ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse reactions (rosacea and seborrheic dermatitis) were reported in adult patient treated with XEPI (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Biofrontera, Inc. at 1-844-829-7434 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety profile of XEPI was assessed in two clinical trials (Trial and Trial 2) in 362 adult and pediatric patients two months of age and older with impetigo. The patients used at least one dose from 5-day, twice day regimen of XEPI. Control groups included 361 patients who used placebo and 152 patients who used retapamulin ointment. The median age of the patients enrolled in the clinical trials was 10 years; % of patients were months to less than years of age, 55 of patients were to less than 12 years of age, 11 of patients were 12 to less than 18 years of age, and 31 of patients were 18 years of age or older.Adverse reactions (rosacea and seborrheic dermatitis) were reported in adult patient treated with XEPI.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals to evaluate carcinogenic potential have not been conducted with ozenoxacin.Ozenoxacin demonstrated no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the Ames test, mouse lymphoma cell assay, or when evaluated in vivo in rat micronucleus test with demonstrated systemic exposure.Oral doses of ozenoxacin did not affect mating and fertility in male and female rats treated up to 500 mg/kg/day (about 8500 and 16,000 times respectively, the maximum human plasma concentration seen with dermal application of ozenoxacin 1% cream).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. XEPI is an antimicrobial drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Exposure-Response RelationshipThe exposure response relationship for ozenoxacin following topical application has not been studied, however; relationship is unlikely because systemic exposure following topical application is negligible [see Clinical Pharmacology (12.3)].. 12.3 Pharmacokinetics. AbsorptionFour pharmacokinetic studies were conducted in 110 patients utilizing varying strengths of ozenoxacin cream, up to 2% (twice the concentration of the marketed formulation). Three of these studies assessed systemic absorption in healthy subjects and in subjects with impetigo. These studies were conducted with either single or repeated application of up to g ozenoxacin cream to intact or abraded skin (up to 200 cm2 surface area). No systemic absorption was observed in 84 of 86 subjects, and negligible systemic absorption was observed at the level of detection (0.489 ng/mL) in subjects.. DistributionPlasma protein binding of [14C]-ozenoxacin was moderate (~80 to 85%) and did not appear to be dependent on concentration. Since negligible systemic absorption was observed in clinical studies, tissue distribution has not been investigated in humans.. Elimination. Metabolism: Ozenoxacin was not metabolized in the presence of fresh human skin discs and was minimally metabolized in human hepatocytes.. Excretion: Studies have not been investigated in humans due to the negligible systemic absorption observed in clinical studies.. 12.4 Microbiology. Mechanism of ActionOzenoxacin is quinolone antimicrobial drug. The mechanism of action involves the inhibition of bacterial DNA replication enzymes, DNA gyrase and topoisomerase IV. Ozenoxacin has been shown to be bactericidal against S. aureus and S. pyogenes organisms.. ResistanceThe mechanism of quinolone resistance can arise through mutations of one or more of the genes that encode DNA gyrase or topoisomerase IV. Resistant organisms will typically carry combination of mutations within gyrA and parC subunits.Overall the frequency of resistant mutants selected by ozenoxacin is <=10-10.. Interaction with Other AntimicrobialsOzenoxacin has been tested in combination with 17 other commonly used antimicrobial agents against S. aureus and S.pyogenes. Antagonism interactions with ozenoxacin were observed with ciprofloxacin against S. aureus.. Antimicrobial ActivityOzenoxacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Gram-positive bacteria Staphylococcus aureus (including methicillin-resistant isolates) Streptococcus pyogenes.