ZYMAR® (gatifloxacin ophthalmic solution) 0.3% is a sterile ophthalmic solution. It is an 8-methoxy fluoroquinolone anti-infective for topical ophthalmic use.

Structure and Empirical Formula:

C₁₉H₂₂FN₃O₄ • 1.5 H₂O                       Mol Wt 402.42

Chemical Name: (±)-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid sesquihydrate

Contains:

Active: gatifloxacin 0.3% (3 mg/mL).

Preservative: benzalkonium chloride 0.005%.

Inactives: edetate disodium; purified water and sodium chloride. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to approximately 6.

ZYMAR® is a sterile, clear, pale yellow colored isotonic unbuffered solution. It has an osmolality of 260-330 mOsm/kg.

Last updated on RxList: 8/14/2007

ZYMAR® solution is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:

Aerobic Gram-Positive Bacteria:

Cornyebacterium propinquum*
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus mitis*
Streptococcus pneumoniae

Aerobic Gram-Negative Bacteria:

Haemophilus influenzae

* Efficacy for this organism was studied in fewer than 10 infections

The recommended dosage regimen for the treatment of bacterial conjunctivitis is:

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.

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 sizes:

2.5 mL in a 6 mL bottle- NDC 0023-9218-03

5 mL in an 10 mL bottle- NDC 0023-9218-05

Note: Store at 15°-25°C (59°-77°F). Protect from freezing.

Revised August 2004 ©2004 Allergan, Inc. Irvine, CA 92612, U.S.A. Licensed from: Kyorin Pharmaceuticals Co., Ltd. Marks owned by Allergan, Inc.
FDA Rev date: 6/20/2005

Last updated on RxList: 8/14/2007

Ophthalmic Use: The most frequently reported adverse events in the overall study population were conjunctival irritation, increased lacrimation, keratitis, and papillary conjunctivitis. These events 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 irritation, eye pain, eyelid edema, headache, red eye, reduced visual acuity and taste disturbance.

Specific drug interaction studies have not been conducted with ZYMAR® ophthalmic solution. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, and enhance the effects of the oral anticoagulant warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving systemic cyclosporine concomitantly.

Last updated on RxList: 8/14/2007

NOT FOR INJECTION.

ZYMAR® solution should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

In patients receiving systemic quinolones, including gatifloxacin, serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. If an allergic reaction to gatifloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.

General: As with other anti-infectives, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

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 2000-fold higher than the maximum recommended ophthalmic dose of 0.04 mg/kg/day in a 50 kg human.

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 (1000 and 3000 -fold higher, respectively, than the maximum recommended ophthalmic dose). A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in males treated with a high dose of approximately 2000-fold higher than the maximum recommended ophthalmic dose. 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.

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 findings may be due to the inhibitory effects of high concentrations on eukaryotic type II DNA topoisomerase.

There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately 4500-fold higher than the maximum recommended ophthalmic dose for ZYMAR®).

Pregnancy: Teratogenic Effects. Pregnancy Category C:

There were no teratogenic effects observed in rats or rabbits following oral gatifloxacin doses up to 50 mg/kg/day (approximately 1000-fold higher than the maximum recommended ophthalmic dose). However, skeletal/craniofacial malformations or delayed ossification, atrial enlargement, and reduced fetal weight were observed in fetuses from rats given ≥150 mg/kg/day (approximately 3000-fold higher than the maximum recommended ophthalmic dose). In a perinatal/postnatal study, increased late post-implantation loss and neonatal/perinatal mortalities were observed at 200 mg/kg/day (approximately 4500 times the maximum recommended ophthalmic dose).

Because there are no adequate and well-controlled studies in pregnant women, ZYMAR® solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Gatifloxacin is excreted in the breast milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when gatifloxacin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in infants below the age of one year have not been established.

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

Last updated on RxList: 8/14/2007

No information provided.

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.

Last updated on RxList: 8/14/2007

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 as described in the INDICATIONS AND USAGE section.

Aerobes, Gram-Positive:

Cornyebacterium propinquum*
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus mitis*
Streptococcus pneumoniae

Aerobes, Gram-Negative:

Haemophilus influenzae

* Efficacy for this organism was 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 2µg/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 microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.

Animal Pharmacology

Quinolone antibacterials have been shown to cause bone or cartilage changes in immature animals. There was no evidence of bone cartilage changes following ocular administration of gatifloxacin in rabbits or dogs.

Last updated on RxList: 8/14/2007

Avoid contaminating the applicator tip with material from the eye, fingers or other source.

Systemic quinolones, including gatifloxacin, have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.

Last updated on RxList: 8/14/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

GATIFLOXACIN - OPHTHALMIC

(gat-ih-FLOX-uh-sin)

COMMON BRAND NAME(S): Zymar

USES: This medication is a quinolone antibiotic used for eye infections.

HOW TO USE: For best results, use exactly as directed for the full time prescribed. Stopping this medication too soon may result in a relapse of the infection.

To apply eye drops, wash hands first. To avoid contamination, do not let the dropper tip touch any surface.

Tilt your head back, gaze upward and pull down the lower eyelid to make a pouch. Place the dropper directly over eye and instill the prescribed number of drops. Look downward and gently close your eye for 1 to 2 minutes. Place one finger at the corner of the eye near the nose and apply gentle pressure. This will prevent the medication from draining away from the eye. Try not to blink and do not rub the eye. Do not rinse the dropper.

If you are using other kinds of eye drops, wait at least five minutes before applying the other medications.

Do not wear contact lenses while you are using this medicine. Sterilize contact lenses according to manufacturer's directions and check with your doctor before using them.

Inform your doctor if your condition does not improve in 7 days.

SIDE EFFECTS: Blurred vision, watery eyes, headache, eye irritation/pain/dryness/redness, bad taste in mouth may occur. If any of these effects persist or worsen, inform your doctor.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: persistent eye redness, swelling of the eye or eyelid.

An allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction include: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: allergies to quinolone antibiotics such as ciprofloxacin.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: contact lens use, other allergies.

Because vision may be temporarily blurred or unstable after applying, use caution driving or performing activities requiring clear vision.

Use of this medication for prolonged or repeated periods may result in a secondary infection.

This drug should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known if this medication is passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription medications you may use, especially of: other antibiotics, other eye medications.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: An overdose of this product may be flushed from the eye(s) with warm tap water.

NOTES: This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

Do not share this medication with others.

MISSED DOSE: If you miss a dose, use it as soon as remembered; do not use if it is almost time for the next dose, instead, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59 and 77 degrees F (between 15 and 25 degrees C) away from moisture and sunlight. Do not freeze. Do not store in the bathroom. Discard the solution if it changes color, turns cloudy, or if it contains particles. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.