 2 and 3 weeks post-treatment.

Overall treatment success was defined as complete clearance (clinical cure and mycological cure) at 3 weeks post-treatment. LUZU Cream, 1% demonstrated complete clearance in subjects with tinea cruris. Treatment outcomes at 3 weeks post-treatment are summarized in Table 2.

14.3 Tinea Corporis

The safety and efficacy of LUZU (luliconazole) Cream, 1% was evaluated in a randomized, double-blind, vehicle-controlled, multi-center clinical trial in 75 subjects age 2 to <18 years old with a clinical and culture-confirmed diagnosis of tinea corporis. Subjects were randomized to receive LUZU Cream, 1% or vehicle cream. Subjects applied either LUZU Cream, 1% or vehicle cream to the affected area and approximately 2.5 cm (1 in) of the surrounding skin once daily for 7 days.

The mean age of the study population was 8 years; 72% were male; 36% were White and 64% were Black or African American. Signs and symptoms of tinea cruris (erythema, scaling, and pruritus), positive KOH exam and dermatophyte culture were assessed at baseline, end-of-treatment (Day 7), 2 and 3 weeks post-treatment.

Treatment outcomes at 3 weeks post-treatment are summarized in Table 3.

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].