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of XEPI for the treatment of impetigo was evaluated in two multi-center, randomized, double-blind placebo controlled clinical trials (Trial 1, (NCT01397461) and Trial 2, (NCT02090764)). Seven-hundred twenty-three (723) subjects two months of age and older with an affected body surface area of up to 100 cm2, and not exceeding 2% for subjects aged months to 11 years were randomized to XEPI or placebo. Subjects applied XEPI or placebo twice daily for days. Subjects with underlying skin disease (e.g., preexisting eczematous dermatitis), skin trauma, clinical evidence of secondary infection, or systemic signs and symptoms of infection (such as fever), were excluded from these studies.Overall clinical success was defined as no need for additional antimicrobial therapy of the baseline affected area(s) and absence/reduction in clinical signs and symptoms assessed at the end of therapy (Day 6-7), as follows: absence of exudates/pus, crusting, tissue warmth, and pain; and erythema/inflammation, tissue edema, and itching assessed as less than mild in Trial 1; and absence of blistering, exudates/pus, crusting, and itching/pain, and mild or improved erythema/inflammation in Trial 2. Table below presents the results for clinical response at the end of therapy.Table Clinical Response at End of Therapy in Trial and Trial in All Randomized SubjectsTrial 1Trial 2XEPIPlaceboXEPIPlacebo(N 155)n (%)(N 156)n (%)(N 206)n (%)(N 206)n (%)a The success rates for ozenoxacin were significantly different than placebo in Study and Study (p 0.002 and = 0.001).Clinical success54 (34.8)30 (19.2)112 (54.4)78 (37.9)Clinical failure98 (63.2)120 (76.9)91 (44.2)121 (58.7)Unable to determine3 (1.9)6 (3.8)3 (1.5)7 (3.4)The most commonly identified bacteria were S. aureus and S. pyogenes. Table below presents the results for clinical success at end of therapy in subjects with S.aureus or S.pyogenes at baseline.Table Clinical Success at End of Therapy in Trial and Trial in Subjects with S. aureus or S. pyogenesTrial 1Trial 2XEPIPlaceboXEPIPlaceboClinical successn/N (%)n/N (%)n/N (%)n/N (%)S. aureus35/93 (37.6)16/98 (16.3)66/115 (57.4)36/108 (33.3)S. pyogenes29/73 (39.7)7/67 (10.4)15/19 (78.9)8/20 (40.0).

DESCRIPTION SECTION.

11 DESCRIPTION. XEPI contains ozenoxacin, quinolone antimicrobial. It is intended for topical use only.The chemical name of ozenoxacin is 1-Cyclopropyl-8-methyl-7-(5-methyl-6-methylamino-pyridin-3-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. Ozenoxacin, white to pale-yellow crystalline solid, has molecular formula of C21H21N3O3, and molecular weight of 363.41. The chemical structure is:Each gram of cream contains 10 mg of ozenoxacin (1% w/w) and the following inactive ingredients: benzoic acid, octyldodecanol, peglicol oleate, pegoxol stearate, propylene glycol, purified water, stearyl alcohol.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Apply thin layer of XEPI topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age.Wash hands after applying XEPI cream.XEPI cream is for topical use only.Not for oral, ophthalmic, intranasal, or intravaginal use.The treated area may be covered with sterile bandage or gauze dressing.. Wash hands after applying XEPI cream.. XEPI cream is for topical use only.. Not for oral, ophthalmic, intranasal, or intravaginal use.. The treated area may be covered with sterile bandage or gauze dressing.. Apply thin layer of XEPI topically to the affected area twice daily for days (2).Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age (2).For topical use only (2).Not for oral, ophthalmic, intranasal, or intravaginal use (2).. Apply thin layer of XEPI topically to the affected area twice daily for days (2).. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age (2).. For topical use only (2).. Not for oral, ophthalmic, intranasal, or intravaginal use (2).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients (and/or their caregivers or guardians) using XEPI of the following information and instructions:Use XEPI as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.XEPI is for external use only.Do not swallow XEPI or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area.The treated area may be covered by sterile bandage or gauze dressing.Use the medication for the entire time recommended by the healthcare practitioner, even though symptoms may have improved.Notify the healthcare practitioner if there is no improvement in symptoms within days after starting use of XEPI.. Use XEPI as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.. XEPI is for external use only.Do not swallow XEPI or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area.. The treated area may be covered by sterile bandage or gauze dressing.. Use the medication for the entire time recommended by the healthcare practitioner, even though symptoms may have improved.. Notify the healthcare practitioner if there is no improvement in symptoms within days after starting use of XEPI.

