Cravit Ophthalmic Solution/Cravit 1.5% Ophthalmic Solution

Levofloxacin.

Levofloxacin is a fluoroquinolone antibacterial active against a broad spectrum of Gram-positive and Gram-negative ocular pathogens; anaerobic bacteria (Cravit ophthalmic only). Levofloxacin is the L-isomer of the racemate ofloxacin, has almost two times more potent antibiotic activity than ofloxacin.
Cravit Ophthalmic has a pH of 6.2-6.8 and osmotic pressure of 1-1.1.

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.
Clinical Studies: Efficacy by diagnosis: The effectiveness rates of Cravit 1.5% ophthalmic solution by diagnosis in open label Phase III study conducted on 176 patients with bacterial conjunctivitis and bacterial keratitis are summarized as follows. (See Table 1.)

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Efficacy by organism susceptible to levofloxacin: The effectiveness rates in the above 176 patients classified by the causative organisms are listed as follows. (See Table 2.)

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Efficacy on aseptic treatment during a perioperative period for ocular surgery: (data on Cravit 0.5%, for reference): As the result of evaluation of preoperative aseptic effect of Cravit 0.5% ophthalmic solution on patients before ophthalmic operation, the aseptic ratio was 70% (35/55).
Pharmacokinetics: Plasma concentrations: 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 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 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 maximum levofloxacin concentration of 14.7 μg/g in bulbar conjunctiva and palpebral conjunctiva slightly rapidly decreased by 1 hour. The 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.
Microbiology: 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. aeruginosa 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.

The following infections caused by levofloxacin-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., Morganella morganii, Haemophilus influenzae, Haemophilus aegyptius [Koch-Weeks bacillus], Pseudomonas sp., Pseudomonas aeruginosa, Stenotrophomonas (Xanthomonas) maltophilia, Acinetobacter sp., and Propionibacterium acnes.
Blepharitis, dacrocystitis, hordeolum, conjunctivitis, tarsadenitis, keratitis (including corneal ulcer), and aseptic treatment during a perioperative period for ocular surgery.

Usually, instill 1 drop at a time 3 times daily. The dosage may be adjusted according to the patient's symptoms.
Precautions concerning use: Ophthalmic use only.
At the time of administration, instruct the patient not to touch the tip of the bottle to the eye directly in order to avoid the contamination of the drug.
When more than one ophthalmic drug is used, at least 5 minutes of intervals should be taken.

No particularly specified.

Patients with a history of hypersensitivity to levofloxacin, ofloxacin or any quinolone antibiotic.

In order to avoid the emergence of resistant bacteria, bacterial susceptibility should be confirmed and treatment with levofloxacin should be limited to the minimum period required for the eradication of the infection.
The efficacy of this product to methicillin-resistant Staphylococcus aureus (MRSA) has not been proven. Therefore, other drugs having a potent anti-MRSA activity should be administered immediately to patients positively infected with MRSA and not showing any improvement of symptoms with Cravit Ophthalmic.
Use in Children: 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.

Clinically significant adverse reactions (rarely: <0.1%; occasionally: ≥0.1% to <5%; and no specific designation: ≥5% or incidence unknown): Shock, anaphylactoid reaction: Since shock and anaphylactoid reaction may occur levofloxacin ophthalmic solution, 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.
Others: If the following adverse reactions are observed, appropriate measures eg, discontinuing administration, should be taken.
Cravit Ophthalmic Solution 0.5%: (See Table 3.)

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Cravit Ophthalmic Solution 1.5%: Adverse reactions were reported in 7 of 238 patients (2.9%) in clinical trials in Japan. The adverse reactions were eye irritation in 3 patients (1.3%), dysguesia in 2 patients (0.8%), eye itching in 1 patient (0.4%), and urticaria in 1 patient (0.4%). (At the time of approval). (See Table 4.)

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No particularly specified.

Keep below 30°C in a tight container under protection from light.

Eye Anti-Infectives & Antiseptics

S01AE05 - levofloxacin ; Belongs to the class of quinolone antiinfectives. Used in the treatment of eye infections.

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