FLOXIMED

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLOXIMED (FLOXIMED)

Composition:

Active substance: ciprofloxacin;

1 ml of solution contains ciprofloxacin (as ciprofloxacin hydrochloride) 3 mg;

Excipients: sodium acetate trihydrate; disodium edetate; mannitol (E 421); benzalkonium chloride; glacial acetic acid; water for injections.

Pharmaceutical form. Eye and ear drops, solution.

Main physicochemical properties: clear solution, ranging in color from colorless to yellowish-green.

Pharmacotherapeutic group.

Medicinal products for ophthalmological and otological use. Antimicrobial agents. ATC code S03A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

The medicinal product contains ciprofloxacin, a member of the quinolone class. The bactericidal action of quinolones, which primarily affects bacterial DNA synthesis, is expressed through inhibition of DNA gyrase.

Ciprofloxacin demonstrates high in vitro activity against most Gram-negative microorganisms, including Pseudomonas aeruginosa. It is also effective against aerobic Gram-positive microorganisms, such as staphylococci and streptococci.

Microorganism susceptibility.

Ophthalmic use.

Both in vitro studies and clinical use in ocular infections have demonstrated that ciprofloxacin is active against most strains of the following organisms.

Use in Otorhinolaryngology.

Ciprofloxacin has high in vitro activity against most aerobic gram-negative microorganisms, including Pseudomonas aeruginosa. It is also effective against aerobic gram-positive microorganisms such as staphylococci and streptococci. As shown in the table below, ciprofloxacin demonstrates a broad spectrum of in vivo activity (MIC90s ≤2 mcg/mL) against pathogenic microorganisms isolated from patients with acute external otitis in recent clinical studies.

Ciprofloxacin is also active against pathogenic microorganisms isolated from patients with acute otitis media using tympanostomy tubes.

Breakpoints for the diameters of microbial growth inhibition zones.

Use in ophthalmology.

Ciprofloxacin has demonstrated in vitro activity against most strains of the following microorganisms; however, the clinical significance of these findings in ophthalmic infections is unknown. The safety and efficacy of ciprofloxacin in the treatment of corneal ulcers or conjunctivitis caused by these microorganisms have not been established in adequate and well-controlled clinical studies.

The bacteria listed below are considered susceptible when evaluated using systemic breakpoints for the diameters of microbial growth inhibition zones. However, the relationship between systemic in vitro microbial growth inhibition zone diameter values and ophthalmic efficacy has not been established. In vitro, ciprofloxacin demonstrates minimum inhibitory concentrations (MICs) of 1 µg/mL or less (systemic breakpoints for susceptibility based on microbial growth inhibition zone diameters) against most (90%) strains of the following ocular pathogenic microorganisms.

Resistant organisms

Some strains of Burkholderia cepacia and Stenotrophomonas maltophilia are resistant to ciprofloxacin, as are some anaerobic bacteria, particularly Bacteroides fragilis.

Other information

The minimal bactericidal concentration (MBC) usually does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.

Otological use.

Ciprofloxacin has demonstrated in vitro activity against most strains of the microorganisms listed below; however, the clinical significance of these data in ear infections is unknown. The safety and efficacy of ciprofloxacin in the treatment of acute otitis externa caused by these microorganisms have not been established in adequate and well-controlled clinical studies.

The following bacteria are considered susceptible when tested using systemic breakpoint criteria for microbial growth inhibition zone diameters. However, the correlation between systemic in vitro microbial growth inhibition zone diameter values and efficacy when administered into the ear has not been established. Ciprofloxacin demonstrates in vitro minimal inhibitory concentrations (MIC) of 1 µg/mL or less (systemic susceptibility breakpoint criteria for microbial growth inhibition zones) against most (90%) strains of the following pathogenic microorganisms.

Ciprofloxacin has also been shown to be active in vitro against most strains of the following microorganisms causing otitis media:

Resistance to ciprofloxacin generally develops slowly. However, parallel resistance has been observed within this group of gyrase inhibitors.

Bacterial susceptibility studies have shown that most microorganisms resistant to ciprofloxacin are also resistant to other fluoroquinolones. During clinical studies, the frequency of isolating strains with acquired resistance to ciprofloxacin was low.

Due to its unique mechanism of action, there is no cross-resistance between ciprofloxacin and other antibacterial agents with different chemical structures, such as beta-lactam antibiotics, aminoglycosides, tetracyclines, macrolides and peptides, as well as sulfonamides, trimethoprim derivatives, and nitrofurans. Thus, microorganisms resistant to these drugs may remain sensitive to ciprofloxacin.

Preclinical safety data.