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of ozenoxacin in human milk, and the effects of ozenoxacin on the breastfed infant or on milk production. However, breastfeeding is not expected to result in exposure of the child to ozenoxacin due to the negligible systemic absorption of ozenoxacin in humans following topical administration of XEPI. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for XEPI and any potential adverse effects on the breast-fed child from XEPI or from the underlying maternal condition.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionOzenoxacin is quinolone antimicrobial drug. The mechanism of action involves the inhibition of bacterial DNA replication enzymes, DNA gyrase and topoisomerase IV. Ozenoxacin has been shown to be bactericidal against S. aureus and S. pyogenes organisms.. ResistanceThe mechanism of quinolone resistance can arise through mutations of one or more of the genes that encode DNA gyrase or topoisomerase IV. Resistant organisms will typically carry combination of mutations within gyrA and parC subunits.Overall the frequency of resistant mutants selected by ozenoxacin is <=10-10.. Interaction with Other AntimicrobialsOzenoxacin has been tested in combination with 17 other commonly used antimicrobial agents against S. aureus and S.pyogenes. Antagonism interactions with ozenoxacin were observed with ciprofloxacin against S. aureus.. Antimicrobial ActivityOzenoxacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Gram-positive bacteria Staphylococcus aureus (including methicillin-resistant isolates) Streptococcus pyogenes.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals to evaluate carcinogenic potential have not been conducted with ozenoxacin.Ozenoxacin demonstrated no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the Ames test, mouse lymphoma cell assay, or when evaluated in vivo in rat micronucleus test with demonstrated systemic exposure.Oral doses of ozenoxacin did not affect mating and fertility in male and female rats treated up to 500 mg/kg/day (about 8500 and 16,000 times respectively, the maximum human plasma concentration seen with dermal application of ozenoxacin 1% cream).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL PRINCIPAL DISPLAY PANEL 30 Tube CartonXepiTM (ozenoxacin) Cream, 1%NDC 70621-103-10For Topical Use OnlyNot for Ophthalmic, Oral, Intranasal, or Intravaginal Use30gRx OnlyBiofronteraNote to pharmacist:Tamper-evident container enclosedManufactured for:Biofrontera Inc.,Woburn, MA 01801Rev. 12/2019Each gram of XepiTM (ozenoxacin) Cream, 1% contains 10 mg Ozenoxacin in cream base consisting of Benzoic Acid, Octyldodecanol, Peglicol Oleate, Pegoxol Stearate, Propylene Glycol, Purified Water, Stearyl Alcohol.Store at 20oC 25oC (68oF 77oF); excursions permitted to 15oC to 30oC (59oF 86oF) [See USP Controlled Room Temperature]. Protect from heat. Do not freeze.Usual Dose: thin layer should be applied to affected area twice daily for days. Warning: Keep out of reach of children.See package insert for full prescribing information.. PRINCIPAL DISPLAY PANEL 30 Tube Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of XEPI in the treatment of impetigo have been established in pediatric patients months to 17 years of age. Use of XEPI in pediatric patients (2 months to 17 years of age) is supported by evidence from adequate and well-controlled studies of XEPI in which 251 pediatric patients received at least one dose of XEPI. The median age of the patients enrolled in the clinical trials was 10 years; % of patients were months to less than years of age, 55 of patients were to less than 12 years of age, 11 of patients were 12 to less than 18 years of age, and 31 of patients were 18 years of age or older. In these studies, the maximum dose applied was approximately 0.5 of XEPI applied twice daily for up to days (i.e., up to 10 applications total) [see Clinical Studies (14)].The safety profile of XEPI in pediatric patients months and older was similar to that of adults [see Adverse Reactions (6.1)].The safety and effectiveness of XEPI in pediatric patients younger than months of age have not been established [see Clinical Studies (14)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFour pharmacokinetic studies were conducted in 110 patients utilizing varying strengths of ozenoxacin cream, up to 2% (twice the concentration of the marketed