PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in children below the age of six years have not been established. Oral administration of systemic 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Levofloxacin is member of the fluoroquinolone class of anti-infective drugs. (See 12.4 Microbiology).. 12.3 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 2.25 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 mcg/mL during the 60-minute period following the single dose. The mean tear concentrations measured and hours postdose were 17.0 and 6.6 mcg/mL. The clinical significance of these concentrations is unknown.. 12.4 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 topoisomerases), 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 pneumoniaStreptococcus (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.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 mcg/mL or less (systemic susceptible breakpoint) against most (>= 90%) strains of the following ocular pathogens:Aerobic gram-positive microorganismsEnterococcus faecalisStaphylococcus saprophyticusStreptococcus agalactiaeStreptococcus pyogenesAerobic gram-negative microorganismsAcinetobacter anitratusAcinetobacter baumanniiCitrobacter koseriCitrobacter freundiiEnterobacter aerogenesEnterobacter agglomeransEnterobacter cloacaeEscherichia coliHaemophilus parainfluenzaeKlebsiella oxytocaKlebsiella pneumoniaLegionella pneumophilaMoraxella catarrhalisMorganella morganiiNeisseria gonorrhoeaeProteus mirabilisProteus vulgarisProvidencia rettgeriProvidencia stuartiiPseudomonas aeruginosaPseudomonas fluorescens.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In randomized, double-masked, multicenter controlled clinical trials 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 outcomes for the same clinical trials demonstrated an eradication rate for presumed pathogens of 90%.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Levofloxacin ophthalmic solution is contraindicated in patients with history of hypersensitivity to levofloxacin, to other quinolones, or to any of the components in this medication.. Levofloxacin ophthalmic solution is contraindicated in patients with history of hypersensitivity to levofloxacin, to other quinolones, or to any of the components in this medication. (4).

NURSING MOTHERS SECTION.

8.3 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 5mL Bottle Label. NDC 17478-106-10Levofloxacin Ophthalmic Solution 0.5%Rx Only5 mL. Principal Display Panel 5mL Bottle Label.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most frequently reported adverse reactions in the overall study population were transient decreased vision, fever, foreign body sensation, headache, transient ocular burning, ocular pain or discomfort, pharyngitis and photophobia. These reactions occurred in approximately 1% to 3% of patients. Other reported reactions occurring in less than 1% of patients included allergic reactions, lid edema, ocular dryness, and ocular itching.. The most frequently reported adverse reactions in the overall study population were transient decreased vision, fever, foreign body sensation, headache, transient ocular burning, ocular pain or discomfort, pharyngitis and photophobia. These reactions occurred in approximately 1% to 3% of patients. Other reported reactions occurring in less than 1% of patients included allergic reactions, lid edema, ocular dryness, and ocular itching. (6)To report SUSPECTED ADVERSE REACTIONS, contact Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In long term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration for years at doses up to 100 mg/kg/day, corresponding to plasma levels that were 1235 times the maximum clinical exposure, based on Cmax.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, at which systemic exposure was estimated to be 23,000 times that at the maximum recommended human ophthalmic dose.

DESCRIPTION SECTION.

11 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 fluorinated 4-quinolone containing six-member (pyridobenzoxazine) ring from positions to of the basic ring structure. Levofloxacin is the pure (-)-(S)-enantiomer of the racemic drug substance, ofloxacin. It is more soluble in water at neutral pH than ofloxacin. Its structural formula is:Chemical 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 levofloxacin ophthalmic solution, 0.5% contains 5.12 mg of levofloxacin hemihydrate equivalent to mg levofloxacin.Contains: Active: Levofloxacin 0.5% (5 mg/mL); Preservative: Benzalkonium Chloride 0.005%; Inactives: Sodium Chloride and Water for Injection. May also contain Sodium Hydroxide and/or Hydrochloric Acid to adjust pH to approximately 6.5.Levofloxacin ophthalmic solution, 0.5% is isotonic with an osmolality of approximately 300 mOsm/kg.. Figure.

DOSAGE & ADMINISTRATION SECTION.

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

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 10 mL bottle filled with mL sterile ophthalmic solution of levofloxacin, 0.5%.. 10 mL bottle filled with mL sterile ophthalmic solution of levofloxacin, 0.5% (3).

