CLINICAL STUDIES SECTION.

Clinical Studies:In randomized, double-masked, multicenter controlled clinical trial where patients were dosed for days, Levofloxacin Ophthalmic Solution demonstrated clinical cures in 79% of patients treated for bacterial conjunctivitis on the final study visit day (day 6-10). Microbial outcome for the same clinical trials demonstrated an eradication rate for presumed pathogens of 90%.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Levofloxacin Ophthalmic Solution is contraindicated in patients with history of hypersensitivity to levofloxacin, to other quinolones, or to any of the components of this medication.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The most frequently reported adverse events in the overall study populations were transient decreased vision, fever, foreign body sensation, headache, transient ocular burning, ocular pain or discomfort, pharyngitis and photophobia. These events occurred in approximately 1-3% of patients. Other reported reactions occurring in less than 1% of patients included allergic reactions, lid edema, ocular dryness and ocular itching.To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharmaceuticals, Inc. at 1-866-562-4597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility: In long term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration; the highest dose (100 mg/kg/day) was 875 times the highest recommended human ophthalmic dose. Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the in vivo mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and in vitro sister chromatid exchange (CHL/IU cell line) assays. Levofloxacin caused no impairment of fertility or reproduction in rats at oral doses as high as 360 mg/kg/day, corresponding to 3,150 times the highest recommended human ophthalmic dose.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacokinetics: Levofloxacin concentration in plasma was measured in 15 healthy adult volunteers at various time points during 15 day course of treatment with Levofloxacin Ophthalmic Solution. The mean levofloxacin concentration in plasma hour postdose, ranged from 0.86 ng/mL on Day to 2.05 ng/mL on Day 15. The highest maximum mean levofloxacin concentration of 2.5 ng/mL was measured on Day following days of dosing every hours for total of doses per day. Maximum mean levofloxacin concentrations increased from 0.94 ng/mL on Day to 2.15 ng/mL on Day 15, which is more than 1,000 times lower than those reported after standard oral doses of levofloxacin. Levofloxacin concentration in tears was measured in 30 healthy adult volunteers at various time points following instillation of single drop of Levofloxacin Ophthalmic Solution. Mean levofloxacin concentrations in tears ranged from 34.9 to 221.1 ug/mL during the 60-minute period following the single dose. The mean tear concentrations measured and hours postdose were 17.0 and 6.6 ug/mL. The clinical significance of these concentrations is unknown.. Microbiology: Levofloxacin is the L-isomer of the racemate, ofloxacin, quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves the inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoismerases), enzymes required for DNA replication, transcription, repair, and recombination. Levofloxacin has in vitro activity against wide range of Gram-negative and Gram-positive microorganisms and is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from -lactam antibiotics and aminoglycosides, and therefore may be active against bacteria resistant to -lactam antibiotics and aminoglycosides. Additionally, -lactam antibiotics and aminoglycosides may be active against bacteria resistant to levofloxacin. Resistance to levofloxacin due to spontaneous mutation in vitro is rare occurrence (range: 10-9 to 10-10). Levofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:AEROBIC GRAM-POSITIVE MICROORGANISMSCorynebacterium speciesStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus (Groups C/F) Streptococcus (Group G)Viridans group streptococciAEROBIC GRAM-NEGATIVE MICROORGANISMSAcinetobacter lwoffiiHaemophilus influenzaeSerratia marcescensEfficacy for this organism was studied in fewer than 10 infections. The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of levofloxacin in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials. These organisms are considered susceptible when evaluated using systemic breakpoints. However, correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections.Levofloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2ug/mL or less (systemic susceptible breakpoint) against most (>=90%) strains of the following ocular pathogens:Aerobic gram-positive microorganismsEnterococcus faecalisStreptococcus agalactiaeStaphylococcus saprophyticusStreptococcus pyogenesAerobic gram-negative microorganismsAcinetobacter anitratusLegionella pneumophilaAcinetobacter baumanniiMoraxella catarrhalisCitrobacter diversusiMorganella morgqaniiCitrobacter freudiiNeisseria gonorrhoeaeEnterobacter aerogenesProteus mirabilisEnterobacter agglomeransProteus vulgarisEnteroacter cloacaeProvidencia rettgeriEscherichia coliProvidencia stuartiiHaemophilus arainfluenzaePseudomonas aeruginosaKlebsiella oxytocaPseudomonas fluorescensKlebsiella pneumoniae Clinical Studies:In randomized, double-masked, multicenter controlled clinical trial where patients were dosed for days, Levofloxacin Ophthalmic Solution demonstrated clinical cures in 79% of patients treated for bacterial conjunctivitis on the final study visit day (day 6-10). Microbial outcome for the same clinical trials demonstrated an eradication rate for presumed pathogens of 90%.

DESCRIPTION SECTION.

