Ciloxan

INSTRUCTIONS for medical use of the medicinal product CILOXAN® (CILOXAN®)

Composition:

Active substance: ciprofloxacin hydrochloride;

1 ml of solution contains 3.5 mg ciprofloxacin hydrochloride, equivalent to 3 mg ciprofloxacin;

Excipients: benzalkonium chloride, sodium acetate trihydrate, acetic acid, mannitol (E 421), edetate disodium, sodium hydroxide and/or hydrochloric acid concentrated (for pH adjustment), purified water.

Pharmaceutical form. Eye and ear drops.

Main physicochemical properties: clear solution, colorless to pale yellow.

Pharmacotherapeutic group. Agents for ophthalmological and otological use. Anti-infectives. ATC code S03A A07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Cyprofloxacin

CILUXAN® contains ciprofloxacin hydrochloride, 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.

Microbial 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.

Aerobic Gram-positive microorganisms

Staphylococcus aureus (including both methicillin-susceptible and methicillin-resistant strains);

Staphylococcus epidermidis;

Staphylococcus spp., other coagulase-negative Staphylococcus spp., including

S. haemolyticus and S. hominis;

Corynebacterium spp.;

Streptococcus pneumoniae;

Streptococcus group Viridans.

Aerobic Gram-negative microorganisms

Acinetobacter spp.;

Haemophilus influenzae;

Pseudomonas aeruginosa;

Moraxella spp. (including M. catarrhalis).

Otic use

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 μg/mL) against pathogenic microorganisms isolated from patients with acute otitis externa in recent clinical studies.

Type of bacteria	Isolates N=	Min MIC (μg/mL)	50% MIC (μg/mL)	90% MIC (μg/mL)	Max MIC (μg/mL)
Pseudomonas aeruginosa	1089	0.03	0.13	0.25	16
Staphylococcus aureus	221	0.13	0.50	1.0	128
Staphylococcus epidermidis	257	0.06	0.25	0.50	128
Staphylococcus caprae	75	0.13	0.50	0.50	2.0
Enterococcus faecalis	53	0.50	1.0	2.0	4.0
Enterobacter cloacae	45	0.004	0.016	0.032	0.25

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

Type of bacteria	Isolates N=	Min MIC (μg/ml)	50% MIC (μg/ml)	90% MIC (μg/ml)	Max MIC (μg/ml)
Streptococcus pneumoniae	197	0.25	1.0	2.0	8.0
Staphylococcus aureus	134	0.06	0.25	1.0	>128
Pseudomonas aeruginosa	132	0.03	0.25	0.50	128
Haemophilus influenzae	122	0.004	0.008	0.016	0.25
Staphylococcus epidermidis	103	0.06	1.0	64	64
Moraxella catarrhalis	37	0.008	0.03	0.06	0.06
Escherichia coli	15	0.008	0.03	128	>128

Limiting values of diameters of zones 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 data 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 trials.

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

Aerobic Gram-positive microorganisms

Bacillus spp.

Aerobic Gram-negative microorganisms

Acinetobacter calcoaceticus;

Enterobacter aerogenes;

Escherichia coli;

Haemophilus parainfluenzae;

Klebsiella pneumoniae;

Neisseria gonorrhoeae;

Proteus mirabilis;

Proteus vulgaris;

Serratia marcescens.

Others

Peptococcus spp., Peptostreptococcus spp., Propionibacterium acnes, and Clostridium perfringens are susceptible microorganisms.

Resistant

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

Additional information

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

Use in otology

Ciprofloxacin has demonstrated in vitro activity against most strains of the following microorganisms; 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 trials.

The following bacteria are considered susceptible when evaluated using systemic limiting values of diameters of zones of microbial growth inhibition. However, the relationship between systemic in vitro microbial growth inhibition zone diameters and efficacy in otic use has not been established. In vitro, ciprofloxacin demonstrates a minimal inhibitory concentration (MIC) of 1 µg/mL or less (systemic susceptibility zone diameter breakpoints for microbial growth inhibition) against most (90%) strains of the following pathogenic microorganisms.

