FLEOPTIC®

APPROVED

Order of the Ministry of Health of Ukraine

05.03.2024 No. 374

Registration certificate

No. UA/20380/01/01

PACKAGE LEAFLET

FOR MEDICAL USE OF THE MEDICINAL PRODUCT

FLEOPTIK^®

(FLEOPTIK)

Composition:

active substance: levofloxacin;

1 ml of eye drops contains 5 mg of levofloxacin in the form of levofloxacin hemihydrate;

excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Basic physicochemical properties: a clear solution, light yellow to light greenish-yellow in colour, practically free from visible mechanical particles.

Pharmacotherapeutic group. Ophthalmologicals. Antimicrobial agents. Fluoroquinolones. Levofloxacin.

ATC code S01A E05.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is the L-isomer of the racemic drug substance ofloxacin. The antibacterial activity is mainly due to the L-isomer of ofloxacin.

Mechanism of action.

Levofloxacin is an antibacterial agent of the fluoroquinolone class that inhibits the activity of bacterial type II topoisomerases − DNA gyrase and topoisomerase IV. In gram-negative bacteria, the action of levofloxacin is directed mainly at DNA gyrase, whereas in gram-positive bacteria it is directed at topoisomerase IV.

Mechanisms of resistance.

There are two main mechanisms of bacterial resistance to levofloxacin, namely: a decrease in the concentration of the drug inside the bacterial cell, or changes in the set of enzymes targeted by the action of the drug. Such changes arise as a result of mutations in chromosomal genes encoding DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE; grlA and grlB in Staphylococcus aureus). Causes of resistance due to decreased intracellular concentration of the drug include changes in outer membrane porins (OmpF), which reduce the ability of fluoroquinolones to penetrate gram-negative bacteria, or efflux pumps that promote the efflux of substances. Efflux-mediated resistance has been described in pneumococci (PmrA), staphylococci (NorA), and anaerobic and gram-negative bacteria. In addition, plasmid-mediated resistance to quinolones (determined by the qnr gene) has been reported in Klebsiella pneumoniae and E. coli.

Cross-resistance.

Cross-resistance between fluoroquinolones may occur. A single mutation does not cause clinical resistance, but multiple mutations usually cause clinical resistance to all medicinal products of the fluoroquinolone class. Changes in outer membrane porins and efflux systems may have broad substrate specificity, may be directed against several classes of antibacterial agents, and may lead to multiple resistance.

Breakpoints.

The MIC breakpoints (minimum inhibitory concentration) separating susceptible and intermediate organisms from resistant ones, according to the EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoint, are as follows:

Pseudomonas spp., Staphylococcus spp., Streptococcus A, B, C, G:

susceptible ≤ 1 mg/l, resistant > 2 mg/l;

Streptococcus pneumoniae: susceptible ≤ 2 mg/l, resistant > 2 mg/l;

Haemophilus influenzae, Moraxella catarrhalis: susceptible ≤ 1 mg/l, resistant > 1 mg/l.

Other pathogenic microorganisms: susceptible ≤ 1 mg/l, resistant > 2 mg/l.

Spectrum of antibacterial activity.

The prevalence of acquired resistance may vary geographically and over time for particular species, so local information on resistance is desirable, particularly when treating severe infections. Accordingly, the information provided is only an approximate guide as to the probability of microorganisms being susceptible, or not, to levofloxacin. Expert advice should be sought where the local prevalence of resistance is such that the usefulness of the medicinal product against at least some types of infection is questionable.

The table below shows only those bacterial species that commonly cause external ocular infections such as conjunctivitis.

Spectrum of antibacterial activity: susceptibility categories and resistance characteristics according to EUCAST requirements.

* MSSA – methicillin-susceptible Staphylococcus aureus strains.

** MRSA – methicillin-resistant Staphylococcus aureus strains.

The resistance data presented in the table are based on the results of a multicentre surveillance study (ophthalmic study) on the prevalence of resistance among bacterial isolates obtained from patients with ocular infections in Germany, June to November 2004.

