Luliconazole

1 INDICATIONS AND USAGE Luliconazole Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum . Luliconazole Cream, 1% is an azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum. ( 1 )

2 DOSAGE AND ADMINISTRATION For topical use only. Luliconazole Cream, 1% is not for ophthalmic, oral, or intravaginal use. • When treating interdigital tinea pedis, a thin layer of Luliconazole Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for 2 weeks. • When treating tinea cruris or tinea corporis, Luliconazole Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for 1 week. • For topical use only. Not for ophthalmic, oral, or intravaginal use. ( 2 ) • Interdigital Tinea Pedis: Luliconazole Cream, 1% should be applied to the affected and immediate surrounding area(s) once a day for 2 weeks. ( 2 ) • Tinea Cruris and Tinea Corporis: Luliconazole Cream, 1% should be applied to the affected skin and immediate surrounding area(s) once a day for 1 week. ( 2 )

6 ADVERSE REACTIONS The most common adverse reactions observed in clinical trials were application site reactions, which occurred in less than 1% of subjects. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Luliconazole Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied Luliconazole Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with Luliconazole Cream, 1%, the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the Luliconazole 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 Luliconazole 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.

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 Luliconazole 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 Luliconazole Cream, 1% once daily to the affected area and adjacent skin for 15 days, while subjects with tinea cruris applied Luliconazole 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 Luliconazole Cream, 1% for 7 days. The systemic concentrations were quantifiable in all the 12 subjects and the mean ± SD daily dose of Luliconazole 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 Luliconazole 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 Luliconazole 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. Luliconazole 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 Luliconazole Cream, 1% did not induce CYP1A2, 2B6, and 3A4.