LEVOFLOXACIN

LEVOFLOXACIN- levofloxacin solution/ drops
PACK Pharmaceuticals, LLC

Levofloxacin Ophthalmic Solution 0.5%
Sterile

DESCRIPTION:

Levofloxacin Ophthalmic Solution 0.5% is a sterile topical ophthalmic solution. Levofloxacin is a fluoroquinolone antibacterial active against a 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 Structural Formula
(click image for full-size original)
Levofloxacin Hemihydrate
C18 H20 FN3 O4 ½ H2 O Mol Wt 370.38

Chemical Name: (-)-(s)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7Hpyrido [1,2,3-de]-1,4 benzoxazine-6-carboxylic acid hemihydrate. Levofloxacin (hemihydrate) is a yellowish-white crystalline powder. Each mL of Levofloxacin Ophthalmic Solution contains 5.12 mg of levofloxacin hemihydrate equivalent to 5 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 a fluorinated 4-quinolone containing a six-member (pyridobenzoxazine) ring from positions 1 to 8 of the basic ring structure.

CLINICAL PHARMACOLOGY

Pharmacokinetics:

Levofloxacin concentration in plasma was measured in 15 healthy adult volunteers at various time points during a 15 day course of treatment with Levofloxacin Ophthalmic Solution. The mean levofloxacin concentration in plasma 1 hour postdose, ranged from 0.86 ng/mL on Day 1 to 2.05 ng/mL on Day 15. The highest maximum mean levofloxacin concentration of 2.5 ng/mL was measured on Day 4 following 2 days of dosing every 2 hours for a total of 8 doses per day. Maximum mean levofloxacin concentrations increased from 0.94 ng/mL on Day 1 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 a single drop of Levofloxacin Ophthalmic Solution. Mean levofloxacin concentrations in tears ranged from 34.9 to 221.1 μg/mL during the 60-minute period following the single dose. The mean tear concentrations measured 4 and 6 hours postdose were 17.0 and 6.6 μg/mL. The clinical significance of these concentrations is unknown.

Microbiology:

Levofloxacin is the L-isomer of the racemate, ofloxacin, a 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 a 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 β-lactam antibiotics and aminoglycosides, and therefore may be active against bacteria resistant to β-lactam antibiotics and aminoglycosides. Additionally, β-lactam antibiotics and aminoglycosides may be active against bacteria resistant to levofloxacin. Resistance to levofloxacin due to spontaneous mutation in vitro is a 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 MICROORGANISMS

Corynebacterium species*

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus (Groups C/F)

Streptococcus (Group G)

Viridans group streptococci

AEROBIC GRAM-NEGATIVE MICROORGANISMS

Acinetobacter lwoffii*

Haemophilus influenzae

Serratia 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, a 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 2μg/mL or less (systemic susceptible breakpoint) against most (≥90%) strains of the following ocular pathogens:

Aerobic gram-positive microorganisms

Enterococcus faecalis

Streptococcus agalactiae

Staphylococcus saprophyticus

Streptococcus pyogenes

Aerobic gram-negative microorganisms

Acinetobacter anitratus

Legionella pneumophila

Acinetobacter baumannii

Moraxella catarrhalis

Citrobacter diversusi

Morganella morgqanii

Citrobacter freudii

Neisseria gonorrhoeae

Enterobacter aerogenes

Proteus mirabilis

Enterobacter agglomerans

Proteus vulgaris

Enteroacter cloacae

Providencia rettgeri

Escherichia coli

Providencia stuartii

Haemophilus arainfluenzae

Pseudomonas aeruginosa

Klebsiella oxytoca

Pseudomonas fluorescens

Klebsiella pneumoniae

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