Gatifloxacin

There are no adequate and well-controlled studies of gatifloxacin in pregnant women. This drug should not be used in pregnant women unless, in the physician’s opinion, the potential benefit to the mother justifies the potential risk to the fetus. ZYMAR solution has not been studied in pregnant animals. Oral and intravenous studies in pregnant animals indicate that gatifloxacin crosses the placenta and that reproductive and fetal effects occur at doses of 150 mg/kg/day, which cause maternal toxicity.

It is not known whether gatifloxacin is excreted in human milk, although gatifloxacin has been shown to be excreted in the breast milk of rats. Because gatifloxacin may be excreted in human milk, a decision should be made either to discontinue nursing or to discontinue the administration of gatifloxacin, taking into account the importance of gatifloxacin therapy to the mother and the possible risk to the infant.

Carcinogenicity

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.

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. A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in high-dose males (52%) when compared to controls (16%). Although LGL leukemia is commonly seen in the F344 rat, the incidence of this change in high-dose males slightly exceeded the historical control range (5.7 to 40.4%) established for this strain. These findings suggest that gatifloxacin may have exacerbated the onset and development of this commonly occurring neoplasm. The incidence of LGL leukemia in all of the other drug-treated groups was comparable to that in controls. There were no other neoplastic or non-neoplastic lesions observed in the study that were considered directly attributable to treatment with gatifloxacin.

Mutagenicity

Gatifloxacin was negative in five in vivo genotoxicity studies that included oral and intravenous micronucleus tests in mice, an oral cytogenetics test in rats, and oral DNA repair tests in two strains of rats.

Gatifloxacin was evaluated as positive in three in vitro gene-mutation studies and two in vitro chromosomal-aberration studies. These findings were not unexpected; similar findings have been obtained with other quinolone antibiotics and are considered to be due to the inhibitory effects that high concentrations of these compounds have on eukaryotic cell type II DNA topoisomerase. This enzyme is related to bacterial DNA gyrase, the target at which all quinolones exert their antibiotic activity.

Reproduction and Teratology

Animal data shows that there were no teratogenic effects observed in rats or rabbits following oral gatifloxacin doses up to 50 mg/kg/day. However, skeletal/craniofacial malformations or delayed ossification, atrial enlargement, and reduced fetal weight were observed in fetuses from rats given 150 mg/kg/day. In a perinatal/postnatal study, increased late post-implantation loss and neonatal/perinatal mortalities were observed at 200 mg/kg/day.

As with any ocular medication, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.

Adverse Reaction Overview

In clinical studies 364 patients were treated with gatifloxacin for up to 5 days. Treatment-related adverse events were reported for 14.6% (53/364) of patients. The most frequently reported treatment-related adverse events occurring in 0.5% to 5% of patients treated with gatifloxacin are listed below:

Table 1. Percent of Patients in Phase 3 Trials with Treatment-Related Adverse Events Reported by 0.5% to 5% of Patients in the Active Treatment Arm:

Other treatment-related adverse events occurring in less than 0.5% of patients included, conjunctival disorder, conjunctivitis, chemosis, conjunctival cyst, conjunctival hemorrhage, corneal deposits, eye disorder, photophobia, subepithelial opacities, blurred vision, dermatitis, generalized urticaria, nausea, sore throat, sneezing, dizziness, and iritis.

Gatifloxacin was discontinued due to an adverse event, either related or unrelated to the drug, in 1.6% (6/364) of patients.

Post-Market Adverse Reactions

The following additional adverse reactions have been identified during postmarketing use of gatifloxacin ophthalmic solution 0.3% in clinical practice. Because postmarketing reporting of these reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions.

Eye Disorders: blepharitis allergic, corneal disorder, corneal ulcer, endophthalmitis, eye edema (including corneal and conjunctival edema), eye redness, eye pruritus, keratoconjunctivitis, macular edema, uveitis.

Rare cases of corneal melts and perforation have been reported in patients with multiple confounding factors including preexisting large corneal ulcer, corneal thinning, undiagnosed dacryocystitis, and use of multiple topical medications. Thus, it is difficult to determine the relationship of the events to gatifloxacin.

In one case, an elderly female with chronic conjunctivitis due to methicillin-resistant Staphylococcus aureus and a history of dacrocystitis, reported corneal perforation. This patient was using multiple concomitant antibiotics and had demonstrated evidence of a corneal defect associated with the infection prior to using gatifloxacin and continued using gatifloxacin during a successful post operative repair healing period.

Immune System Disorders: anaphylactic reactions, angioneurotic edema (including pharyngeal, oral or facial edema), hypersensitivity, pruritus allergic, rash, Stevens-Johnson syndrome.

Nervous System Disorders: headache, paraesthesia oral, tinnitus, tremor.

Respiratory, Thoracic and Mediastinal Disorders: dyspnea.