Microorganisms were classified as susceptible to levofloxacin on the basis of susceptibility determined in vitro and of plasma concentrations following systemic therapy. Higher peak concentrations were achieved with topical application than in plasma. However, it is not known whether, or how, the kinetics of the product following topical instillation into the eye may alter the antibacterial action of levofloxacin.

Paediatric population.

Pharmacodynamic properties are the same in adults and children aged 1 year and above.

Pharmacokinetics.

Following instillation into the eye, levofloxacin is well retained in the tear film.

In a study in healthy volunteers, the mean levofloxacin concentrations in the tear film, measured at 4 and 6 hours after topical application, were 17.0 and 6.6 μg/ml, respectively. At 4 hours after dosing, concentrations of 2 μg/ml or higher were observed in five of the six volunteers studied. In four of the six volunteers studied, this concentration was also observed at 6 hours after dosing.

Plasma concentrations of levofloxacin were measured in 15 healthy adult volunteers at various time points over a 15-day course of treatment with the product. The mean plasma concentration of levofloxacin at 1 hour after dosing ranged from 0.86 ng/ml on day 1 to 2.05 ng/ml on day 15. The highest peak concentration of levofloxacin − 2.25 ng/ml − was recorded on day 4, after 2 days of dosing every 2 hours (a total of 8 doses per day). Peak concentrations of levofloxacin increased from 0.94 ng/ml on day 1 to 2.15 ng/ml on day 15, which is 1000-fold lower than the concentrations reported after standard oral doses of levofloxacin.

Plasma concentrations of levofloxacin achieved after application of the product to the affected eye are not known.

Clinical particulars.

Indications.

Local treatment of external bacterial eye infections caused by microorganisms susceptible to levofloxacin in patients aged 1 year and above.

Contraindications.

Hypersensitivity to the active substance levofloxacin, hypersensitivity to other quinolones, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No specific interaction studies with other medicinal products have been performed.

Since peak plasma concentrations of levofloxacin after ocular instillation are at least 1000-fold lower than those observed after standard oral doses, the interactions reported for systemic use are unlikely to be clinically relevant with the use of levofloxacin eye drops.

Paediatric population.

No drug interaction studies have been performed.

Special warnings and precautions for use.

The medicinal product must not be injected subconjunctivally. The solution should not be introduced directly into the anterior chamber of the eye.

As with other anti-infective medicinal products, prolonged use may result in overgrowth of non-susceptible microorganisms, including fungi. If the patient's condition worsens due to the infection, or if there is no clinical improvement within an appropriate period of time, treatment should be discontinued and alternative therapy initiated.

Where clinically indicated, the patient should be examined using magnification, e.g. slit-lamp biomicroscopy and, where appropriate, fluorescein staining.

Use of systemic fluoroquinolones has been associated with hypersensitivity reactions, even following a single dose. If an allergic reaction to levofloxacin occurs, treatment with the product should be discontinued.

Tendinitis and tendon rupture may occur during systemic therapy with fluoroquinolones, including levofloxacin, particularly in elderly patients concomitantly treated with corticosteroids. Caution should therefore be exercised, and treatment with levofloxacin eye drops should be discontinued at the first signs of tendon inflammation.

Patients with a bacterial external eye infection should not wear contact lenses.

Use during pregnancy and lactation.

Pregnancy. There are insufficient data on the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. The potential risk to humans is unknown. Fleoptik^® eye drops should be prescribed during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the foetus.

Breast-feeding. Levofloxacin passes into breast milk. However, no effect on the breast-fed infant is anticipated with therapeutic doses of Fleoptik^®. Fleoptik^® eye drops should be used during breast-feeding only if the expected benefit to the mother justifies the potential risk to the infant.

Fertility. Levofloxacin did not cause a reduction in fertility in rats at exposures significantly exceeding the maximum human exposure following ophthalmic use.

