Floximed

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

Composition:

Active substance: ciprofloxacin;

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

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

Pharmaceutical form. Eye and ear drops, solution.

Main physicochemical properties: clear solution, from colorless to slightly greenish-yellow.

Pharmacotherapeutic group.

Ophthalmological and otological preparations. 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 exhibits 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.

Susceptibility of microorganisms.

Use in ophthalmology.

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 broad-spectrum in vivo activity (MIC90s [minimum inhibitory concentration] ≤2 mcg/mL) against pathogenic microorganisms isolated from patients with acute otitis externa in recent clinical studies.

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

Breakpoints for zone diameters of microbial growth inhibition.

Ophthalmic use.

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 following bacteria are considered susceptible when tested using systemic breakpoints for zone diameters of microbial growth inhibition. However, the correlation between systemic in vitro zone diameter breakpoints for microbial growth inhibition and ophthalmic efficacy has not been established. In vitro, ciprofloxacin demonstrates MIC values of 1 µg/mL or less (systemic breakpoints for zone diameters of microbial susceptibility) against most (90%) strains of the following ocular pathogenic microorganisms.

Resistant species.

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

Other information.

The minimum bactericidal concentration (MBC) is generally not more than twice the MIC.

Use in otology.

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 external otitis 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 relationship between systemic in vitro microbial growth inhibition zone diameter breakpoints and clinical efficacy when administered into the ear has not been established. Ciprofloxacin demonstrates in vitro MICs of 1 μg/mL or less (systemic susceptibility breakpoints 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 is observed among this group of gyrase inhibitors.

Bacterial susceptibility testing has shown that most microorganisms resistant to ciprofloxacin are also resistant to other fluoroquinolones. During clinical trials, the frequency of isolation of 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 susceptible to ciprofloxacin.

Preclinical safety data.

Ciprofloxacin and other quinolones cause arthropathy in young animals of most species studied after oral administration. When ciprofloxacin was administered at 30 mg/kg, effects on joints were minimal. This dose is 270 times higher than the recommended clinical dose for otic use in a child weighing 10 kg (0.27 mg of ciprofloxacin in each ear twice daily). In a one-month study in young dogs (beagles) using topical ophthalmic drops of ciprofloxacin, no joint lesions were observed. There was also no evidence that topical administration had any effect on joints. Furthermore, 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 ophthalmic daily dose in humans, and 900 times higher than the recommended otic dose (for a child weighing 10 kg: 0.27 mg, for an adult weighing 50 kg: 0.36 mg of ciprofloxacin in each ear twice daily), showed no evidence of impaired fertility or harmful effects on the fetus due to ciprofloxacin administration.

Ciprofloxacin administered orally at doses of 30 and 100 mg/kg did not cause 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 ocular administration in humans, ciprofloxacin is well absorbed. Concentrations of ciprofloxacin detected in the tear film, cornea, and anterior chamber of the eye are from ten to several hundred times higher than the MIC90 for susceptible ocular pathogenic microorganisms.

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

In children with otitis media with tympanostomy tubes or perforated tympanic membranes, topical otic administration of ciprofloxacin resulted in plasma concentrations of ciprofloxacin below quantifiable levels, 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 administration 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 a single oral dose of 250–750 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[s]) 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, and/or to any excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Since ciprofloxacin has low systemic concentration when administered topically in ophthalmology or otology, its interaction with other medicinal products is 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 in 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, sometimes after the first dose. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, ringing in the ears, swelling of the throat or face, dyspnea, urticaria, and pruritus. Only a few patients had a history of hypersensitivity reactions.

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

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

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.

Tendon inflammation and rupture are possible during systemic therapy with 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 eye drops.

Clinical experience with the use of ciprofloxacin eye drops in children under 1 year of age, especially neonates, is limited.

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

When clinically indicated, patients should be examined using a slit lamp.