Ciprofloxacin and other quinolones cause arthropathy in young animals of most species studied following oral administration. When ciprofloxacin was administered at 30 mg/kg, the effect on joints was minimal. This dose is 270 times higher than the recommended clinical dose for ear use in a 10 kg child, applying 0.27 mg of ciprofloxacin into each ear twice daily. In a one-month study in young dogs (beagles) using topical application of ciprofloxacin eye drops, no joint lesions were observed. Furthermore, there was no evidence that topical application had any effect on joints. Additionally, in 634 children who received oral ciprofloxacin, clinical and radiological examinations revealed no toxic effects on the skeleton.

Reproductive function studies conducted in rats and mice using doses 50 times higher than the maximum daily ophthalmic dose for humans, and 900 times higher than the recommended ear dose (for a 10 kg child or a 50 kg adult receiving 0.27 mg or 0.36 mg of ciprofloxacin per ear twice daily, respectively), showed no evidence of impaired fertility or adverse effects on the fetus due to ciprofloxacin.

Oral administration of ciprofloxacin at doses of 30 and 100 mg/kg did not result in teratogenic effects in rabbits, although significant maternal toxicity was observed at both doses. After intravenous administration of doses up to 20 mg/kg, no maternal toxicity, embryotoxicity, or teratogenic effects were observed.

Pharmacokinetics.

After topical application to the human eye, ciprofloxacin is well absorbed. The concentration of ciprofloxacin detected in the tear film, cornea, and anterior chamber of the eye is ten to several hundred times higher than the MIC₉₀ for susceptible ocular pathogenic microorganisms.

Systemic absorption of ciprofloxacin after topical ocular application is low. Plasma levels of ciprofloxacin after seven days of topical administration ranged from undetectable levels (<1.25 ng/mL) to 4.7 ng/mL. The mean maximum plasma concentration of ciprofloxacin after topical ocular application was approximately 450 times lower than that observed after oral administration of a single 250 mg dose of ciprofloxacin.

In children with otitis media with tympanostomy tubes or perforated tympanic membranes, topical application of ciprofloxacin to the ear resulted in plasma concentrations of ciprofloxacin below the quantifiable limit, with a detection limit of 5 ng/mL. In chinchillas, ciprofloxacin distributed into plasma and middle ear fluid after intramuscular injection and was absorbed into the inner ear after topical application to the middle ear.

The systemic pharmacokinetic properties of ciprofloxacin are well characterized.

Ciprofloxacin is well distributed into body tissues, with tissue concentrations generally higher than plasma concentrations. The volume of distribution at steady state is 1.7–2.71 L/kg. Plasma protein binding ranges from 16% to 43%. The elimination half-life of ciprofloxacin in plasma is 3–5 hours. After oral administration of single doses ranging from 250 to 750 mg in adult patients with normal renal function, 15–50% of the dose is excreted in urine as unchanged drug and 10–15% as metabolites within 24 hours. Both ciprofloxacin and its four primary metabolites are excreted in urine and feces. Renal clearance of ciprofloxacin is typically 300–479 mL/min. Approximately 20–40% of the dose is eliminated in feces as unchanged drug and metabolites over 5 days.

Clinical characteristics.

Indications.

Corneal ulcers and superficial ocular infections (eye or eyes) and its adnexa caused by bacterial strains sensitive to ciprofloxacin.

Acute external otitis, as well as acute otitis media with drainage through a tympanostomy tube, caused by bacterial strains sensitive to ciprofloxacin.

Contraindications.

Hypersensitivity to ciprofloxacin, other quinolones, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No interaction studies have been conducted.

Since ciprofloxacin has low systemic concentrations when administered topically in ophthalmology or otology, interactions with other medicinal products are unlikely.

If several topical ophthalmic medicinal products are used simultaneously, at least 5 minutes should be waited between their applications. Ophthalmic ointments should be applied last.

Special precautions for use.

General.

The medicinal product is intended for topical use (in the conjunctival sac or into the external auditory canal). It should not be administered by injection or taken orally.

Serious and sometimes fatal (anaphylactic) hypersensitivity reactions have been reported in patients treated with quinolones, some occurring after the first dose. Some of these reactions were accompanied by cardiovascular collapse, loss of consciousness, ringing in the ears, throat or facial swelling, dyspnea, urticaria, and pruritus. Only some of these patients had a history of hypersensitivity reactions.

Severe acute hypersensitivity reactions to ciprofloxacin may require emergency treatment. In clinically indicated cases, oxygen therapy and airway maintenance should be initiated.

The medicinal product should be discontinued at the first signs of skin rash or any other signs of hypersensitivity.

As with all antibacterial agents, prolonged use of ciprofloxacin may result in overgrowth of microorganisms not susceptible to the antibiotic, including fungi. If superinfection occurs, appropriate therapy should be instituted.

Tendinitis and tendon rupture may occur with systemic therapy of fluoroquinolones, including ciprofloxacin, particularly in elderly patients and in patients receiving concomitant corticosteroids. Therefore, the medicinal product should be discontinued at the first signs of tendon inflammation (see section "Adverse reactions").

