FLOXAL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLOXAL®

Composition:

Active substance: ofloxacin;

1 g of eye ointment contains 3 mg of ofloxacin; one dose (1 cm strip of ointment) contains 0.12 mg of ofloxacin;

Excipients: lanolin, white soft paraffin, liquid paraffin.

Pharmaceutical form. Eye ointment.

Main physicochemical properties: light yellow soft consistency ointment.

Pharmacotherapeutic group.

Medicinal products used in ophthalmology. Antibacterials. Ofloxacin.

ATC code S01AE01.

Pharmacological properties.

Pharmacodynamics. Ofloxacin, a derivative of quinolonic acid, is a fluoroquinolone (a gyrace inhibitor) antibiotic with bactericidal activity.

Breakpoints

Testing of ofloxacin involves the use of standard dilution series. The following minimum inhibitory concentrations have been established for susceptible and resistant bacteria:

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints:

* Mainly based on serum pharmacokinetics.

The spectrum of activity of ofloxacin includes obligate anaerobes, facultative anaerobes, aerobes, and other microorganisms, such as chlamydia.

The prevalence of acquired resistance in certain species may vary locally over time. Therefore, local information on resistance patterns is desirable, especially when dealing with severe infections. If there is uncertainty regarding the efficacy of ofloxacin due to local resistance, expert advice on antimicrobial therapy should be sought. In particular, for severe infections or therapeutic failure, microbiological diagnosis should be performed to confirm the pathogen and its susceptibility to ofloxacin. Chronic resistance to ofloxacin may occur with other fluoroquinolones.

The information provided below is primarily based on a contemporary resistance study involving 1391 ocular isolates (mainly from external swabs) from 31 German centers. These data form the basis for the systematic use of the above-mentioned breakpoint values. For topical application of ofloxacin to the anterior segment of the eye, significantly higher antibiotic concentrations are achieved compared to systemic administration; therefore, clinical efficacy in approved indications may also be expected for pathogens identified as resistant in vitro, e.g., Enterococcus spp. during *in vitro testing.

Typically susceptible species

Gram-positive aerobes: Bacillus spp., Staphylococcus aureus (methicillin-susceptible),

Gram-negative aerobes: Acinetobacter baumannii, Acinetobacter lwoffi, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Serratia marcescens.

Species that may be resistant due to acquired resistance and thus unresponsive to treatment

Gram-positive aerobes: Corynebacterium spp., Enterococcus faecalis, Staphylococcus aureus (methicillin-resistant)¹, Staphylococcus epidermidis, Streptococcus pneumoniae², streptococci (excluding Streptococcus pneumoniae)².

Gram-negative aerobes: Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Species with inherent resistance to the drug

Gram-positive aerobes: Enterococcus spp.

¹ Resistance rates exceed 50% in at least one region.

² The inherent susceptibility of most individual strains lies within intermediate ranges. However, in tear fluid, a concentration of at least 4 mg/L is achieved after a single instillation and persists for 4 hours, which is sufficient to kill 100% of microorganisms.

Pharmacokinetics.

Efficacy depends on the ratio between the maximum drug concentration in tissues (C_max) and the minimum inhibitory concentration (MIC) for the causative organism.

Animal studies have shown that after topical administration, ofloxacin can be detected in the cornea, conjunctiva, ocular muscles, sclera, iris, ciliary body, and anterior chamber of the eye. Repeated administration also leads to therapeutic concentrations in the vitreous humor.

After a single application of a 1 cm strip of ointment (equivalent to approximately 0.12 mg of ofloxacin), maximum concentrations of ofloxacin in the conjunctiva (9.72 µg/g) and sclera (1.61 µg/g) are reached within 5 minutes. Concentrations then gradually decrease.

After one hour, concentrations in intraocular fluid and cornea reach peak levels of 0.69 µg and 4.87 µg, respectively.

Clinical characteristics.

Indications.

