Xepi

DESCRIPTION

XEPI contains ozenoxacin, a quinoloneantimicrobial. 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-oxo1,4-dihydro-quinoline-3-carboxylic acid. Ozenoxacin, a white to pale-yellow crystalline solid, has a molecular formula of C₂₁H₂₁N₃O₃, and a 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 5 oleate, pegoxol 7 stearate, propylene glycol, purified water, stearyl alcohol.

INDICATIONS

局部XEPI™表示treatment of impetigo dueto Staphylococcus aureusorStreptococcus pyogenesin adult and pediatric patients 2 months of age and older [seeClinical Studies].

DOSAGE AND ADMINISTRATION

Apply a thin layer of XEPI topically to the affected area twice daily for five days. Affected area may be up to 100 cm²in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm²in 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.
• 治疗面积covered with a sterile bandage or gauze dressing.

HOW SUPPLIED

Dosage Forms And Strengths

Cream

1%, pale yellow cream. Each gram of XEPI contains 10 mg of ozenoxacin.

Storage And Handling

XEPI cream, 1%is a pale yellow cream supplied in a 30-gram tube. Each gram of cream contains 10 mg of ozenoxacin.

NDC70621-103-01 (30-gram tube)
NDC70621-103-10 (Cardbox containing one 30-gram tube)

商店20°C - 25°C(68°F - 77°F);远足/mitted to 15°C to 30°C (59°F - 86°F) [See USP Controlled Room Temperature].

Distributed by: Biofrontera Inc.,120 Presidential Way, Suite 330, Woburn, MA 01801, USA. Revised: Jan 2020

SIDE EFFECTS

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.

The safety profile of XEPI was assessed in two clinical trials (Trial 1 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 a 5-day, twice a 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; 3 % of patients were 2 months to less than 2 years of age, 55 % of patients were 2 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 1 adult patient treated with XEPI.

DRUG INTERACTIONS

No Information Provided

警告

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Potential For Microbial Overgrowth

The prolonged use of XEPI may result in overgrowth of nonsusceptible bacteria and fungi. If such infections occur during therapy, discontinue use and institute appropriate supportive measures.

Nonclinical Toxicology

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 evaluatedin vitrofor gene mutation and/or chromosomal effects in the Ames test, mouse lymphoma cell assay, or when evaluatedin vivoin a 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).

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data on the use of XEPI in pregnant women to inform a 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) [seeCLINICAL PHARMACOLOGY]. 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.

Lactation

Risk Summary

No 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 mother's clinical need for XEPI and any potential adverse effects on the breast-fed child from XEPI or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of XEPI in the treatment of impetigo have been established in pediatric patients 2 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; 3 % of patients were 2 months to less than 2 years of age, 55 % of patients were 2 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 g of XEPI applied twice daily for up to 5 days (i.e., up to 10 applications total) [seeClinical Studies].

The safety profile of XEPI in pediatric patients 2 months and older was similar to that of adults [seeADVERSE REACTIONS].

The safety and effectiveness of XEPI in pediatric patients younger than 2 months of age have not been established [seeClinical Studies].

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.

OVERDOSE

Any sign or symptom of overdose, either topically or by accidental ingestion, should be treated symptomatically. No specific antidote is known.

CONTRAINDICATIONS

None.

CLINICAL PHARMACOLOGY

Mechanism Of Action

XEPI is an antimicrobial drug [seeMicrobiology].

Pharmacodynamics

Exposure-Response Relationship

The exposure response relationship for ozenoxacin following topical application has not been studied, however; a relationship is unlikely because systemic exposure following topical application is negligible [seePharmacokinetics].

Pharmacokinetics

Absorption

Four 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 1 g ozenoxacin cream to intact or abraded skin (up to 200 cm²surface 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 2 subjects.

Distribution

Plasma 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.

Microbiology

Mechanism Of Action

Ozenoxacin is a quinolone antimicrobial drug. The mechanism of action involves the inhibition of bacterial DNA replication enzymes, DNA gyrase A and topoisomerase IV. Ozenoxacin has been shown to be bactericidal againstS. aureusandS. pyogenesorganisms.

Resistance

The 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 a combination of mutations withingyrAandparCsubunits.

Overall the frequency of resistant mutants selected by ozenoxacin is ≤10^-10.

Interaction With Other Antimicrobials

Ozenoxacin has been tested in combination with 17 other commonly used antimicrobial agents againstS. aureusandS.pyogenes. Antagonism interactions with ozenoxacin were observed with ciprofloxacin againstS. aureus.

Antimicrobial Activity

Ozenoxacin has been shown to be active against most isolates of the following microorganisms, bothin vitroand in clinical infections [seeINDICATIONS]:

Gram-positive bacteria
Staphylococcus aureus(including methicillin-resistant isolates)
Streptococcus pyogenes

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 cm , and not exceeding 2% for subjects aged 2 months to 11 years were randomized to XEPI or placebo. Subjects applied XEPI or placebo twice daily for 5 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 2 below presents the results for clinical response at the end of therapy.

Table 2 Clinical Response at End of Therapy in Trial 1 and Trial 2 in All Randomized Subjects

	Trial 1		Trial 2
	XEPI	Placebo	XEPI	Placebo
	(N = 155) n (%)	(N = 156) n (%)	(N = 206) n (%)	(N = 206) n (%)
Clinical success	54 (34.8)	30 (19.2)	112 (54.4)	78 (37.9)
Clinical failure	98 (63.2)	120 (76.9)	91 (44.2)	121 (58.7)
Unable to determine	3 (1.9)	6 (3.8)	3 (1.5)	7 (3.4)
aThe success rates for ozenoxacin were significantly different than placebo in Study 1 and Study 2 (p = 0.002 and p = 0.001).

The most commonly identified bacteria wereS. aureusandS. pyogenes. Table 3 below presents the results for clinical success at end of therapy in subjects withS.aureusorS.pyogenesat baseline.

Table 3 Clinical Success at End of Therapy in Trial 1 and Trial 2 in Subjects with S. aureus or S. pyogenes

Clinical success	Trial 1		Trial 2
	XEPI	Placebo	XEPI	Placebo
	n/N (%)	n/N (%)	n/N (%)	n/N (%)
S. aureus	35/93 (37.6)	16/98 (16.3)	66/115 (57.4)	36/108 (33.3)
S. pyogenes	29/73 (39.7)	7/67 (10.4)	15/19 (78.9)	8/20 (40.0)

PATIENT 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 femalegenitalarea.
• 治疗面积可能覆盖无菌班达ge 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 3 days after starting use of XEPI.