Levonekt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LevoNext (LevoNext)

Composition:

Active substance: levofloxacin hemihydrate;

1 ml of solution contains levofloxacin hemihydrate 5.12 mg, equivalent to 5 mg of levofloxacin;

Excipients: benzalkonium chloride, sodium chloride, sodium hydroxide 1N or hydrochloric acid 1N, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: transparent aqueous solution of yellowish-green color.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Antimicrobial agents. Fluoroquinolones. Levofloxacin. ATC code S01AE05.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is the L-isomer of the racemic drug substance ofloxacin. The antibacterial activity is predominantly exerted by the L-isomer of ofloxacin.

Mechanism of action.

Levofloxacin is a fluoroquinolone antibacterial agent that inhibits the activity of bacterial type II topoisomerases – DNA gyrase and topoisomerase IV. The action of levofloxacin is directed primarily against DNA gyrase in Gram-negative bacteria and against topoisomerase IV in Gram-positive bacteria.

Mechanisms of resistance development.

There are two main mechanisms by which bacteria develop resistance to levofloxacin: reduced intracellular concentration of the drug or alterations in the target enzymes against which the drug acts. These changes arise due to 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 reduced intracellular drug concentration include alterations in outer membrane porins (OmpF), which reduce the ability of fluoroquinolones to penetrate into Gram-negative bacteria, or efflux pumps that promote drug expulsion. Efflux-mediated resistance has been described in pneumococci (PmrA), staphylococci (NorA), anaerobic, and Gram-negative bacteria. Additionally, plasmid-mediated quinolone resistance (determined by the qnr gene) has been reported in Klebsiella pneumoniae and E. coli.

Cross-resistance.

Cross-resistance among fluoroquinolones may occur. A single mutation does not usually lead to clinical resistance, but multiple mutations typically result in clinical resistance to all agents within the fluoroquinolone class. Alterations in outer membrane porins and efflux systems may have broad substrate specificity, affecting multiple classes of antibacterial agents and leading to the development of multidrug resistance.

Breakpoints.

The MIC (minimum inhibitory concentration) breakpoints distinguishing susceptible and moderately resistant organisms from resistant ones according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) 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.

All other pathogenic microorganisms: susceptible ≤ 1 mg/L, resistant > 2 mg/L.

Antibacterial spectrum.

The prevalence of acquired resistance in specific microorganisms may vary geographically and over time; therefore, local resistance data should be consulted, especially when treating severe infections. Thus, the information provided below offers only approximate guidance and recommendations regarding possible susceptibility or lack thereof of microorganisms to levofloxacin. Expert consultation should be sought when local resistance patterns raise doubts about the benefit of using the medicinal product against at least some types of infections.

The table below includes only those bacterial species commonly causing external ocular infections such as conjunctivitis.

Antibacterial spectrum – susceptibility categories and resistance characteristics according to EUCAST criteria.

* MSSA – methicillin-susceptible Staphylococcus aureus strains.

** MRSA – methicillin-resistant Staphylococcus aureus strains.

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

Microorganisms were classified as susceptible to levofloxacin based on in vitro susceptibility testing and plasma concentrations achieved after systemic therapy. Higher maximum concentrations than those in plasma were achieved with topical application. However, it is unknown whether the drug kinetics after topical ocular administration may alter the antibacterial activity of levofloxacin, and if so, how.

Paediatric patients.

Pharmacodynamic properties are similar in adults and children aged 1 year and older.

Pharmacokinetics.

After ocular instillation, levofloxacin is well maintained in the tear film.

In a study involving healthy volunteers, mean concentrations of levofloxacin in the tear film measured 4 and 6 hours after topical administration were 17.0 and 6.6 µg/mL, respectively. Four hours after dosing, concentrations were ≥2 µg/mL in five out of six subjects. In four out of six subjects, this concentration was still observed 6 hours after dosing.

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

Plasma concentrations of levofloxacin achieved after administration of the medication into the affected eye are unknown.

Clinical characteristics.

Indications.

Local treatment in patients aged 1 year and older with external bacterial ocular infections caused by microorganisms sensitive to levofloxacin.

Contraindications.

Hypersensitivity to the active substance levofloxacin, increased sensitivity to other quinolones, or to any of the excipients of the medicinal product, such as benzalkonium chloride.

Interaction with other medicinal products and other forms of interaction.

No specific studies on interactions of this medicinal product with other drugs have been conducted.

Since maximum plasma concentrations of levofloxacin after ocular instillation are at least 1000 times lower than those observed after standard oral doses, interactions reported for systemic administration are unlikely to be clinically significant when using Levonext eye drops.

Paediatric population.

Drug interaction studies have not been conducted.

Special precautions for use

The drug must not be administered subconjunctivally. The solution should not be injected directly into the anterior chamber of the eye.

As with other antimicrobial agents, prolonged use may result in overgrowth of non-susceptible microorganisms, including fungi. If the patient's condition worsens or fails to improve after an appropriate period, treatment with this drug should be discontinued and alternative therapy initiated.

