Oftaquix®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Oftaquix® (Oftaquix®)

Composition:

Active substance: levofloxacin;

1 ml of eye drops contains 5 mg of levofloxacin as levofloxacin hemihydrate;

Excipients: benzalkonium chloride, sodium chloride, hydrochloric acid concentrated, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear solution, ranging from light yellow to light greenish-yellow, practically free from visible mechanical particles.

Pharmacotherapeutic group. Agents 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 attributed 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 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 bacterial resistance to levofloxacin develops: reduced intracellular concentration of the drug or alterations in the target enzymes against which the drug acts. These alterations 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 changes in outer membrane porins (OmpF), which reduce the penetration of fluoroquinolones 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 resistance to quinolones (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; however, 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.

Spectrum of antibacterial activity.

The prevalence of acquired resistance in specific microorganisms may vary geographically and over time; therefore, local resistance data are desirable, especially when treating severe infections. Thus, the information provided below offers only approximate guidance and recommendations regarding possible susceptibility or lack of susceptibility of microorganisms to levofloxacin. Consultation with a specialist should be considered if 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 bacterial species commonly causing external ocular infections such as conjunctivitis.

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

* MSSA – methicillin-sensitive 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 pharmacokinetics of the drug after local ocular instillation may alter the antibacterial activity of levofloxacin and, if so, to what extent.

Paediatric population

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 conducted in healthy volunteers, mean concentrations of levofloxacin in the tear film measured at 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. This concentration was still observed at 6 hours after dosing in four out of six subjects.

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 highest maximum concentration of levofloxacin—2.25 ng/mL—was observed 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 times lower than the concentrations reported after administration of standard oral doses of levofloxacin.

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

Clinical characteristics.

Indications.

Topical 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 the interaction 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 Oftaquix® 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 nonsusceptible microorganisms, including fungi. If the patient's condition worsens or fails to improve clinically within an appropriate period of time, 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, if necessary, fluorescein staining.

Systemic use of fluoroquinolones has 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 and those receiving concomitant corticosteroid therapy. Therefore, caution is advised and treatment with Oftaquix® should be discontinued at the first signs of tendon inflammation.

Oftaquix® contains benzalkonium chloride as a preservative. Contact lenses must be removed prior to instillation and at least 15 minutes should elapse before reinsertion. 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 should be exercised when administering to patients with dry eye or 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 function. The potential risk to humans is unknown. Oftaquix® 5 mg/mL eye drops 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 adverse effects on the breastfed infant are expected with therapeutic doses of Oftaquix®. Oftaquix® 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 systemic exposures significantly exceeding the maximum human exposure following ophthalmic administration.

Effect on ability to drive and use machines

Oftaquix® has a negligible effect on the ability to drive or use machinery.

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

Dosage and Administration

One to two 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 concomitantly, an interval of at least 15 minutes should be maintained between instillations.

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.

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

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

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

Use in elderly patients.

No dose adjustment is necessary for elderly patients.

Route of administration.

Ophthalmic use.

Children.

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

Safety and efficacy of OFTAQUIN® have been established in children aged 1 year and older.

Safety and efficacy of OFTAQUIN® in children under 1 year of age have not been established. There are no adequate data available.

Overdose.

The total amount of levofloxacin in the 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 population.

Management of overdose is similar in 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, transient, and mainly confined to the eye area.

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

The adverse reactions listed below are definitely, probably, or possibly related to treatment and have been reported during clinical studies and post-marketing surveillance.

Immune system disorders.

Uncommon (≥1/1,000 to <1/100): extracocular allergic reactions, including skin rash.

Rare (<1/10,000): anaphylaxis.

Nervous system disorders.

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

Eye disorders.

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

Uncommon (≥1/1,000 to <1/100): eyelid crusting, chemosis, conjunctival papillary reaction, eyelid edema, ocular 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 to <1/100): rhinitis.

Rare (<1/10,000): laryngeal edema.

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

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 experience with systemic quinolones have shown that the risk of tendon rupture may be increased in patients receiving 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 registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

3 years.

The opened bottle should be used within 1 month.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Santen AT/ Santen Oy.

Manufacturer's address and place of business.

Kelloportinkatu 1, Tampere, 33100, Finland/

Kelloportinkatu 1, Tampere, 33100, Finland

Date of last review.