DESCRIPTION:. Levofloxacin Ophthalmic Solution 0.5% is sterile topical ophthalmic solution. Levofloxacin is fluoroquinolone antibacterial active against broad spectrum of Gram-positive and Gram-negative ocular pathogens. Levofloxacin is the pure (-)-(s)-enantiomer of the racemic drug substance, ofloxacin. It is more soluble in water neutral pH than ofloxacin.Structural formula:Levofloxacin HemihydrateC18H20FN3O4. 1/2 H2O Mol Wt. 370.38Chemical Name:(-)-(s)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H pyrido [1,2,3-de]-1,4 benzoxazine-6-carboxylic acid hemihydrate. Levofloxacin (hemihydrate) is yellowish-white crystalline powder. Each mL of Levofloxacin Ophthalmic Solution contains 5.12 mg of levofloxacin hemihydrate equivalent to mg levofloxacin.Contains: Active: Levofloxacin 0.5% mg/mL); Preservative: benzalkonium chloride 0.005%; Inactives: sodium chloride and water for injection. May also contain hydrochloric acid and/or sodium hydroxide to adjust pH. Levofloxacin Ophthalmic Solution is isotonic and formulated at pH 6.5 with an osmolality of approximately 300 mOsm/kg. Levofloxacin is fluorinated 4-quinolone containing six-member (pyridobenzoxazine) ring from positions to of the basic ring structure. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Days and 2:Instill one to two drops in the affected eye(s) every hours while awake, up to times per day.Days through 7: Instill one to two drops in the affected eye(s) every hours while awake, up to times per day.

DRUG INTERACTIONS SECTION.

Drug Interactions: Specific drug interaction studies have not been conducted with Levofloxacin 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.

GENERAL PRECAUTIONS SECTION.

GeneralAs with other anti-infectives, prolonged use may result in overgrowth of non-susceptible 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 slitlamp biomicroscopy, and where appropriate, fluorescein staining. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

GERIATRIC USE SECTION.

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Levofloxacin Ophthalmic Solution 0.5% is supplied in natural, low density polyethylene bottle with controlled dropper tip and tan, high density polyethylene cap in the following size:Bottles of mL NDC 16571-150-50 Store at 20-25C (68-77F) Rx OnlyManufactured in India for:Rising Pharmaceuticals Inc.Allendale, NJ 07401Distributed by:Pack Pharmaceuticals, LLCAllendale, NJ 07401.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Levofloxacin Ophthalmic Solution is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:AEROBIC GRAM-POSITIVE MICROORGANISMSCorynebacterium speciesStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus (Groups C/F) Streptococcus (Group G)Viridans group streptococciAEROBIC GRAM-NEGATIVE MICROORGANISMSAcinetobacter lwoffiiHaemophilus influenzaeSerratia marcescens Efficacy for this organism was studied in fewer than 10 infections.

INFORMATION FOR PATIENTS SECTION.

Information for Patients Avoid contaminating the applicator tip with material from the eye, fingers or other source. Systemic quinolones have been associated with hypersensitivity reactions, even following single dose. Discontinue use immediately and contact your physician at the first sign of rash or allergic reactions.

MICROBIOLOGY SECTION.

Microbiology: Levofloxacin is the L-isomer of the racemate, ofloxacin, quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves the inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoismerases), enzymes required for DNA replication, transcription, repair, and recombination. Levofloxacin has in vitro activity against wide range of Gram-negative and Gram-positive microorganisms and is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from -lactam antibiotics and aminoglycosides, and therefore may be active against bacteria resistant to -lactam antibiotics and aminoglycosides. Additionally, -lactam antibiotics and aminoglycosides may be active against bacteria resistant to levofloxacin. Resistance to levofloxacin due to spontaneous mutation in vitro is rare occurrence (range: 10-9 to 10-10). Levofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:AEROBIC GRAM-POSITIVE MICROORGANISMSCorynebacterium speciesStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus (Groups C/F) Streptococcus (Group G)Viridans group streptococciAEROBIC GRAM-NEGATIVE MICROORGANISMSAcinetobacter lwoffiiHaemophilus influenzaeSerratia marcescensEfficacy for this organism was studied in fewer than 10 infections. The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of levofloxacin in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials. These organisms are considered susceptible when evaluated using systemic breakpoints. However, correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections.Levofloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2ug/mL or less (systemic susceptible breakpoint) against most (>=90%) strains of the following ocular pathogens:Aerobic gram-positive microorganismsEnterococcus faecalisStreptococcus agalactiaeStaphylococcus saprophyticusStreptococcus pyogenesAerobic gram-negative microorganismsAcinetobacter anitratusLegionella pneumophilaAcinetobacter baumanniiMoraxella catarrhalisCitrobacter diversusiMorganella morgqaniiCitrobacter freudiiNeisseria gonorrhoeaeEnterobacter aerogenesProteus mirabilisEnterobacter agglomeransProteus vulgarisEnteroacter cloacaeProvidencia rettgeriEscherichia coliProvidencia stuartiiHaemophilus arainfluenzaePseudomonas aeruginosaKlebsiella oxytocaPseudomonas fluorescensKlebsiella pneumoniae.

