Each mL of solution contains Levofloxacin hydrate 1.5%.
Levofloxacin is a fluoroquinone antibacterial active against a broad spectrum of Gram-positive and Gram-negative ocular pathogens.
Levofloxacin hydrate, is the L-isomer of the racemate ofloxacin, has almost two times more potent antibiotic activity than ofloxacin.
Its pH is 6.1-6.9 and its osmolar ratio is 1.0-1.1.
Nonproprietary name: Levofloxacin Hydrate.
Chemical Name: (3S)-9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de][1, 4] benzoxazine-6-carboxylic acid hemihydrate.
Molecular formula: C18H20FN3O4･1/2H2O.
Molecular weight: 370.38.
Levofloxacin hydrate occurs as light yellowish white to yellowish white crystals or crystalline powder.
It is freely soluble in acetic acid (100), sparingly soluble in water and in methanol, slightly soluble in ethanol (99.5). It is freely soluble in 0.1 mol/l hydrochloric acid.
A light dark yellowish white gradually develops by light.
Melting point: Approx. 226°C (with decomposition).
Excipients/Inactive Ingredients: Concentrated glycerin, dilute hydrochloric acid and sodium hydroxide.
Pharmacotherapeutic Group: Sensory Organs, Ophthalmologicals, Antiinfectives, Antibiotics. ATC Code: S01AE05.
Pharmacology: Pharmacodynamics: Levofloxacin
hydrate, is the L-isomer of the racemate ofloxacin, has almost two
times more potent antibiotic activity than ofloxacin.
Mechanism of Action: Main mechanism of action of levofloxacin hydrate is to inhibit bacterial DNA synthesis by inhibiting DNA gyrase (topoisomerase II) and topoisomerase IV activities. It depends on the bacteria strain as to how much potency is exerted: against DNA gyrase (topoisomerase II) or topoisomerase IV.
Antibacterial Activity: Antibacterial activity: Levofloxacin hydrate exerts a broad-spectrum potent antibacterial activity in vitro against organisms causing ophthalmological infections, including gram-positive bacteria (Staphylococcus sp., Streptococcus sp. [including S. pneumoniae], Micrococcus sp., Enterococcus sp., Corynebacterium sp., etc.), gram-negative bacteria (Pseudomonas sp. [including P. aeruginosa], Haemophilus influenzae, Moraxella sp., Serratia sp., Klebsiella sp., Proteus sp., Acinetobacter sp., Enterobacter sp. etc.), and anaerobic bacteria (Propionibacterium acnes, etc.).
Impact of dosage on emergence of levofloxacin resistance: In studies using in vitro ocular tissue concentration simulation model, this product, instilled 3 times daily was more effective than 0.5% product, in preventing the emergence of the levofloxacin-resistant methicillin-susceptible Staphylococcus aureus strain (HSA201-00027, levofloxacin MIC: 0.5 μg/mL) and the levofloxacin-resistant P. aeruginonosa strain (HSA201-00094, levofloxacin MIC: 1 μg/mL). Both of this product and 0.5% product, prevented the emergence of levofloxacin-resistant methicillin-susceptible coagulase-negative Staphylococci strain (HSA201-00039, levofloxacin MIC: 0.25 μg/mL).
Pharmacokinetics: Plasma concentration: Levofloxacin concentration in plasma was measured in 8 healthy adult volunteers during 8-day course of treatment with this product, bilateral instillation at one drop/eye/time, once daily for Day 1 and 8 times daily for 7 days (from Day 2-8). On Day 8, the mean maximum levofloxacin concentration of 24.1 ng/mL was measured after 26 minutes of the last instillation.
Ocular distribution in animals (white rabbit): Fifty μL of this product were ocular instilled once in the right eyes of rabbits. The mean maximum levofloxacin concentration of 32.5 μg/g in cornea was measured after 15 minutes of the instillation, and then levofloxacin concentration in cornea gradually decreased with half-life of 86 minutes. The mean maximum levofloxacin concentration of 14.7 μg/g in bulbar conjunctiva and palpebral conjunctiva was measured after 15 minutes of the instillation, and then levofloxacin concentration in bulbar conjunctiva and palpebral conjunctiva slightly rapidly decreased by 1 hour. The mean maximum levofloxacin concentration of 3.1 μg/mL in aqueous humor was measured after 30 minutes of the instillation, and then levofloxacin concentration in aqueous humor gradually decreased with half-life of 71 minutes.
Toxicology: Preclinical safety data: Ocular toxicity of levofloxacin (LVFX) ophthalmic solutions was evaluated in various regimens using albino or pigmented rabbits.