Anterior segment of the eye infections caused by pathogens sensitive to ofloxacin: chronic conjunctivitis, keratitis, corneal ulcer, and chlamydial infections.

Contraindications.

Hypersensitivity to any component of the drug or to other quinolones.

Interaction with other medicinal products and other forms of interactions.

Unknown. Studies on drug interaction conducted with systemic administration of ofloxacin have shown that the clearance of caffeine and theophylline metabolites is slightly affected by ofloxacin.

Special precautions for use.

The safety and efficacy of the use of the drug in children under 1 year of age have not been established. There have been reports of severe and potentially fatal (anaphylactic and anaphylactoid) hypersensitivity reactions, sometimes after administration of the first doses in patients who received quinolones, including ofloxacin, systemically. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioneurotic edema (including laryngeal, pharyngeal, and facial edema), airway obstruction, dyspnea, urticaria, and pruritus. If an allergic reaction occurs during ofloxacin use, the drug should be discontinued. FLOXAL® 3 mg/g eye ointment should be used with caution in patients who have previously shown hypersensitivity to other quinolone antibiotics. When using an eye ointment containing ofloxacin, the risk of nasopharyngeal passage should be considered, which may lead to the emergence and development of bacterial resistance. As with other antibiotics, prolonged use may lead to overgrowth of non-susceptible microorganisms. If infection worsens or clinical improvement is not observed within an appropriate time interval, the drug should be discontinued and alternative therapy initiated. There is only limited evidence of efficacy and safety of ophthalmic preparations containing 0.3% ofloxacin in the treatment of conjunctivitis in newborns. The use of ophthalmic preparations containing ofloxacin in newborns for the treatment of ophthalmia neonatorum caused by Neisseria gonorrhoeae or Chlamydia trachomatis is not recommended, as their use in this patient group has not been studied. Clinical and non-clinical publications have reported corneal perforation in patients with corneal epithelial deficiency or corneal ulceration who were treated with topical fluoroquinolone antibiotics. However, many of these reports contain significant confounding factors such as advanced age, presence of large ulcers, concomitant ocular diseases (e.g., severe dry eye), systemic inflammatory diseases (e.g., rheumatoid arthritis), or concomitant use of steroids or nonsteroidal anti-inflammatory drugs. Nevertheless, given the risk of corneal perforation, caution is required when administering this medicinal product to patients with existing corneal epithelial defects or corneal ulceration. During the use of ophthalmic preparations containing ofloxacin, deposits on the cornea have been observed. However, no causal relationship can be established. During treatment with ofloxacin, excessive exposure to sunlight or ultraviolet radiation (e.g., tanning beds, sunlamps) should be avoided, as photosensitivity may occur. Contact lenses should not be used during treatment of eye infections. Lanolin may cause skin irritation (e.g., contact dermatitis). Before the first administration of the drug, microbiological examination of smears taken from the conjunctival sac is advisable to determine bacterial strain sensitivity to the drug. With prolonged use, bacterial resistance and the emergence of microorganisms insensitive to the antibacterial agent may occur. If symptoms worsen or clinical improvement does not occur, treatment should be discontinued and alternative therapy initiated. During treatment, rigid contact lenses should not be used. Therefore, it is recommended to remove rigid lenses before applying the medicinal product and not to reinsert them earlier than 20 minutes after administration. During treatment with FLOXAL® eye ointment, soft contact lenses should not be used. FLOXAL® eye ointment should be administered no sooner than 15 minutes after another ophthalmic drop or ointment. In any case, the eye ointment should be applied last. When systemic therapy with fluoroquinolones, particularly ofloxacin, is used, tendon inflammation and tendon rupture may occur, especially in elderly patients and in patients receiving concomitant corticosteroid therapy. Therefore, caution should be exercised and treatment with FLOXAL® eye ointment should be discontinued at the first signs of tendon inflammation (see section "Adverse reactions"). When fluoroquinolones are used systemically, caution is required in patients at risk of QT interval prolongation, namely: those with congenital long QT syndrome, those receiving concomitant medications that prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics), those with uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia), elderly patients, and patients with cardiac conditions (e.g., heart failure, myocardial infarction, bradycardia).
Use during pregnancy or breastfeeding. Despite the absence of evidence of any embryotoxic effects, FLOXAL® eye ointment should not be used during pregnancy or breastfeeding.
Ability to influence reaction rate when driving or operating machinery. After instillation into the conjunctival sac, the drug may cause blurred vision for several minutes. Until vision clarity is restored, patients should refrain from driving or operating machinery.

