5.1 Flammability

Ecoza is flammable. Avoid heat, flame, and smoking during and immediately following application. Contents under pressure. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C) even when empty. Do not store in direct sunlight.

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 two double-blind, vehicle-controlled clinical trials, 495 subjects with interdigital tinea pedis applied Ecoza or vehicle once daily for approximately 28 days (246 subjects were exposed to Ecoza and 249 were exposed to vehicle). During clinical trials with Ecoza, the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the Ecoza and vehicle arms.

7.1 Warfarin

Concomitant administration of econazole and warfarin has resulted in enhancement of anticoagulant effect. Most cases reported product application with use under occlusion, genital application, or application to a large body surface area which may increase the systemic absorption of econazole nitrate. Monitoring of International Normalized Ratio (INR) and/or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion.

8.1 Pregnancy

Risk Summary

There are no available data on Ecoza 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, econazole nitrate did not cause malformation in mice, rabbits and/or rats at oral doses 80 or 40 times the human dermal dose (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.

Data

Animal Data

Econazole nitrate did not cause malformation in mice, rabbits and/or rats. Fetotoxic or embryotoxic effects were observed in oral fertility studies in rats receiving 10 to 40 times the human dermal dose. Similar effects were observed in embryofetal and pre- and postnatal developmental studies in mice, rabbits and/or rats receiving oral doses 80 or 40 times the human dermal dose.

8.2 Lactation

Risk Summary

There is no information available on the presence of econazole nitrate 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 Ecoza to women who are breastfeeding. It is not known whether econazole nitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when econazole nitrate is administered to a nursing woman. Following oral administration of econazole nitrate to lactating rats, econazole and/or metabolites were excreted in milk and were found in nursing pups.

The lack of clinical data during lactation precludes a clear determination of the risk Ecoza to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ecoza and any potential adverse effects on the breastfed infant from Ecoza or from the underlying maternal condition.

8.4 Pediatric Use

Of the 173 subjects treated with Ecoza in the clinical trials, 2 subjects were 12-17 years old. In a pediatric maximal use trial, Ecoza was applied once daily to eighteen subjects aged 12 to 17 years with interdigital tinea pedis for 28 days [see Clinical Pharmacology (12.3)]. The safety findings for subjects 12 to 17 years were similar to those in adult population.

8.5 Geriatric Use

Of the 173 subjects treated with Ecoza in the adult clinical trials, 6 subjects were 65 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

12.1 Mechanism of Action

Ecoza is an azole antifungal [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

The pharmacodynamics of Ecoza have not been established.

12.3 Pharmacokinetics

The systemic absorption of Ecoza following topical application was studied in one clinical trial in adults and one clinical study in pediatric subjects.

In the adult trial, 19 subjects (male and female) with tinea pedis applied Ecoza once daily for 29 days. Subjects applied a mean daily amount of 2.4 g of Ecoza to soles, toes, interdigital spaces and tops of both feet up to the ankles. Blood samples were obtained on Day 29 at pre-dose and 1, 2, 4, 6, 8, and 12 hours after application. Results (mean ± SD) showed the time to reach peak plasma concentrations (Tmax) was 6.8 ± 5.1 h with maximum concentration (Cmax) of 417 ± 218 pg/mL. The area under the concentration time curve for the first 12 hours post application on Day 29 (AUC(0-12)) was 3440 ± 1920 pg-h/ml.

In the pediatric trial, 18 subjects (male and female ages 12 - 17) with interdigital tinea pedis and positive fungal cultures were treated with Ecoza once daily for 4 weeks. Subjects applied a mean daily amount of 3.2 g of Ecoza to soles, toes, interdigital spaces and tops of both feet up to the ankles. Blood samples were obtained on Day 28 at pre-dose and 7 h and 11 h post-dose. The mean ± SD econazole plasma concentration was 397 ± 289, 534 ± 745 and 575 ± 638 pg/mL at pre-dose and 7 h and 11 h post-dose, respectively.

Drug Interaction Studies

Ecoza is not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, or induce CYP1A2, 2B6, and 3A4.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to determine the carcinogenic potential of Ecoza have not been performed.

Oral administration of econazole nitrate in rats has been reported to produce prolonged gestation.