L-optic rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT L-OPTICROMPHARM (L-OPTICROMPHARM)

Composition:

Active substance: levofloxacin;

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

Excipients: benzalkonium chloride; sodium chloride; hydrochloric acid 1 M or sodium hydroxide 1 M; purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear solution, from slightly yellow to slightly yellow with a greenish tint, practically free from visible particles.

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

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action.

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

Mechanisms of resistance development.

There are two main mechanisms by which bacterial resistance to levofloxacin develops: reduced intracellular concentration of the drug or alterations in the target enzymes against which the drug acts. Such changes occur 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.

Resistance to quinolones via plasmid-mediated mechanisms (determined by the qnr gene) has been reported in Klebsiella pneumoniae and E. coli.

Cross-resistance.

Cross-resistance among fluoroquinolones may occur. Single mutations do not typically lead to clinical resistance, but multiple mutations usually result in clinical resistance to all agents within the fluoroquinolone class. Alterations in outer membrane porins and efflux systems may have broad substrate specificity, may affect multiple classes of antibacterial agents, and may lead 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 bacterial species may vary depending on geographical location and time; therefore, local resistance data are desirable, especially when treating severe infections. Hence, the information provided below serves only as approximate guidance and recommendations regarding possible microbial susceptibility to levofloxacin. If local resistance prevalence renders the use of the medicinal product questionable for at least some types of infections, expert consultation should be sought when necessary.

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

Antibacterial spectrum—categories of susceptibility 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 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 achieved after systemic therapy. Higher maximum concentrations than in plasma were achieved with topical administration. However, it is unknown whether the drug's kinetics following topical ocular instillation may alter the antibacterial activity of levofloxacin and how this might occur.

Children

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 of healthy volunteers, the mean concentration of levofloxacin in the tear film measured at 4 and 6 hours after topical dosing was 17.0 and 6.6 µg/mL, respectively. Four hours after dosing, five out of six subjects had concentrations of 2 µg/mL or higher. 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. The mean plasma concentration of levofloxacin one hour after dosing ranged from 0.86 ng/mL on day 1 to 2.05 ng/mL on day 15. The maximum plasma concentration of levofloxacin—2.25 ng/mL—was observed on day 4, after two days of dosing every 2 hours (a total of 8 doses per day). The maximum plasma concentration 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 administration of standard oral doses of levofloxacin.

The plasma concentration of levofloxacin achieved after administration of the drug into the affected eye is 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, increased sensitivity to other quinolones, or to any of the excipients of the medicinal product.

Children under 1 year of age.

Interaction with other medicinal products and other forms of interaction.

Systemic administration of some quinolones has demonstrated increased plasma concentrations of theophylline, interference with caffeine metabolism, potentiation of the effect of the oral anticoagulant warfarin and its derivatives, and has been associated with transient increases in serum creatinine in patients concurrently receiving systemic cyclosporine.

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

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

Paediatric population.

No drug interaction studies have 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.

Systemic fluoroquinolones have been associated with serious, and sometimes fatal, allergic (anaphylactic) reactions, even after a single dose.

Some of these reactions have been accompanied by cardiovascular collapse, loss of consciousness, angioedema (including swelling of the larynx, pharynx, or facial swelling), airway obstruction, dyspnea, urticaria, and pruritus.

If an allergic reaction to levofloxacin occurs, the drug should be discontinued immediately.

As with other anti-infective agents, prolonged use may result in overgrowth of nonsusceptible microorganisms, including fungi. If the patient's condition worsens or if there is no clinical improvement within a reasonable time, the drug should be discontinued and alternative therapy initiated.

As clinically indicated, patients should be examined, including biomicroscopy using a slit lamp, and, if necessary, fluorescein staining.

Use in elderly patients

There is no need to adjust the dose for elderly patients.

Contact lenses

The eye drops contain 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. The product should be used with caution in patients with dry eye and in those 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 any direct or indirect harmful effects on reproductive performance. The potential risk to humans is unknown. Levofloxacin eye drops should be used during pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding

Levofloxacin passes into breast milk. However, no adverse effects on the nursing infant are expected at therapeutic doses. Levofloxacin eye drops may be used during breastfeeding only 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 drive or operate machinery

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

If any transient visual disturbances occur, patients should wait until vision clears before driving or operating machinery.

Dosage and Administration

Adults and children aged 1 year and older: 1–2 drops into the affected eye(s) every 2 hours up to 8 times daily immediately after waking during the first 2 days, then reduce to 4 times daily from day 3 to day 5.

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

The duration of treatment depends on the severity of the infection and the clinical and bacteriological course of the disease. The treatment course is usually 5 days.

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

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

Route of administration

Ophthalmic use.

Children

For use in children aged 1 year and older.

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 applied. In case of local overdose, the eyes should be rinsed with clean water at room temperature.

Side effects

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

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

The following adverse reactions, identified as certain, probable or possible related to treatment, have been reported during clinical trials and post-marketing surveillance.

Immune system disorders

Rare (>1/10,000, <1/1,000): extraocular ocular allergic reactions, including skin rash.

Very rare (<1/10,000), unknown (cannot be estimated from available data): anaphylaxis.

Nervous system disorders

Uncommon (>1/1,000, <1/100): headache.

Eye disorders

Common (>1/100, <1/10): burning sensation in eyes, blurred vision, and mucus strands.

Uncommon (>1/1,000, <1/100): eyelid dullness, chemosis, conjunctival papillary reaction, eyelid swelling, eye discomfort, foreign body sensation, eye itching, 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 (>1/1,000, <1/100): rhinitis, pharyngitis.

Very rare (<1/10,000), unknown (cannot be estimated from available data): laryngeal edema.

General disorders and administration site conditions

Very rare (<1/10,000), unknown (cannot be estimated from available data): fever.

Paediatric population

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

Additional adverse reactions observed with systemic administration of the active substance (levofloxacin) and potentially possible also with use of

L-Optic

Tendon ruptures of the shoulder, hand, Achilles tendon or other tendons, requiring surgical intervention or leading to prolonged disability, have been reported in patients receiving systemic fluoroquinolones. Studies and post-marketing experience with systemic quinolones indicate that the risk of such ruptures may be increased in patients receiving corticosteroids, especially in elderly patients, as well as in tendons subjected to high stress, including the Achilles tendon (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life

3 years.

Do not use after the expiry date stated on the packaging.

The shelf life of the product after first opening of the bottle is 28 days.

Storage conditions

Store in the original packaging, out of the reach of children, at temperatures not exceeding 25 ºC.

Packaging

5 ml in a 5 ml polyethylene bottle with dropper cap and screw-on polyethylene cap with tamper-evident ring.

One bottle in a cardboard box.

Prescription status

Prescription only.

Manufacturer

K.T. ROMPHARM COMPANY S.R.L.

(S.C. ROMPHARM COMPANY S.R.L.)

Manufacturer's address and location of its business operations

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