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 (residue of the medicinal product) has been observed in the eye with frequent use of ciprofloxacin; this precipitate disappeared with continued use. 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 during treatment of ocular infection is not recommended. If contact lenses are used, they should be removed before instillation of the medicinal product and not reinserted until at least 15 minutes after instillation.

After instillation of eye drops, firm closure of the eyelids for 2 minutes or nasolacrimal occlusion for 2 minutes is recommended. This reduces systemic absorption of the drug administered into the eye, thereby decreasing the likelihood of systemic adverse reactions.

For ear drops.

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

Frequent medical monitoring is required when administering the medicinal product into the ear to allow timely implementation of additional therapeutic measures.

The medicinal 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 direct harmful effects via reproductive toxicity. Use of the medicinal product during pregnancy should be avoided.

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 influence 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, patients 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.

Use in Ophthalmology.

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) every hour;
• From day 3 to day 14: instill 2 drops into the conjunctival sac(s) of the affected eye(s) every 4 hours.

In cases of corneal ulceration, treatment may last longer than 14 days; the dosage regimen and duration of treatment are determined by the physician.

Bacterial superficial eye infections and associated structures. The standard dose of the medicinal product is 1–2 drops 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.

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

Clinical studies in neonates 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 ophthalmic medications and decreases the likelihood of systemic adverse effects.

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

Use in Otolaryngology.

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 wicks, the dose may be doubled only at the first application (i.e., 6 drops for children and 8 drops for adults).

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

When treating concurrently with other local medicinal products, an interval of 10–15 minutes between applications should be maintained.

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 ear drops have been evaluated 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 ear 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 use the solution at room temperature or body temperature.

The patient should lie on the side opposite to the affected ear. Remaining in this position for 5–10 minutes is advisable. After local cleansing, a moistened gauze or absorbent cotton pledget may be inserted into the ear canal for 1–2 days, but it must be rewetted twice daily to maintain saturation with the medicinal product.

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.

Use in Ophthalmology. The medicinal product may 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 were reported in this patient population.

Use in Otolaryngology. The medicinal product may be used in children aged 1 year and older.

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

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 following ophthalmic/otologic administration at recommended doses or after 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 observed adverse reactions were corneal deposits, eye discomfort, dysgeusia following ocular administration of ciprofloxacin, and otorrhea, ear pruritus — when administered into the ear.

The frequency of the adverse reactions listed below was classified as follows: very common (≥ 1/10), common (≥ 1/100 — < 1/10), uncommon (≥ 1/1000 — < 1/100), rare (≥ 1/10000 — < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity. 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 population.

Adverse reactions 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 the use of ciprofloxacin were reported in this patient population.

Description of individual adverse reactions.

Very rare reactions following 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 reported with ocular use of ciprofloxacin.

In patients with corneal ulceration, 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 require 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 the application of any substance to the skin, there is always a possibility of an allergic reaction to any excipient in the medicinal product.

Severe, 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, throat or facial swelling, dyspnea, urticaria, and pruritus.

Tendon ruptures of the shoulder, hand, Achilles tendon, or other tendons requiring surgical repair or leading to prolonged disability have been observed in patients receiving systemic fluoroquinolones. Clinical studies and post-marketing experience with systemic fluoroquinolones indicate that the risk of such tendon ruptures is increased in patients receiving corticosteroids, particularly in elderly patients, and in those with significant 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 reactions affecting the musculoskeletal or connective tissue.

Phototoxicity ranging from moderate to severe has been observed in patients receiving systemic quinolones. However, phototoxic reactions to ciprofloxacin are uncommon.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

After first opening of the vial, the product can be used for up to 28 days.

Storage conditions.

Store at temperatures not exceeding 25 °C, in the original packaging, in a place inaccessible to children.

Packaging.

5 mL of solution in a dropper bottle; 1 dropper bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

K.O. Rompharm Company S.R.L., Romania /
S.C. Rompharm Company S.R.L., Romania.

Manufacturer's address and location of operations.

Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov /
Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.