Dosage and Administration

The dosage and duration of treatment are always determined by a physician based on the severity of the disease and the patient's age. Unless otherwise prescribed, adults and children (from 1 year of age) should instill into the conjunctival sac of the affected eye a 1 cm strip of ointment (equivalent to 0.12 mg of ofloxacin) three times daily (in chlamydial infections – five times daily). Treatment with FLOXAL® eye ointment should not exceed two weeks.

Instructions for Use: Gently pull the lower eyelid downward and, by lightly pressing the tube, apply the required amount of ointment into the conjunctival sac. Then close the eyelid and gently press on the eyeball in different directions to evenly distribute the ointment.

Note: If you are also using other eye drops or eye ointments, the interval between applications should be 15 minutes; always apply the ointment last.

Children

FLOXAL® eye ointment may be prescribed to children from 1 year of age.

Overdose

No cases of overdose have been reported to date.

Treatment: Symptomatic; immediately rinse the eye(s) with water.

Adverse Reactions.

Blurred vision may occur immediately after administration and last for several minutes.

General manifestations

Serious reactions following systemic use of ofloxacin are rare; most symptoms are reversible. Although only a small amount of ofloxacin is absorbed into the systemic circulation with topical application, the possibility of adverse effects reported with systemic use cannot be ruled out.

Immune system disorders

Rare: conjunctival hyperemia and/or mild burning sensation in the eye. These symptoms are usually transient. Very rare (<1/10,000): hypersensitivity reactions, including angioneurotic edema, dyspnea, anaphylactic reactions/shock, swelling of the mouth and throat, itching of eyes and eyelids.

Nervous system disorders

In isolated cases: dizziness.

Eye disorders

Common: eye discomfort, eye irritation;

Rare: keratitis, conjunctivitis, blurred vision, photophobia, eye swelling, eye redness, foreign body sensation, increased lacrimation, dry eyes, eye pain, itching, eyelid edema. In rare cases (from 1/10,000 to 1/1,000), corneal deposits may occur, especially in patients with a history of corneal disease.

There have been reports of very rare reactions following topical application, such as toxic epidermal necrolysis and Stevens-Johnson syndrome. A causal relationship with FLOXAL\®, eye ointment, has not been established for these events.

Gastrointestinal disorders

In isolated cases: nausea.

Skin and subcutaneous tissue disorders

In isolated cases: facial swelling, periorbital edema.

Serious, sometimes fatal, hypersensitivity reactions, occasionally after the first dose, have been observed with systemic use of quinolones.

The product contains lanolin, which may cause contact dermatitis.

Tendon ruptures of the shoulder, hand, Achilles tendon, or other tendons requiring surgical repair or resulting in prolonged disability have been reported in patients receiving systemic fluorquinolones. Clinical studies and post-marketing experience with systemic fluorquinolones indicate that the risk of such ruptures may be increased in patients receiving corticosteroids, particularly elderly patients, and in cases of high tendon stress, especially involving the Achilles tendon.

Shelf life.

The shelf life of the medicinal product is 3 years.

The shelf life after opening the tube is 6 weeks.

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

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

3 g of ointment in a laminated tube with a plastic nozzle and a screw cap.

One tube per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Dr. Gerhard Mann Chem.-pharm. Fabrik GmbH, Germany.

Manufacturer's address and place of business. Brunsbütteler Damm 165/173, 13581 Berlin, Germany.