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 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 eva luate carcinogenic potential have not been conducted with ozenoxacin.

Ozenoxacin demonstrated no genotoxicity when eva luated in vitro for gene mutation and/or chromosomal effects in the Ames test, mouse lymphoma cell assay, or when eva luated 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 eva luated 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.