Oftaquix®

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

Composition:

Active substance: levofloxacin;

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

1 dropper tube (0.3 ml) contains 1.5 mg of levofloxacin;

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

Pharmaceutical form. Eye drops.

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

Pharmacotherapeutic group. Ophthalmological agents. Antimicrobial agents. Fluoroquinolones. Levofloxacin.

ATC code S01AE05.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is the L-isomer of the racemic drug substance ofloxacin. The L-isomer of ofloxacin possesses the predominant antibacterial activity.

Mechanism of action

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

Mechanism 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 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 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 in anaerobic and Gram-negative bacteria. Resistance to quinolones mediated by plasmid genes (encoded 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 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, may affect multiple classes of antibacterial agents, and can lead to the development of multidrug resistance.

Breakpoints

The minimum inhibitory concentration (MIC) breakpoints that distinguish susceptible organisms and organisms with intermediate susceptibility from resistant ones 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 information on resistance patterns is desirable, especially when treating severe infections.

Thus, the information provided offers only approximate guidance and recommendations regarding possible susceptibility or lack of susceptibility of microorganisms to levofloxacin. If local resistance prevalence renders the benefit of using the medicinal product questionable against at least some types of infections, expert consultation should be sought when necessary.

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

The spectrum of antibacterial activity—categories of susceptibility and resistance characteristics—according to EUCAST requirements.

* MSSA = methicillin-susceptible strains of Staphylococcus aureus

** MRSA = methicillin-resistant strains of Staphylococcus aureus

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 and plasma concentrations following systemic therapy. Higher maximum concentrations were achieved with topical application than in plasma. However, it is unknown whether the pharmacokinetics of the drug after local ocular instillation may alter the antibacterial activity of levofloxacin, and if so, how.

Children

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

Pharmacokinetics

After administration, levofloxacin is well maintained in the tear film.

Mean concentrations of levofloxacin in the tear film measured at 4 and 6 hours after topical dosing were 17 and 6.6 µg/mL, respectively. Four hours after dosing, concentrations were ≥2 µg/mL in five out of six subjects; this concentration was observed in four out of six subjects even 6 hours after dosing.

Plasma concentrations of levofloxacin were measured in 15 healthy 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 recorded on Day 4, following two days of dosing every 2 hours (total of 8 doses per day).

Maximum 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 reported concentrations following standard oral doses of levofloxacin.

The plasma concentration of levofloxacin after administration into the affected eye is currently unknown.

Clinical characteristics.

Indications.

Local treatment of bacterial external ocular infections in patients from 1 year of age caused by microorganisms sensitive to levofloxacin.

Contraindications.

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

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.

No studies on drug interactions 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.

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 or fails to improve after an appropriate period of time, treatment with this drug should be discontinued and alternative therapy initiated.

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

Contact lenses.

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

Systemic administration 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.

Tendon inflammation and rupture may occur during systemic fluoroquinolone therapy, including levofloxacin, particularly in elderly patients receiving concomitant corticosteroids. Therefore, caution is required, and the use of Oftaquix® should be discontinued at the first signs of tendon inflammation.

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. Oftaquix® 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 passes into breast milk. However, no 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 exposures significantly exceeding the maximum human exposure following ophthalmic administration.

Ability to affect reaction speed when driving vehicles or operating machinery.

Oftaquix® has a negligible influence on the ability to drive vehicles or operate machinery. If any transient visual disturbances occur, patients should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage.

Dosing

1-2 drops into the affected eye(s) every 2 hours up to 8 times daily during the first two days after onset, 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.

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

Use in elderly patients.

No dose adjustment is necessary for elderly patients.

The content of the dropper bottle is sufficient for instillation into both eyes.

Ophthalmic drops should be used immediately after opening the single-dose dropper bottle.

Used dropper bottles and any remaining medicinal product should be disposed of according to local requirements.

Children.

Safety and efficacy for the treatment of corneal ulceration and ophthalmia neonatorum have not been established. The drug is not recommended for use in children under 1 year of age.

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

Special precautions and warnings for use are the same for adults and children aged 1 year and older.

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

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

Overdose.

The amount of levofloxacin in a single-dose eye drop vial 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, rinse the eyes thoroughly with clean water at room temperature.

Pediatric patients.

Management in case 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.

The following adverse reactions, identified as definitely, probably, or possibly related to treatment, have been reported during clinical trials and post-marketing use of ophthalmic drops containing levofloxacin:

Immune system disorders

Uncommon (≥1/1,000 to <1/100): Extraceocular 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, blepharitis with symptoms of eyelid swelling and erythema, eye discomfort, eye itching, eye pain, conjunctival infection, conjunctival hyperemia, conjunctival follicles, dry eye, 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 observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization 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

2 years.

After opening the foil pouch containing the dropper-dispensers:

• The eye drops should be used within 3 months after opening the pouch;
• Store the dropper-dispensers in the pouch to protect from light;
• After single use, the dropper-dispenser should be discarded together with any remaining content.

Storage conditions

Store at temperatures not exceeding 25°C, in the original packaging.

Keep out of the reach of children.

Packaging

0.3 mL of ophthalmic drops in a dropper-dispenser; 10 dropper-dispensers in a foil pouch. One foil pouch in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Santen Oy, Finland.

Manufacturer's name and address

Kelloportinkatu 1, Tampere, 33100, Finland.