Xtoro 0.3 % Otic Suspension

5.1 Growth of Resistant Organisms with Prolonged Use

As with other antibacterial preparations, prolonged use of XTORO may lead to overgrowth of nonsusceptible organisms, including yeast and fungi. If this occurs, discontinue use and institute alternative therapy.

5.2 Allergic Reactions

Allergic reactions to XTORO may occur in patients with a history of hypersensitivity to finafloxacin, to other quinolones, or to any of the components in this medication. If this occurs, discontinue use and institute alternative therapy.

8.1 Pregnancy

Risk Summary

There are no adequate or well-controlled studies with XTORO in pregnant women. Finafloxacin was shown to be teratogenic in rabbits and rats following oral administration. Neural tube defects and skeletal anomalies in both species, and limb anomalies in rabbits, were observed at exposures estimated to be at least 1300 times the maximum human systemic exposure following topical otic administration of 0.3% finafloxacin. Because animal studies are not always predictive of human responses, XTORO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Animal Data

In rabbit embryofetal studies, maternal toxicity was not observed at oral doses up to 9 mg/kg/day (estimated 8000 times the maximum human systemic exposure [0.234 ng/mL] following topical otic administration with 0.3% finafloxacin). Fetal toxicity was observed at the lowest dose tested, 1 mg/kg/day (estimated 1300 times the maximum human systemic exposure following topical otic administration with 0.3% finafloxacin), and included exencephaly, enlarged fontanel, spina bifida, phocomelia, paw hyperflexure, missing lumbar vertebra, missing lumbar arch, and sternebra fusion.

In a rat embryofetal study, no adverse maternal toxicity was observed at oral doses up to 100 mg/kg/day (estimated 60,000 times the maximum human systemic exposure following topical otic administration with 0.3% finafloxacin). The developmental no observed adverse effect level (NOAEL) was 30 mg/kg (estimated 22,000 times the maximum human systemic exposure following topical otic administration with 0.3% finafloxacin). Exencephaly was observed in one fetus at 100 mg/kg. At 500 mg/kg, additional developmental toxicities were observed including increased preimplantation loss, decreased fetal weight, decreased placental weight, increased incidence of non-ossified sternebrae, and delayed ossifications in the sternebrae, xiphisternum, sacral arches and metacarpals.

8.2 Lactation

Finafloxacin has been identified in the milk of nursing rats following oral administration. The human systemic concentration of XTORO following topical otic treatment is low [see Clinical Pharmacology (12.3)]. It is not known whether topical otic administration could result in sufficient systemic absorption to produce detectable quantities in the human breast milk. Caution should be exercised when finafloxacin is administered to a nursing mother.

8.4 Pediatric Use

The safety and efficacy of XTORO in infants below one year of age have not been established. The safety and efficacy of XTORO in treating acute otitis externa in pediatric patients one year or older have been demonstrated in adequate and well controlled clinical trials [see Clinical Studies (14)].

8.5 Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

12.1 Mechanism of Action

Finafloxacin is a fluoroquinolone antimicrobial [see Microbiology (12.4)].

12.3 Pharmacokinetics

Finafloxacin plasma concentrations were evaluated following single or repeated ototopical doses of XTORO (finafloxacin otic suspension) 0.3%. In healthy subjects administered 4 drops in each ear twice daily for seven days, quantifiable finafloxacin concentrations were observed in 2 of 14 subjects; and these concentrations were just above the quantitation limit (0.05 ng/mL). Similarly, in AOE patients administered a single dose of 4 or 8 drops in each ear, quantifiable finafloxacin concentrations of up to 0.234 ng/mL were observed in plasma samples from 2 of 36 AOE patients.

12.4 Microbiology

Finafloxacin belongs to the fluoroquinolone class of antibacterials which involves the inhibition of bacterial type II topoisomerase enzymes, DNA gyrase and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair and recombination.

Finafloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and clinical studies as described in the INDICATIONS and USAGE section of the package insert for XTORO

      Pseudomonas aeruginosa
      Staphylococcus aureus

Mechanism of Resistance

Resistance to fluoroquinolones occurs primarily by mutations in the chromosomal DNA that encode for DNA gyrase and DNA topoisomerase enzymes, decreased outer membrane permeability or drug efflux mechanisms. In vitro resistance to finafloxacin due to spontaneous mutation is rare.

Cross Resistance

Cross-resistance has been observed between finafloxacin and other fluoroquinolones. No cross-resistance has been observed between finafloxacin and other classes of antibacterial agents.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity
Animal studies have not been conducted to determine the carcinogenic potential of finafloxacin.

Mutagenesis
Finafloxacin was shown to be genotoxic and clastogenic in vitro, with and without metabolic activation, and in vivo. In a bacterial reverse mutation assay, finafloxacin was positive in only one strain (TA102). Finafloxacin was positive in mammalian cell culture assays: mouse lymphoma cell forward mutation assays, a mutagenicity assay in V79 Chinese hamster lung cells, and a micronucleus test in V79 cells. Finafloxacin was clastogenic in mouse micronucleus studies.

Impairment of fertility
An oral rat fertility study detected a NOAEL for male and female fertility of 100 mg/kg/day (estimated 60,000 times the maximum human systemic exposure following topical otic administration with 0.3% finafloxacin). At 500 mg/kg/day, males were completely infertile, presumably due to low sperm count and sperm immobility.

General toxicity studies in rats have confirmed sperm toxicity following oral and intravenous dosing. Following intravenous dosing, the NOAEL for sperm toxicity was 30 mg/kg/day (150,000 times the maximum human exposure following topical otic administration with 0.3% finafloxacin).