When clinically indicated, patients should be examined using magnification techniques, such as slit-lamp biomicroscopy, and fluorescein staining when necessary.

Systemic fluoroquinolones have been associated with hypersensitivity reactions, even after a single dose. If an allergic reaction to levofloxacin occurs, the drug should be discontinued immediately.

Tendon inflammation and tendon rupture may occur with systemic fluoroquinolone therapy, including levofloxacin, particularly in elderly patients receiving concomitant corticosteroids. Therefore, caution is advised, and treatment with Levonext should be discontinued at the first signs of tendon inflammation.

Levonext contains benzalkonium chloride as a preservative. Contact lenses should be removed prior to instillation and at least 15 minutes should elapse before reinserting them. Benzalkonium chloride may alter the color of soft contact lenses.

Patients with bacterial external ocular infections should not wear contact lenses.

Benzalkonium chloride has been reported to cause ocular irritation, symptoms of dry eye, and may affect the tear film and corneal surface. Caution is advised when using in patients with dry eye or in those with potentially compromised corneal integrity. Patients should be monitored during prolonged use.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of levofloxacin in pregnant women. Animal studies do not indicate any direct or indirect harmful effects on reproductive function. The potential risk to humans is unknown. Levonext eye drops 5 mg/mL should be prescribed during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

Levofloxacin is excreted in breast milk. However, no effects on the breastfed infant are expected with therapeutic doses of Levonext. Levonext eye drops should be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility

Levofloxacin did not impair fertility in rats at exposures significantly exceeding the maximum human exposure following ophthalmic administration.

Ability to drive or operate machinery

Levonext has negligible influence on the ability to drive or operate machinery.

If any transient effect on vision occurs, patients should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage

1−2 drops into the affected eye(s) every 2 hours up to 8 times daily, immediately after awakening during the first 2 days, then 4 times daily from day 3 to day 5.

When using different topical ophthalmic medicinal products simultaneously, the interval between instillations should be at least 15 minutes.

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

The duration of treatment depends on the severity of the condition as well as on the clinical and bacteriological course of the disease. The usual duration of treatment is 5 days.

The safety and efficacy of treatment of corneal ulceration and neonatal ophthalmia have not been established.

Due to lack of data on safety and efficacy, Levonext is not recommended for use in patients under 1 year of age.

Use in elderly patients

No dose adjustment is required for elderly patients.

Method of administration

Ophthalmic use.

Children

Dosages used in adults and children aged 1 year and older are similar.

The safety and efficacy of Levonext in children aged 1 year and older have been established.

The safety and efficacy of Levonext in children under 1 year of age have not been established. There are no adequate data 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 monitored and supportive measures applied. In case of local overdose, the eyes should be rinsed with clean water at room temperature.

Pediatric patients

Management in case of overdose is similar for adults and children aged 1 year and older.

Adverse reactions.

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

Since the product contains benzalkonium chloride, the active ingredient of this preservative may cause contact dermatitis and/or irritation.

The following adverse reactions, which are definitely, probably or possibly related to treatment, have been reported during clinical trials and post-marketing surveillance.

Immune system disorders.

Uncommon (≥1/1000 to <1/100): extracocular allergic reactions, including skin rash.

Rare (<1/10000): anaphylaxis.

Nervous system disorders.

Uncommon (≥1/1000 to <1/100): headache.

Eye disorders.

Common (≥1/100 to <1/10): burning sensation in eyes, blurred vision, and mucus threads.

Uncommon (≥1/1000 to <1/100): eyelid crusting, chemosis, conjunctival papillary reaction, eyelid edema, ocular discomfort, foreign body sensation, eye pruritus, eye pain, conjunctival infection, conjunctival follicles, dry eye, eyelid erythema, and photophobia.

Corneal deposits were not observed during clinical studies.

Respiratory, thoracic and mediastinal disorders.

Uncommon (≥1/1000 to <1/100): rhinitis.

Rare (<1/10000): laryngeal edema.

Additional adverse reactions observed with systemic administration of the active substance (levofloxacin) and which may potentially occur during use of Levonext.

In patients receiving systemic fluoroquinolones, tendon ruptures of the shoulder, hand, Achilles tendon, and other tendons have been reported, requiring surgical intervention or resulting in prolonged disability. Post-marketing studies and clinical experience with systemic quinolones have shown that the risk of tendon rupture may be increased in patients receiving concomitant corticosteroids, particularly in elderly patients, and in 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 authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

After first opening, use within 28 days.

Storage conditions.

No special storage conditions required. Keep container tightly closed. Store out of reach of children.

Packaging.

5 ml in a dropper bottle; 1 dropper bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

RAFARM SA/RAFARM SA.

Manufacturer's address and location of its business operations.

Thesi Pousi-Xatzi Agiou Louka, Paiania (Attiki), P.O. Box 37, 19002 Greece/Thesi Pousi-Xatzi Agiou Louka, Paiania Attiki, TK 19002, TO 37, Greece.