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Iquix (Levofloxacin Ophthalmic) - Description and Clinical Pharmacology

 
 



DESCRIPTION

IQUIX® (levofloxacin ophthalmic solution) 1.5% 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 a fluorinated 4-quinolone containing a six-member (pyridobenzoxazine) ring from positions 1 to 8 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.

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 a yellowish-white crystalline powder.

Each mL of IQUIX® contains 15.36 mg of levofloxacin hemihydrate equivalent to 15 mg levofloxacin.

Contains

Active: Levofloxacin 1.5% (15 mg/mL); Inactives: glycerin and water. May also contain hydrochloric acid and/or sodium hydroxide to adjust pH to approximately 6.5. IQUIX® solution is isotonic with an osmolality of approximately 290 mOsm/kg.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Levofloxacin concentration in plasma was measured in 14 healthy adult volunteers during a 16-day course of treatment with IQUIX® solution. The dosing schedule was 1-2 drops per eye once in the morning on Days 1 and 16; 1-2 drops per eye every two hours Days 2 through 8; and 1-2 drops per eye every four hours Days 9 through 15. The mean levofloxacin concentration in plasma 1 hour postdose ranged from 3.13 ng/mL on Day 1 to 10.4 ng/mL on Day 16. Maximum mean levofloxacin concentrations increased from 3.22 ng/mL on Day 1 to 10.9 ng/mL on Day 16, which is more than 400 times lower than those reported after standard oral doses of levofloxacin.

Levofloxacin concentration in tears was measured in 100 healthy adult volunteers at various time points following instillation of 2 drops of IQUIX® solution. Mean tear concentration measured 15 minutes after instillation was 757 µg/mL.

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 topoisomerases), 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-Iactam antibiotics and aminoglycosides, and therefore may be active against bacteria resistant to β-Iactarn antibiotics and aminoglycosides. Additionally, β-Iactam 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: AEROBIC GRAM-NEGATIVE MICROORGANISMS:
Corynebacterium species 1 Pseudomonas aeruginosa
Staphylococcus aureus Serratia marcescens
Staphylococcus epidermidis
Streptococcus pneumoniae
Viridans group streptococci

1 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 corneal ulcer. Levofloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 µg/mL or less (systemic susceptible breakpoint) against most (≥90%) strains of the following ocular pathogens:

AEROBIC GRAM-POSITIVE MICROORGANISMS:
Enterococcus faecalis (many strains are only moderately susceptible)
Staphylococcus saprophyticus
Streptococcus agalactiae
Streptococcus pyogenes
Streptococcus (Group C/F)
Streptococcus (Group G)
AEROBIC GRAM-NEGATIVE MICROORGANISMS:
Acinetobacter baumannii Legionella pneumophila
Acinetobacter Iwoffii Moraxella catarrhalis
Citrobacter koseri Morganella morganii
Citrobacter freundii Neisseria gonorrhoeae
Enterobacter aerogenes Pantoea agglomerans
Enterobacter cloacae Proteus mirabilis
Escherichia coli Proteus vulgaris
Haemophilus influenzae Providencia rettgeri
Haemophilus parainfluenzae Providencia stuartii
Klebsiella oxytoca Pseudomonas fluorescens
Klebsiella pneumoniae

Clinical Studies

In two randomized, double-masked, multicenter controlled clinical trials of 280 patients with positive cultures, subjects were dosed with IQUIX® or ofloxacin 0.3% ophthalmic solution. Dosing occurred on Days 1 through 3 every two hours while awake and 4 and 6 hours after retiring. Dosing occurred on Day 4 through treatment completion 4 times daily while awake. Clinical cure was defined as complete re-epithelialization and no progression of the infiltrate for two consecutive visits. The IQUIX® treated subjects had an approximately equal mean clinical cure rate of 80% (73% to 87%) compared to 84% (82% to 86%) for the subjects treated with ofloxacin 0.3% ophthalmic solution.

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