Xepi (Page 2 of 3)

12.4 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 against S. aureus and S. pyogenes organisms.

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 within gyrA and parC subunits.

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 against S. aureus and S.pyogenes. Antagonism interactions with ozenoxacin were observed with ciprofloxacin against S. aureus.

Antimicrobial Activity

Ozenoxacin 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

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 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).

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 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 (%)
a The success rates for ozenoxacin were significantly different than placebo in Study 1 and Study 2 (p = 0.002 and p = 0.001).
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)

The most commonly identified bacteria were S. aureus and S. pyogenes. Table 3 below presents the results for clinical success at end of therapy in subjects with S.aureus or S.pyogenes at baseline.

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

16 HOW SUPPLIED/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.

NDC 70363-011-30 (30-gram tube)

Store at 20ºC — 25ºC (68ºF — 77ºF); excursions permitted to 15ºC to 30ºC (59ºF — 86ºF) [See USP Controlled Room Temperature].

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 a 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 3 days after starting use of XEPI.

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Manufactured for :
Cutanea Life Sciences, Inc., Wayne, PA, 19087

All product names or other trademarks included herein are trademarks of Dermarc, LLC, a wholly owned subsidiary of Cutanea Life Sciences, Inc., unless otherwise noted. All rights reserved.
Xepi™ is used by Cutanea Life Sciences, Inc. under license from Ferrer Internacional, S.A. and its licensees.

© 2019 Dermarc, LLC. All rights reserved.
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