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Levofloxacin ophthalmic solution, 0.5% is supplied in white, low density polyethylene bottle with controlled dropper tip and tan polypropylene cap in the following size:5 mL fill in 10 mL capacity bottle NDC 17478-106-10. Storage: Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Levofloxacin ophthalmic solution is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:Gram-positive bacteriaCorynebacterium speciesStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaStreptococcus (Groups C/F)Streptococcus (Group G)Viridans group streptococciGram-negative bacteriaAcinetobacter lwoffiiHaemophilus influenzaeSerratia marcescens Efficacy for this organism was studied in fewer than 10 infections.. Levofloxacin ophthalmic solution is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms:Gram-positive bacteriaCorynebacterium speciesStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaStreptococcus (Groups C/F)Streptococcus (Group G)Viridans group streptococciGram-negative bacteriaAcinetobacter lwoffiiHaemophilus influenzaeSerratia marcescens Efficacy for this organism was studied in fewer than 10 infections (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Avoid Contamination of the Product. Advise patients to avoid contaminating the applicator tip with material from the eye, finger, or other source.. 17.2 Avoid Contact Lens Wear. Advise patients not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.. 17.3 Hypersensitivity Reactions. Systemically administered quinolones, including levofloxacin, have been associated with hypersensitivity reactions, even following single dose. Advise patients to discontinue use immediately and contact their physician at the first sign of rash or allergic reaction.AKORN Manufactured by: Akorn, Inc. Lake Forest, IL 60045LV00N Rev. 02/17.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Levofloxacin is member of the fluoroquinolone class of anti-infective drugs. (See 12.4 Microbiology).

MICROBIOLOGY SECTION.

12.4 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 topoisomerases), 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 pneumoniaStreptococcus (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.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 mcg/mL or less (systemic susceptible breakpoint) against most (>= 90%) strains of the following ocular pathogens:Aerobic gram-positive microorganismsEnterococcus faecalisStaphylococcus saprophyticusStreptococcus agalactiaeStreptococcus pyogenesAerobic gram-negative microorganismsAcinetobacter anitratusAcinetobacter baumanniiCitrobacter koseriCitrobacter freundiiEnterobacter aerogenesEnterobacter agglomeransEnterobacter cloacaeEscherichia coliHaemophilus parainfluenzaeKlebsiella oxytocaKlebsiella pneumoniaLegionella pneumophilaMoraxella catarrhalisMorganella morganiiNeisseria gonorrhoeaeProteus mirabilisProteus vulgarisProvidencia rettgeriProvidencia stuartiiPseudomonas aeruginosaPseudomonas fluorescens.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In long term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration for years at doses up to 100 mg/kg/day, corresponding to plasma levels that were 1235 times the maximum clinical exposure, based on Cmax.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, at which systemic exposure was estimated to be 23,000 times that at the maximum recommended human ophthalmic dose.

PHARMACOKINETICS SECTION.

12.3 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 2.25 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 mcg/mL during the 60-minute period following the single dose. The mean tear concentrations measured and hours postdose were 17.0 and 6.6 mcg/mL. The clinical significance of these concentrations is unknown.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category CTeratogenic Effects: Levofloxacin at oral doses of 810 mg/kg/day in rats 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, at which systemic exposure was approximately 2,250 times that observed at the maximum recommended human ophthalmic dose, or when dosed intravenously as high as 25 mg/kg/day, at which systemic exposure was approximately 1000 times that observed at the maximum recommended human ophthalmic dose.There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

SPL UNCLASSIFIED SECTION.

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

STORAGE AND HANDLING SECTION.

Storage: Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category CTeratogenic Effects: Levofloxacin at oral doses of 810 mg/kg/day in rats 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, at which systemic exposure was approximately 2,250 times that observed at the maximum recommended human ophthalmic dose, or when dosed intravenously as high as 25 mg/kg/day, at which systemic exposure was approximately 1000 times that observed at the maximum recommended human ophthalmic dose.There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. 8.3 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.. 8.4 Pediatric Use. Safety and effectiveness in children below the age of six years have not been established. Oral administration of systemic 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.. 8.5 Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity and anaphylaxis have been reported with systemic use of levofloxacin as well as topical use of other fluoroquinolones, including levofloxacin ophthalmic solution. (5.1)Prolonged use may result in the overgrowth of non-susceptible organisms, including fungi. (5.2)Patients should not wear contact lenses if they have signs or symptoms of bacterial conjunctivitis. (5.3). Hypersensitivity and anaphylaxis have been reported with systemic use of levofloxacin as well as topical use of other fluoroquinolones, including levofloxacin ophthalmic solution. (5.1). Prolonged use may result in the overgrowth of non-susceptible organisms, including fungi. (5.2). Patients should not wear contact lenses if they have signs or symptoms of bacterial conjunctivitis. (5.3). 5.1 Hypersensitivity Reactions. In patients receiving systemically administered quinolones, including levofloxacin, 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 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.. 5.2 Growth of Resistant Organisms with Prolonged Use. As 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 slit-lamp biomicroscopy, and where appropriate, fluorescein staining.. 5.3 Avoidance of Contact Lens Wear. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.