LUZU Cream, 1% Ref.[10128] Active ingredients: Luliconazole

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

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 (C_max) 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 C_max (T_max) 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 (AUC_0–24), 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 C_max was 4.91 ± 2.51 ng/mL after the first dose and 7.36 ± 2.66 ng/mL after the final dose. The mean T_max 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 AUC_0–24, 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 C_max 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 AUC_0-24 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 C_max 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 AUC_0-24 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.

Mechanism of Action

Luliconazole is an antifungal that belongs to the azole class. Although the exact mechanism of action against dermatophytes is unknown, luliconazole appears to inhibit ergosterol synthesis by inhibiting the enzyme lanosterol demethylase. Inhibition of this enzyme’s activity by azoles results in decreased amounts of ergosterol, a constituent of fungal cell membranes, and a corresponding accumulation of lanosterol.

Mechanism of Resistance

To date, a mechanism of resistance to luliconazole has not been described.

LUZU Cream, 1% 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
• Epidermophyton floccosum

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.

Table 1. Efficacy Results at 4 Weeks Post-treatment – Interdigital Tinea Pedis:

* Proportion of subjects who achieved both clinical cure and mycological cure
^† Negative KOH and culture and at most mild erythema and/or scaling and no pruritus
^‡ Absence of erythema, scaling and pruritus
^§ Negative KOH and negative fungal culture

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.

Table 2. Efficacy Results at 3 Weeks Post-treatment – Tinea Cruris:

* Proportion of subjects who achieved both clinical cure and mycological cure
^† Negative KOH and culture and at most mild erythema and/or scaling and no pruritus
^‡ Absence of erythema, scaling and pruritus
^§ Negative KOH and negative fungal culture

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.

Table 3. Efficacy Results at 3 Weeks Post-treatment – Tinea Corporis:

* Proportion of subjects who achieved both clinical cure and mycological cure
^† Negative KOH and culture and at most mild erythema and/or scaling and no pruritus
^‡ Absence of erythema, scaling and pruritus
^§ Negative KOH and negative fungal culture