For ophthalmic drops.

Clinical experience with ophthalmic ciprofloxacin drops in children under 1 year of age, especially neonates, is quite limited.

The medicinal product is not recommended for use in neonates with gonococcal or chlamydial neonatal ophthalmia, as it has not been evaluated in this patient population. Neonates with neonatal ophthalmia should receive treatment appropriate for their condition.

Clinical examination using a slit lamp should be performed when indicated.

When using the medicinal product, the risk of its entry into the nasopharynx should be considered, as this may promote the development and spread of bacterial resistance.

In patients with corneal ulceration, a white precipitate (drug residue) in the eye has been observed with frequent use of ciprofloxacin, which disappeared with continued administration. The presence of precipitate does not require discontinuation of the medicinal product and has no negative impact on the clinical course of recovery.

The medicinal product contains benzalkonium chloride, which may cause irritation and may discolor soft contact lenses. Wearing contact lenses is not recommended during treatment of ocular infection. If contact lenses are used, they should be removed and 15 minutes should be waited after instillation before reinserting the lenses.

After instillation of ophthalmic drops, it is recommended to keep the eyelids tightly closed for 2 minutes or perform nasolacrimal occlusion for 2 minutes. This reduces systemic absorption of the agent administered into the eye, thereby decreasing the likelihood of systemic adverse effects.

For otic drops.

The efficacy and safety of ciprofloxacin otic drops in children under 1 year of age have not been established.

Frequent medical monitoring is required during administration of the product into the ear to allow timely implementation of additional therapeutic measures.

The product contains benzalkonium chloride, which may cause skin irritation.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the topical use of ciprofloxacin in pregnant women. Animal studies do not indicate a direct harmful effect via reproductive toxicity. It is advisable to avoid using the medicinal product during pregnancy.

Breastfeeding.

Ciprofloxacin has been detected in breast milk following oral administration. It is unknown whether ciprofloxacin passes into breast milk after topical administration to the eye or ear. The medicinal product should be used with caution during breastfeeding.

Fertility.

No studies have been conducted in humans to assess the effect of topical ciprofloxacin on fertility. Oral administration in animals does not indicate a direct harmful effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Ciprofloxacin for topical use has no or negligible effect on the ability to drive or operate machinery. Transient blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs during instillation, the patient should wait until vision clears before driving or operating machinery.

There are no data on the effect of the medicinal product on the ability to drive or operate machinery.

Method of Administration and Dosage.

Ophthalmological Use.

Dosage.

Adolescents and adults, including elderly patients.

Corneal ulcers.

The medicinal product should be administered at the following intervals, including during nighttime:

• On day 1: instill 2 drops into the conjunctival sac(s) of the affected eye(s) every 15 minutes for the first 6 hours, then 2 drops every 30 minutes throughout the first day;
• On day 2: instill 2 drops into the conjunctival sac(s) of the affected eye(s) hourly;
• From day 3 to day 14: instill 2 drops into the conjunctival sac(s) of the affected eye(s) every 4 hours.

Treatment for corneal ulcers may last longer than 14 days; the dosage regimen and duration of treatment should be determined by a physician.

Bacterial superficial eye infections and associated structures.

The standard dose is 1–2 drops instilled into the conjunctival sac(s) of the affected eye(s) 4 times daily.

In severe infections, the dose may be increased to 1–2 drops every 2 hours during daytime for the first two days.

Treatment typically lasts 7–14 days.

Children.

Dosage for children aged 1 year and older is the same as for adults.

Clinical studies in newborns and infants up to 1 month of age have shown that ciprofloxacin is clinically and microbiologically effective in treating bacterial conjunctivitis in this patient group when administered 3 times daily for 4 days.

Patients with hepatic or renal impairment.

The use of ciprofloxacin ophthalmic drops in this patient population has not been studied.

Method of Administration.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the tip of the dropper bottle.

After instillation, it is recommended to close the eyelids tightly or perform nasolacrimal occlusion. This reduces systemic absorption of drugs administered into the eye, thereby decreasing the likelihood of systemic adverse effects.

If multiple topical ophthalmic medicinal products are used simultaneously, at least 5 minutes should elapse between each administration. Ophthalmic ointments should be applied last.

Otolaryngological Use.

Dosage.

Adults, including elderly patients.

The medicinal product should be administered at a dose of 4 drops into the ear canal twice daily.

For patients requiring ear packing, the dose may be doubled only at the first application (i.e., 6 drops for children and 8 drops for adults).

Generally, treatment duration should not exceed 5–10 days. In some cases, treatment may be extended; however, in such instances, it is recommended to reassess local flora sensitivity.

If other topical medicinal products are used concomitantly, an interval of 10–15 minutes between administrations should be observed.

Children.

