Zymar

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

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.

• 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)

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.

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.

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 , 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.

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity
• Growth of Resistant Organisms With Prolonged Use
• Corneal Endothelial Cell Injury

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.

The following serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity
• Growth of Resistant Organisms With Prolonged Use
• Corneal Endothelial Cell Injury

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.

No information provided.

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.