Effects on ability to drive and use machines.

Levofloxacin eye drops have a minor influence on the ability to drive and use machines.

If any transient blurring of vision occurs, the patient must wait until vision clears before driving or using machines.

Posology and method of administration.

For ophthalmic use.

Instil 1−2 drops into the affected eye(s) every 2 hours, up to 8 times a day, starting immediately upon waking, for the first 2 days, then 4 times a day from day 3 to day 5.

If more than one topical ophthalmic medicinal product is being used, an interval of at least 15 minutes should be allowed between instillations.

To prevent contamination of the dropper tip and the solution, the tip must not come into contact with the eyelids or the surrounding area of the eye.

The duration of treatment depends on the severity of the disorder and on the clinical and bacteriological course of the disease. Treatment usually lasts 5 days.

The safety and efficacy of treatment for corneal ulcer and ophthalmia neonatorum have not been established.

As safety and efficacy data are lacking, levofloxacin eye drops are not recommended for use in patients under 1 year of age.

Use in the elderly.

No dose adjustment is required for elderly patients.

Children.

The doses used in adults and in children aged 1 year and above are similar.

The safety and efficacy of levofloxacin eye drops have been established in children aged 1 year and above.

The safety and efficacy of levofloxacin eye drops in children under 1 year of age have not yet been established. No relevant data are available.

Overdose.

The total amount of levofloxacin in a bottle of eye drops is too small to cause toxic effects following accidental oral ingestion. If necessary, the patient should be clinically examined and supportive measures taken. Following topical overdose of the product, the eyes should be flushed with clean water at room temperature.

Paediatric population.

Management of overdose is similar for adults and children aged 1 year and above.

Undesirable effects.

Adverse reactions can be expected in approximately 10% of patients. These reactions are usually mild or moderate, are transient, and are mainly limited to the eye area.

Listed below are the adverse reactions considered to be definitely, probably, or possibly related to treatment, which have been reported during clinical trials and post-marketing use.

Frequency criteria for adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).

Immune system disorders: rare − extraocular allergic reactions, including skin rash; very rare − anaphylaxis.

Nervous system disorders: uncommon − headache.

Eye disorders: common − ocular burning, decreased vision, and stringy discharge; uncommon − eyelid matting, chemosis, conjunctival papillary reaction, eyelid oedema, ocular discomfort, foreign body sensation, ocular pruritus, ocular pain, conjunctival infection, conjunctival follicles, dry eye, eyelid erythema, and photophobia.

Corneal deposits were not observed during clinical trials.

Respiratory, thoracic and mediastinal disorders: uncommon – rhinitis; very rare − laryngeal oedema.

Additional adverse reactions observed with systemic use of the active substance (levofloxacin) that may potentially occur with use of this medicinal product.

In patients treated with systemic fluoroquinolones, ruptures of the shoulder, hand, Achilles, and other tendons have been reported, requiring surgical repair or resulting in prolonged disability. Post-marketing studies and experience with systemic quinolones have shown a possible increased risk of rupture in patients treated with corticosteroids, particularly elderly patients, and of tendons under high stress, including the Achilles tendon.

Paediatric population.

The frequency, type, and severity of adverse reactions in children are expected to be similar to those in adults.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are asked to report any suspected adverse reactions and any lack of efficacy of the medicinal product via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

After opening the bottle, store the eye drops in the carton to protect from light. Use within 4 weeks.

Storage conditions.

Store in the original package at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

5 ml in a bottle, 1 bottle per carton.

Dispensing category.

Prescription only.

Manufacturer.

JSC "Kyiv Vitamin Plant" (manufactured from in bulk product of "Rafarm S.A.", Greece).

Manufacturer's location and address of the place of business.

38 Kopylivska str., Kyiv, 04073, Ukraine.

Website: [www.vitamin.com.ua](https://www.vitamin.com.ua).