The medicinal product should be administered at a dose of 3 drops into the ear canal twice daily. The safety and efficacy of ciprofloxacin have been studied in children aged 1 to 12 years. Safety and efficacy in children under 1 year of age have not been established.

Patients with hepatic or renal impairment.

The use of ciprofloxacin otic drops in this patient population has not been studied.

Method of Administration.

The external auditory canal should be carefully cleaned. To avoid vestibular stimulation, it is recommended to instill the solution at room temperature or body temperature.

The patient should lie on the side opposite to the affected ear. It is advisable to remain in this position for 5–10 minutes. After local cleaning, a gauze or absorbent cotton pledget moistened with the solution may be inserted into the ear canal for 1–2 days and should be rewetted twice daily to maintain saturation with the drug.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the auricle, external auditory canal, adjacent areas, or other surfaces with the tip of the dropper bottle.

Children.

Ophthalmological Use.

The medicinal product can be used in children from birth.

The safety and efficacy of ciprofloxacin ophthalmic drops were evaluated in 230 children aged 0 to 12 years. No serious adverse reactions related to the use of the drug in this patient group were reported.

Otolaryngological Use.

The medicinal product can be used in children aged 1 year and older.

The safety and efficacy of ciprofloxacin otic drops were evaluated in 193 children aged 1 to 12 years. No serious adverse reactions related to the use of the drug in this patient group were reported.

Safety and efficacy in children under 1 year of age have not been established.

Overdose.

Symptoms.

Due to the characteristics of this medicinal product intended for topical use, no toxic effects are expected when used in ophthalmology/otology at recommended doses, or even in case of accidental ingestion of the contents of one bottle.

Treatment.

In case of local overdose, rinse the eye(s) with warm water. Symptomatic and supportive therapy should be administered if necessary.

Adverse reactions.

In clinical trials, the most commonly reported adverse reactions were corneal deposits, eye discomfort, dysgeusia with ocular administration of ciprofloxacin, and otorrhea, ear pruritus with its otic use.

The adverse reactions listed below are classified as follows: 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), or not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing severity of manifestations. Data on adverse effects were obtained from clinical studies and post-marketing experience.

Adverse effects observed after ocular administration of ciprofloxacin.

Children.

The safety and efficacy of ciprofloxacin ophthalmic drops were evaluated in 230 children aged 0 to 12 years. No serious adverse reactions related to the use of ciprofloxacin were reported in this patient group.

Adverse effects observed after administration of ciprofloxacin in the ear

Children.

The safety and efficacy of ciprofloxacin otic drops were evaluated in 193 children aged 1 to 12 years. No serious adverse reactions related to ciprofloxacin use were reported in this patient population.

Description of reported adverse reactions.

Very rare systemic reactions associated with topical application of fluoroquinolones include (generalized) rash, toxic epidermal necrolysis, exfoliative dermatitis, Stevens–Johnson syndrome, and urticaria.

Rare cases of blurred vision, decreased visual acuity, and signs of drug residue have been observed following ocular administration of ciprofloxacin.

In patients with corneal ulcers, a white precipitate (drug residue) in the eye has been observed with frequent use of ciprofloxacin; this precipitate typically resolves with continued treatment. The presence of precipitate does not necessitate discontinuation of the medication and does not negatively affect the clinical course of recovery.

Rarely, components of the medicinal product may cause hypersensitivity reactions when administered into the ear. However, as with topical application of any substance, there is always a possibility of developing an allergic reaction to any excipient of the medicinal product.

Serious, and in some cases fatal (anaphylactic) hypersensitivity reactions, sometimes after the first dose, have been reported in patients receiving systemic quinolone therapy. Some of these reactions were accompanied by cardiovascular collapse, loss of consciousness, paresthesia, swelling of the throat or face, dyspnea, urticaria, and pruritus.

Tendon ruptures of the shoulder, hand, Achilles tendon, or other tendons requiring surgical intervention or resulting in prolonged disability have been reported in patients receiving systemic fluoroquinolones. Clinical studies and post-marketing experience with systemic fluoroquinolones indicate that the risk of such tendon ruptures may be increased in patients receiving concomitant corticosteroids, particularly in elderly patients, and in those with high tendon stress, including the Achilles tendon. To date, clinical and post-marketing data have not demonstrated a clear association between topical use of ciprofloxacin and adverse musculoskeletal or connective tissue effects.

Photosensitivity reactions ranging from moderate to severe have been observed in patients receiving systemic quinolones. However, photosensitivity reactions to ciprofloxacin are uncommon.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions following marketing authorization of the medicinal product is extremely important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

After opening the bottle, use within 28 days.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

Packaging.

5 ml in an amber dropper bottle; 1 dropper bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.S./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

LLC «WORLD MEDICINE», Ukraine/
WORLD MEDICINE, LLC, Ukraine.