5.1 Hypersensitivity

5.2 Growth of Resistant Organisms with Prolonged Use

5.3 Corneal Endothelial Cell Injury

6.1 Clinical Studies Experience

In clinical studies of patients with bacterial conjunctivitis treated with gatifloxacin ophthalmic solution 0.5% (N=717), the most frequently reported adverse reactions occurring in ≥1% of patients were: worsening of the conjunctivitis, eye irritation, dysgeusia, and eye pain.

Additional adverse reactions reported with other formulations of gatifloxacin ophthalmic solution in other clinical studies included chemosis, conjunctival hemorrhage, dry eye, eye discharge, eyelid edema, headache, increased lacrimation, keratitis, red eye, papillary conjunctivitis, and reduced visual acuity.

6.2 Postmarketing Experience

8.1 Pregnancy

There are no available data on the use of gatifloxacin ophthalmic solution 0.5% in pregnant women to inform a drug-associated risk. Administration of oral gatifloxacin to pregnant rats and rabbits throughout organogenesis did not produce adverse development outcomes at clinically relevant doses. Administration of gatifloxacin to rats during late gestation through lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses.

Data

Animal Data

Oral administration of gatifloxacin to pregnant rats throughout organogenesis produced teratogenic effects in rat fetuses, including skeletal/craniofacial malformations, delayed ossification, atrial enlargement, and reduced fetal weight, at doses greater than or equal to 150 mg/kg/day (approximately 600-fold higher than the maximum recommended human ophthalmic dose [MRHOD] for gatifloxacin of 0.04 mg/kg/day, on a mg/m 2 basis). No teratogenic effects were observed in rat or rabbit fetuses at doses of gatifloxacin up to 50 mg/kg/day (approximately 200-and 400-fold higher than the MRHOD, respectively, on a mg/m 2 basis).

In a perinatal/postnatal study in rats, oral administration of gatifloxacin during late gestation through lactation produced an increase in late gestation fetal loss and neonatal/perinatal mortality at 200 mg/kg/day (approximately 800-fold higher than the MRHOD on a mg/m 2 basis).

8.2 Lactation

There is no information regarding the presence of gatifloxacin ophthalmic solution 0.5% in human milk, the effect of gatifloxacin on breastfed infants, or the effect of gatifloxacin on milk production. Gatifloxacin was found in the breast milk of rats following oral administration of gatifloxacin during lactation. However, systemic levels of gatifloxacin following topical ocular administration are low [see Clinical Pharmacology ( 12.3)], and it is not known whether gatifloxacin would be present in maternal milk at measurable levels following topical ocular administration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gatifloxacin ophthalmic solution 0.5% and any potential adverse effects on the breastfed child from gatifloxacin ophthalmic solution 0.5%.

8.4 Pediatric Use

8.5 Geriatric Use

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

Resistance to gatifloxacin in vitro develops via multiple-step mutations. Resistance to gatifloxacin in vitro occurs at a general frequency of 1 x 10 -7 to 10 -10.

Gatifloxacin has been shown to be active against most isolates of the following organisms both microbiologically and clinically, in conjunctival infections:

• Aerobic gram-positive bacteria:

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus mitis group*

Streptococcus oralis*

Streptococcus pneumonia

• Aerobic gram-negative bacteria:

Haemophilus influenzae

* Efficacy for these organisms were studied in fewer than 10 infections.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no increase in neoplasms among B6C3F1 mice given gatifloxacin in the diet for 18 months at doses averaging 81 mg/kg/day in males and 90 mg/kg/day in females. These doses are approximately 175-fold higher than the maximum recommended ophthalmic dose (MRHOD) of 0.04 mg/kg/day gatifloxacin in a 60 kg human (on a mg/m 2 basis).

A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in male rats treated with 100 mg/kg/day (approximately 405-fold higher than the MRHOD, on a mg/m 2 basis). Fischer 344 rats have a high spontaneous background rate of LGL leukemia and the incidence in high-dose males only slightly exceeded the historical control range established for this strain. There was no increase in neoplasms among Fischer 344 rats given gatifloxacin in the diet for 2 years at doses averaging 47 mg/kg/day in males and 139 mg/kg/day in females (approximately 190 - and 560-fold higher than the MRHOD, respectively), on a mg/m 2 basis.

Mutagenesis

In genetic toxicity tests, gatifloxacin was positive in 1 of 5 strains used in bacterial reverse mutation assays: Salmonella strain TA102. Gatifloxacin was positive in in vitro mammalian cell mutation and chromosome aberration assays. Gatifloxacin was positive in in vitro unscheduled DNA synthesis in rat hepatocytes but not human leukocytes. Gatifloxacin was negative in in vivo micronucleus tests in mice, cytogenetics test in rats, and DNA repair test in rats. The genotoxic findings are similar to findings obtained with other quinolones and may be due to the pharmacologic inhibitory effects of high concentrations of gatifloxacin on eukaryotic type II DNA topoisomerase.

Impairment of Fertility

Oral administration of gatifloxacin produced no adverse effects on fertility or reproduction in rats at doses up to 200 mg/kg/day (approximately 800-fold higher than the MRHOD, on a mg/m 2 basis).