Ocular irritation of LVFX ophthalmic solutions was assessed at concentrations up to 25% after 10 repeated instillations in a single day at 30-minute intervals using albino rabbits. Ocular irritation was noted at 10% or higher, but not at 3.0% or lower.
Ocular toxicity of LVFX ophthalmic solutions was evaluated after 2 weeks instillations to the eyes of albino rabbits at concentrations up to 1.0%, and 4 and 26 weeks instillations to the eyes of pigmented rabbits at concentrations up to 3.0%. No evidences of ocular toxicity were observed in these studies.
Skin sensitization and skin photosensitization studies indicate that LVFX topically applied to the skin of guinea pigs is not immunogenic and photosensitizing.
Ocular safety of light-exposed and light-degraded LVFX ophthalmic solutions was assessed by 1 day ocular irritation study, since the reduction in LVFX content and production of degraded substance were recognized when LVFX ophthalmic solution was exposed to light in stressed condition. The light-induced degraded substances produced no abnormalities in the eyes.
Susceptible strains of Staphylococcus sp., Streptococcus sp., Streptococcus pneumoniae, Enterococcus sp., Micrococcus sp., Moraxella sp., Corynebacterium sp., Klebsiella sp., Enterobacter sp., Serratia sp., Proteus sp., Haemophilus influenzae, Haemophilus aegyptius [Koch-Weeks bacillus], Pseudomonas sp., Pseudomonas aeruginosa, Acinetobacter sp., and Propionibacterium acnes.
Blepharitis, dacryocystitis, hordeolum, conjunctivitis, tarsadenitis, keratitis (including corneal ulcer), and postoperative infections.
Usually, instill 1 drop a time to the eye 3 times daily. The dosage may be adjusted according to the patient's symptoms.
Patients with a history of hypersensitivity to the ingredient of this product, ofloxacin or any quinolone antibiotics.
Effects on ability to drive and use machine: Not specified.
Pregnancy and Lactation: This product should be used in pregnant women or women who may possibly be pregnant only if the expected therapeutic benefits are judged to outweigh the possible risks associated with treatment. [The safety of this product during pregnancy has not been established.]
Paediatric use: The safety of this product to low birth weight infants, neonates, infants or children has not been established. (No clinical experience with low birth weight infants, neonates or infants. Limited clinical experience with children).
This product should be used in pregnant women or women who may possibly be pregnant only if the expected therapeutic benefits are judged to outweigh the possible risks associated with treatment. [The safety of this product during pregnancy has not been established.]
Adverse reactions (treatment-related adverse events) were reported in 7 of 238 patients (2.9%) and in 1 of 8 healthy subjects (12.5%) in clinical trials in Japan. The adverse reactions were eye irritation in 3 patients (1.3%), dysgeusia in 2 patients (0.8%) and 1 healthy subject (12.5%), eye itching in 1 patient (0.4%), and urticaria in 1 patient (0.4%).
Clinically significant adverse reactions:
Shock, anaphylactoid reaction (incidences unknown): Since shock and anaphylactoid reaction may occur, patients should be carefully observed. If any symptoms such as erythema, rash, dyspnoea, decreased blood pressure, and eyelid oedema, etc. are observed, administration should be discontinued and appropriate measures should be taken.
Other adverse reactions:
If any adverse reactions are observed, appropriate measures such as discontinuing administration should be taken. (See table as follows.)
Click on icon to see table/diagram/image
Precautions concerning use: Route of administration: Ophthalmic use only.
At the time of administration: i. Instruct the patient to be careful not to touch the tip of the bottle to the eye directly in order to avoid contamination of the drug.
ii. When more than one ophthalmic drug is used, at least 5 minutes of intervals should be taken.
Precautions related to indications: 1. In order to avoid the emergence of resistant bacteria, bacterial susceptibility should be limited to the minimum period required for the eradication of the infection.
2. The efficacy of this product to methicillin-resistant Staphylococcus aureus (MRSA) has not been proven. Therefore, other drug having a potent anti-MRSA activity should be administered immediately to patients positively infected with MRSA and not showing any improvement of symptoms with this product.
Special precautions for disposal: No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: None known.
Store at or below 30°C in a tight container under protection from light.
Shelf-life: 3 years (36 months).
After first opening: to be used within one month.
S01AE05 - levofloxacin ; Belongs to the class of quinolone antiinfectives. Used in the treatment of eye infections.
Ophth soln 1.5% (clear, pale yellow to yellow, sterile aqueous solution) x 5 mL x 1's.