Levoximed

INSTRUCTIONS for medical use of the medicinal product LEVOXIMED (LEVOXIMED)

Composition:

Active substance: levofloxacin;

1 ml of solution contains levofloxacin (as hemihydrate) 5 mg;

Excipients: sodium chloride, benzalkonium chloride, sodium hydroxide solution or hydrochloric acid, purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear solution, practically free from mechanical particles.

Pharmacotherapeutic group.

Medicinal products used in ophthalmology. Anti-infectives. Fluoroquinolones. Levofloxacin. ATC code S01AE05.

Pharmacological Properties.

Pharmacodynamics.

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

Mechanism of action.

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

Resistance.

There are two main mechanisms by which bacterial resistance to levofloxacin develops: reduced intracellular concentration of levofloxacin or alterations in the target enzymes against which it acts. These changes occur 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 reduced intracellular concentration of levofloxacin 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), and anaerobic and Gram-negative bacteria. Resistance to quinolones mediated by plasmid DNA (encoded by the qnr gene) has been reported in Klebsiella pneumoniae and E. coli.

Cross-resistance.

Cross-resistance may occur among fluoroquinolones. Single mutations do 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 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.

Spectrum of antibacterial activity.

The prevalence of acquired resistance in specific species may vary geographically and over time; therefore, local information on resistance patterns is desirable, especially when treating severe infections. Thus, the information provided offers only approximate guidance and recommendations regarding possible microbial susceptibility to levofloxacin. When local resistance prevalence renders the use of levofloxacin questionable for at least some types of infections, consultation with a specialist should be considered if necessary.

The table below includes 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 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 surveillance 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 and plasma concentrations following systemic therapy. Higher maximum concentrations were achieved with topical administration than in plasma. However, it is unknown whether the kinetics of the drug after topical ocular instillation may alter the antibacterial activity of levofloxacin and how.

Special patient populations.

Pediatric patients.

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

Pharmacokinetics.

After ocular instillation, levofloxacin is well maintained in the tear film. In a study of healthy volunteers, mean concentrations of levofloxacin in the tear film measured at 4 and 6 hours after topical dosing were 17.0 and 6.6 µg/mL, respectively. Four hours after dosing, concentrations were 2 µg/mL or higher in five out of six subjects. In four out of six subjects, this concentration was still observed at 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. The mean plasma concentration of levofloxacin one hour after dose administration 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—2.25 ng/mL—was recorded on day 4, following two days of dosing every 2 hours (a total of 8 doses per day). Peak plasma 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 concentrations reported after administration of standard oral doses of levofloxacin.

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

Clinical characteristics.

Indications.

Local treatment of external bacterial eye infections in patients aged 1 year and older, caused by microorganisms sensitive to levofloxacin.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

No specific studies on the interaction of levofloxacin eye drops with other agents 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 levofloxacin eye drops.

Paediatric population.

No studies on the interaction of levofloxacin eye drops with other agents have been conducted.

Special precautions for use

The medicinal product must not be administered under the conjunctiva or directly into the anterior chamber of the eye.

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

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

Hypersensitivity reactions have been reported with systemic fluoroquinolones, even after a single dose. If hypersensitivity reactions occur, the medicinal product should be discontinued.

With systemic administration of fluoroquinolones, including levofloxacin, tendon inflammation and tendon rupture may occur, particularly in elderly patients and those concurrently receiving corticosteroids. Caution should be exercised during treatment, and the medicinal product should be discontinued at the first sign of tendon inflammation.

The medicinal product 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 change the color of soft contact lenses.

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

Benzalkonium chloride has also been reported to cause ocular irritation, symptoms of dry eye, and may affect the tear film and corneal surface. The medicinal product should be used with caution in patients with dry eye and in patients who may have 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 a direct or indirect harmful effect on reproductive performance. The potential risk to humans is unknown.

During pregnancy, the medicinal product should only be used if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding

Levofloxacin is excreted in breast milk. However, no effect on the breastfed infant is expected with therapeutic doses of the medicinal product. During breastfeeding, the medicinal product should only be used if the expected benefit to the woman 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 affect reaction speed when driving or operating machinery

Levofloxacin eye drops have negligible influence on the ability to drive or operate machinery.

If any transient effect on vision is observed during use of the medicinal product, the patient should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage

The medicinal product is intended for topical application.

The recommended dose is 1–2 drops instilled into the affected eye(s) every 2 hours up to 8 times daily, starting immediately after awakening during the first 2 days, then reduced to 4 times daily from day 3 to day 5.

To prevent contamination of the dropper tip and solution, the tip of the dropper must not touch the eyelids or surrounding areas of the eye.

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

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 treatment duration is 5 days.

Safety and efficacy for the treatment of corneal ulceration and ophthalmia neonatorum have not been established.

Due to lack of safety and efficacy data, the medicinal product is not recommended for use in children under 1 year of age.

Elderly Patients

No dosage adjustment is required for elderly patients.

Children

The dosage of the medicinal product used in adults and children aged 1 year and older is similar.

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

The safety and efficacy of levofloxacin ophthalmic drops in children under 1 year of age have not yet been established. There are no adequate data available.

Overdose

The total amount of levofloxacin in the ophthalmic drop bottle is too small to cause toxic effects following accidental oral ingestion. If necessary, the patient should be clinically monitored and supportive measures should be administered. In case of local overdose, the eyes should be rinsed with clean water at room temperature.

Pediatric Patients

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

Side effects.

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

Since the medicinal product contains benzalkonium chloride, it may cause contact eczema and/or irritation.

The adverse reactions listed below have been identified as definitely, probably, or possibly related to treatment with levofloxacin-containing eye drops, reported during clinical trials and post-marketing use.

Assessment criteria for frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (frequency cannot be estimated from available data).

Immune system disorders:

rare – extracocular hypersensitivity reactions, including skin rash; very rare – anaphylaxis.

Nervous system disorders:

uncommon – headache.

Eye disorders:

common – burning sensation in eyes, decreased visual acuity, mucus strands; uncommon – eyelid crusting, chemosis, conjunctival papillary reaction, eyelid swelling, eye 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 – rhinitis; very rare – laryngeal edema.

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

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 indicate 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 observed in adults.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

After opening the bottle, the product can be used for up to 4 weeks.

Storage conditions.

Store at temperatures not exceeding 25 °C, in the original packaging, and in a place inaccessible to children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

K.O. Rompharm Company S.R.L., Romania / S.C. Rompharm Company S.R.L., Romania.

Manufacturer's address and place of business.

Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov, Romania.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine / WORLD MEDICINE, LLC, Ukraine.