formulation). Three of these studies assessed systemic absorption in healthy subjects and in subjects with impetigo. These studies were conducted with either single or repeated application of up to g ozenoxacin cream to intact or abraded skin (up to 200 cm2 surface area). No systemic absorption was observed in 84 of 86 subjects, and negligible systemic absorption was observed at the level of detection (0.489 ng/mL) in subjects.. DistributionPlasma protein binding of [14C]-ozenoxacin was moderate (~80 to 85%) and did not appear to be dependent on concentration. Since negligible systemic absorption was observed in clinical studies, tissue distribution has not been investigated in humans.. Elimination. Metabolism: Ozenoxacin was not metabolized in the presence of fresh human skin discs and was minimally metabolized in human hepatocytes.. Excretion: Studies have not been investigated in humans due to the negligible systemic absorption observed in clinical studies.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on the use of XEPI in pregnant women to inform drug associated risk. Systemic absorption of XEPI in humans is negligible following topical administration of XEPI (up to twice the concentration of the marketed formulation) [see Clinical Pharmacology (12.3)]. Due to the negligible systemic exposure, it is not expected that maternal use of XEPI will result in fetal exposure to the drug.Animal reproduction studies were not conducted with XEPI. However, toxicity studies conducted in pregnant rats and rabbits administered the oral form of ozenoxacin showed no significant adverse developmental effects (at >10,000 times the maximum human plasma concentration seen with dermal application of ozenoxacin).The estimated background risk of major birth defects and miscarriage for the indicated population are 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on the use of XEPI in pregnant women to inform drug associated risk. Systemic absorption of XEPI in humans is negligible following topical administration of XEPI (up to twice the concentration of the marketed formulation) [see Clinical Pharmacology (12.3)]. Due to the negligible systemic exposure, it is not expected that maternal use of XEPI will result in fetal exposure to the drug.Animal reproduction studies were not conducted with XEPI. However, toxicity studies conducted in pregnant rats and rabbits administered the oral form of ozenoxacin showed no significant adverse developmental effects (at >10,000 times the maximum human plasma concentration seen with dermal application of ozenoxacin).The estimated background risk of major birth defects and miscarriage for the indicated population are 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.. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of ozenoxacin in human milk, and the effects of ozenoxacin on the breastfed infant or on milk production. However, breastfeeding is not expected to result in exposure of the child to ozenoxacin due to the negligible systemic absorption of ozenoxacin in humans following topical administration of XEPI. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for XEPI and any potential adverse effects on the breast-fed child from XEPI or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of XEPI in the treatment of impetigo have been established in pediatric patients months to 17 years of age. Use of XEPI in pediatric patients (2 months to 17 years of age) is supported by evidence from adequate and well-controlled studies of XEPI in which 251 pediatric patients received at least one dose of XEPI. The median age of the patients enrolled in the clinical trials was 10 years; % of patients were months to less than years of age, 55 of patients were to less than 12 years of age, 11 of patients were 12 to less than 18 years of age, and 31 of patients were 18 years of age or older. In these studies, the maximum dose applied was approximately 0.5 of XEPI applied twice daily for up to days (i.e., up to 10 applications total) [see Clinical Studies (14)].The safety profile of XEPI in pediatric patients months and older was similar to that of adults [see Adverse Reactions (6.1)].The safety and effectiveness of XEPI in pediatric patients younger than months of age have not been established [see Clinical Studies (14)].. 8.5 Geriatric Use. Clinical studies of XEPI did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.