Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Gatifloxacin is a quinolone antimicrobial drug [see Microbiology]. Pharmacokinetics Gatifloxacin ophthalmic solution 0.3% or 0.5% was administered to one eye of 6 healthy male subjects each in an escalated dosing regimen starting with a single 2-drop dose, then 2 drops 4 times daily for 7 days and finally 2 drops 8 times daily for 3 days. At all time points, serum gatifloxacin levels were below the lower limit of quantification (5 ng/mL) in all subjects. Microbiology Gatifloxacin is an 8-methoxyfluoroquinolone with a 3-methylpiperazinyl substituent at C7. The antibacterial action of gatifloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. The mechanism of action of fluoroquinolones including gatifloxacin is different from that of aminoglycoside, macrolide, and tetracycline antibiotics. Therefore, gatifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to gatifloxacin. There is no cross-resistance between gatifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic gatifloxacin and some other fluoroquinolones. Resistance to gatifloxacin in vitro develops via multiple-step mutations. Resistance to gatifloxacin in vitro occurs at a general frequency of between 1 x 10-7 to 10-10. Gatifloxacin has been shown to be active against most strains of the following organisms both in vitro and clinically, in conjunctival infections: Aerobes, Gram-Positive Corynebacterium propinquum* Staphylococcus aureus Staphylococcus epidermidis Streptococcus mitis group* Streptococcus pneumoniae Aerobes, Gram-Negative Haemophilus influenzae * Efficacy for these organisms were studied in fewer than 10 infections. The following in vitro data are available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of ZYMAR® in treating ophthalmic infections due to the following organisms have not been established in adequate and well-controlled clinical trials. The following organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The following list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections. Gatifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less (systemic susceptible breakpoint) against most (= 90%) strains of the following ocular pathogens. Aerobes, Gram-Positive Listeria monocytogenes Staphylococcus saprophyticus Streptococcus agalactiae Streptococcus pyogenes Streptococcus viridans Group Streptococcus Groups C, F, G Aerobes, Gram-Negative Acinetobacter lwoffii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Citrobacter freundii Citrobacter koseri Haemophilus parainfluenzae Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Neisseria meningitidis Proteus mirabilis Proteus vulgaris Serratia marcescens Vibrio cholerae Yersinia enterocolitica Other Microorganisms Chlamydia pneumoniae Legionella pneumophila Mycobacterium marinum Mycobacterium fortuitum Mycoplasma pneumoniae Anaerobic Microorganisms Bacteroides fragilis Clostridium perfringens Clinical Studies In a randomized, double-masked, multicenter clinical trial, where patients were dosed for 5 days, ZYMAR® solution was superior to its vehicle on day 5-7 in patients with conjunctivitis and positive conjunctival cultures. Clinical outcomes for the trial demonstrated clinical cure of 77% (40/52) for the gatifloxacin-treated group versus 58% (28/48) for the placebo-treated group. Microbiological outcomes for the same clinical trial demonstrated a statistically superior eradication rate for causative pathogens of 92% (48/52) for gatifloxacin vs. 72% (34/48) for placebo. Please note that microbiological eradication does not always correlate with clinical outcome in anti-infective trials. In a randomized, double-masked, multicenter clinical trial of pediatric patients with bacterial conjunctivitis between birth and 31 days of age, patients were dosed with ZYMAR or another anti-infective agent for 7 days. Clinical outcomes for the trial demonstrated clinical cure of 79% (44/56) for the gatifloxacin-treated group.

ZYMAR (gatifloxacin) Ophthalmic Solution 0.3% for Topical Ophthalmic Use DESCRIPTION ZYMAR® is a quinolone antimicrobial topical ophthalmic solution for the treatment of bacterial conjunctivitis. Its chemical name is (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3quinolinecarboxylic acid, sesquihydrate. Its molecular formula is C19H22FN3O4 • 1.5 H2O, and its molecular weight is 402.42. Its chemical structure is: ZYMAR® is a clear, pale yellow, sterile, preserved aqueous solution with an osmolality of 260-330 mOsm/kg and a pH of approximately 6. ZYMAR® contains the active ingredient gatifloxacin 0.3% (3 mg/mL) and the inactive ingredients benzalkonium chloride 0.005%, edetate disodium, purified water and sodium chloride. ZYMAR® may contain hydrochloric acid and/or sodium hydroxide to adjust pH.