NURSING MOTHERS SECTION.

Nursing Mothers: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, it can be presumed that levofloxacin is excreted in human milk. Caution should be exercised when Levofloxacin Ophthalmic Solution is administered to nursing mother.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

------PRINCIPAL DISPLAY PANEL------NDC 16571-150-50PACKPharmaceuticals, LLCLEVOFLOXACINOPHTHALMICSOLUTION0.5%FOR TOPICALAPPLICATIONIN THE EYERx only (5 mL) Sterile. Levofloxacin Ophthalmic mL Carton Label.

PEDIATRIC USE SECTION.

Pediatric Use: Safety and effectiveness in infants below the age of one year have not been established. Oral administration of quinolones has been shown to cause arthropathy in immature animals. There is no evidence that the ophthalmic administration of levofloxacin has any effect on weight bearing joints.

PHARMACOKINETICS SECTION.

Pharmacokinetics: Levofloxacin concentration in plasma was measured in 15 healthy adult volunteers at various time points during 15 day course of treatment with Levofloxacin Ophthalmic Solution. The mean levofloxacin concentration in plasma hour postdose, ranged from 0.86 ng/mL on Day to 2.05 ng/mL on Day 15. The highest maximum mean levofloxacin concentration of 2.5 ng/mL was measured on Day following days of dosing every hours for total of doses per day. Maximum mean levofloxacin concentrations increased from 0.94 ng/mL on Day to 2.15 ng/mL on Day 15, which is more than 1,000 times lower than those reported after standard oral doses of levofloxacin. Levofloxacin concentration in tears was measured in 30 healthy adult volunteers at various time points following instillation of single drop of Levofloxacin Ophthalmic Solution. Mean levofloxacin concentrations in tears ranged from 34.9 to 221.1 ug/mL during the 60-minute period following the single dose. The mean tear concentrations measured and hours postdose were 17.0 and 6.6 ug/mL. The clinical significance of these concentrations is unknown.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralAs with other anti-infectives, prolonged use may result in overgrowth of non-susceptible 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 slitlamp biomicroscopy, and where appropriate, fluorescein staining. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.. Information for Patients Avoid contaminating the applicator tip with material from the eye, fingers or other source. Systemic quinolones have been associated with hypersensitivity reactions, even following single dose. Discontinue use immediately and contact your physician at the first sign of rash or allergic reactions.. Drug Interactions: Specific drug interaction studies have not been conducted with Levofloxacin 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.. Carcinogenesis, Mutagenesis, Impairment of Fertility: In long term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration; the highest dose (100 mg/kg/day) was 875 times the highest recommended human ophthalmic dose. Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the in vivo mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and in vitro sister chromatid exchange (CHL/IU cell line) assays. Levofloxacin caused no impairment of fertility or reproduction in rats at oral doses as high as 360 mg/kg/day, corresponding to 3,150 times the highest recommended human ophthalmic dose.. Pregnancy: Teratogenic Effects. Pregnancy Category Levofloxacin at oral doses of 810 mg/kg/day in rats, which corresponds to approximately 7,000 times the highest recommended human ophthalmic dose, caused decreased fetal body weight and increased fetal mortality. No teratogenic effect was observed when rabbits were dosed orally as high as 50 mg/kg/day, which corresponds to approximately 400 times the highest recommended maximum human ophthalmic dose, or when dosed intravenously as high as 25 mg/kg/day, corresponding to approximately 200 times the highest recommended human ophthalmic dose. There are, however, no adequate and well-controlled studies in pregnant woman. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nursing Mothers: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, it can be presumed that levofloxacin is excreted in human milk. Caution should be exercised when Levofloxacin Ophthalmic Solution is administered to nursing mother.. Pediatric Use: Safety and effectiveness in infants below the age of one year have not been established. Oral administration of quinolones has been shown to cause arthropathy in immature animals. There is no evidence that the ophthalmic administration of levofloxacin has any effect on weight bearing joints.. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

PREGNANCY SECTION.

Pregnancy: Teratogenic Effects. Pregnancy Category Levofloxacin at oral doses of 810 mg/kg/day in rats, which corresponds to approximately 7,000 times the highest recommended human ophthalmic dose, caused decreased fetal body weight and increased fetal mortality. No teratogenic effect was observed when rabbits were dosed orally as high as 50 mg/kg/day, which corresponds to approximately 400 times the highest recommended maximum human ophthalmic dose, or when dosed intravenously as high as 25 mg/kg/day, corresponding to approximately 200 times the highest recommended human ophthalmic dose. There are, however, no adequate and well-controlled studies in pregnant woman. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. NOT FOR INJECTION. Levofloxacin Ophthalmic Solution should not be injected subconjunctially, nor should it be introduced directly into the anterior chamber of the eye.In patients receiving systemic quinolones, serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported, some following the first dose. 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 levofloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.