INDICATIONS ZYMAR® is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms: Aerobic Gram-Positive Bacteria Corynebacterium propinquum* Staphylococcus aureus Staphylococcus epidermidis Streptococcus mitis group* Streptococcus pneumoniae Aerobic Gram-Negative Bacteria Haemophilus influenzae * Efficacy for these organisms were studied in fewer than 10 infections. DOSAGE AND ADMINISTRATION Days 1 and 2: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times daily. Days 3 through 7: Instill one drop up to four times daily while awake. Dosage Forms And Strengths Ophthalmic solution: 0.3% gatifloxacin (3 mg/mL) HOW SUPPLIED Storage And Handling ZYMAR® (gatifloxacin ophthalmic solution) 0.3% is supplied sterile in a white, low density polyethylene (LDPE) bottle with a controlled dropper tip and a tan, high impact polystyrene (HIPS) cap in the following size: 5 mL in 10 mL bottle - NDC 0023-9218-05 Storage Store at 15°-25°C (59°-77°F). Protect from freezing. Allergan Inc., Irvine, CA 92612. Revised: Feb 2017

PATIENT INFORMATION Avoiding Contamination of the Product Advise patients to avoid contaminating the applicator tip with material from the eye, fingers or other source. Potential for Hypersensitivity Reactions Advise patients to discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction [see WARNINGS AND PRECAUTIONS].

OVERDOSE No information provided. CONTRAINDICATIONS ZYMAR® solution is contraindicated in patients with a history of hypersensitivity to gatifloxacin, to other quinolones, or to any of the components in this medication [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS The following serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] Growth of Resistant Organisms With Prolonged Use [see WARNINGS AND PRECAUTIONS] Corneal Endothelial Cell Injury [see WARNINGS AND PRECAUTIONS] Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies with ZYMAR®, the most frequently reported adverse reactions in the overall study population were: conjunctival irritation, increased lacrimation, keratitis, and papillary conjunctivitis. These reactions occurred in approximately 5-10% of patients. Other reported reactions occurring in 1-4% of patients were chemosis, conjunctival hemorrhage, dry eye, eye discharge, eye pain, eyelid edema, headache, red eye, reduced visual acuity and taste disturbance. An additional adverse reaction reported with gatifloxacin ophthalmic solution in other clinical studies includes worsening of the conjunctivitis. Postmarketing Experience The following adverse reactions have been identified during post-approval use of gatifloxacin ophthalmic solution 0.3%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: anaphylactic reactions and angioedema (including pharyngeal, oral or facial edema), blepharitis, dyspnea, eye pruritus, eye swelling (including corneal and conjunctival edema), hypersensitivity, nausea, pruritus (including pruritus generalized), rash, urticaria, vision blurred. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Patients receiving topical gatifloxacin have experienced hypersensitivity reactions including anaphylactic reactions, angioedema (including pharyngeal, laryngeal, or facial edema), dyspnea, urticaria, and itching, even following a single dose. There have been rare reports of Stevens-Johnson Syndrome reported in association with topical ophthalmic gatifloxacin use. If an allergic reaction to gatifloxacin occurs, discontinue the drug and contact your physician [see PATIENT INFORMATION]. Growth of Resistant Organisms with Prolonged Use Prolonged use of ZYMAR® may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, examine the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. Corneal Endothelial Cell Injury ZYMAR® is for topical ophthalmic use. ZYMAR® may cause corneal endothelial cell injury if introduced directly into the anterior chamber of the eye. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 290-fold higher than the maximum recommended human ophthalmic dose (MRHOD) of 0.024 mg/kg/day ZYMAR® in a 60 kg human (on a mg/m2 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 675-fold higher than the MRHOD, on a mg/m2 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 315-fold and 935-foldhigher, respectively, than the MRHOD, on a mg/m2 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 There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately 1350-fold higher than the MRHOD, on a mg/m2 basis). Use In Specific Populations Pregnancy Risk Summary There are no available data on the use of ZYMAR® 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 1010-fold higher than the maximum recommended human ophthalmic dose [MRHOD] for ZYMAR® of 0.024 mg/kg/day, on a mg/m2 basis). No teratogenic effects were observed in rat or rabbit fetuses at doses of gatifloxacin up to 50 mg/kg/day (approximately 335- and 675-fold higher than the MRHOD, respectively, on a mg/m2 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 1350-fold higher than the MRHOD on a mg/m2 basis). Lactation Risk Summary There is no information regarding the presence of ZYMAR® 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], 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 ZYMAR® and any potential adverse effects on the breastfed child from ZYMAR®. Pediatric Use The safety and effectiveness of ZYMAR (gatifloxacin ophthalmic solution) 0.3% have been established in all ages. Use of ZYMAR is supported by evidence from adequate and well controlled studies of ZYMAR in adults, children and neonates [see Clinical Studies]. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.