Aerobic Gram-positive microorganisms

Bacillus spp.;

Corynebacterium spp.;

Enterococcus faecalis;

Staphylococcus aureus;

Staphylococcus epidermidis;

Staphylococcus caprae;

Staphylococcus capitis;

Staphylococcus haemolyticus;

Streptococcus pneumoniae;

Streptococcus group Viridans.

Aerobic Gram-negative microorganisms

Achromobacter xylosoxidans subsp. xylosoxidans;

Acinetobacter baumannii;

Acinetobacter junii;

Acinetobacter lwoffii;

Acinetobacter radioresistens;

Acinetobacter genomic species 3;

Citrobacter freundii;

Citrobacter koseri;

Enterobacter aerogenes;

Enterobacter cloacae;

Escherichia coli;

Haemophilus influenzae;

Klebsiella oxytoca;

Klebsiella pneumoniae;

Moraxella catarrhalis;

Proteus mirabilis;

Pseudomonas stutzeri;

Serratia marcescens.

Ciprofloxacin has also demonstrated in vitro activity against most strains of the following microorganisms causing otitis media:

Aerobic Gram-positive microorganisms

Staphylococcus aureus;

Staphylococcus epidermidis;

Streptococcus pneumoniae.

Aerobic Gram-negative microorganisms

Escherichia coli;

Haemophilus influenzae;

Moraxella catarrhalis;

Pseudomonas aeruginosa.

Resistance to ciprofloxacin generally develops slowly. However, cross-resistance is observed within this group of gyrase inhibitors.

Susceptibility testing has shown that most microorganisms resistant to ciprofloxacin are also resistant to other fluoroquinolones. During clinical trials, the frequency of isolates 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 still be 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, joint effects were minimal. This dose is 270 times higher than the recommended clinical dose for otic use in a child weighing 10 kg, using 0.27 mg of ciprofloxacin in each ear twice daily. In a one-month study in young dogs (beagles), topical ophthalmic administration of CILUXAN® did not reveal any joint lesions. There was also no evidence that topical application affects joints in any way. 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 otic dose (for treatment of a child weighing 10 kg or an adult weighing 50 kg, using 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 ocular administration in humans, 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 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 oral administration of a single 250 mg dose of ciprofloxacin.

In children with otorrhea due to tympanostomy tubes or perforated tympanic membranes, topical otic administration of ciprofloxacin 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 administration to the middle ear.

Systemic pharmacokinetic properties of ciprofloxacin are well characterized.

Ciprofloxacin is widely distributed in body tissues, with tissue concentrations generally exceeding plasma levels. The steady-state volume of distribution is 1.7–2.71 L/kg. Protein binding to serum proteins ranges from 16% to 43%. The serum half-life of ciprofloxacin 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 typically ranges from 300 to 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 suppurative otitis media with drainage through a tympanostomy tube, caused by bacterial strains sensitive to ciprofloxacin.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Since ciprofloxacin administered topically in ophthalmic or otologic use achieves low systemic concentrations, interaction with other medicinal products is unlikely. If multiple 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.

For ophthalmic use only.

General

• Serious and occasionally fatal (anaphylactic) hypersensitivity reactions have been reported in patients receiving quinolone therapy, some occurring after the first dose. Some of these reactions were accompanied by cardiovascular collapse, loss of consciousness, ringing in the ears, swelling of the throat or face, dyspnea, urticaria, and pruritus.
• Severe acute hypersensitivity reactions to ciprofloxacin may require emergency treatment. In case of clinical indications, oxygen therapy and restoration of airway patency should be initiated.
• Ciprofloxacin should be discontinued at the first sign of a skin rash or any other sign of hypersensitivity reaction.
• As with all antibacterial agents, prolonged use may result in overgrowth of organisms not susceptible to the antibiotic, including fungi. If superinfection occurs, appropriate therapy should be instituted.
• Tendon inflammation and rupture have been reported with systemic fluoroquinolone therapy, including ciprofloxacin, particularly in elderly patients and in patients receiving concomitant corticosteroid therapy. Therefore, treatment with ЦІЛОКСАН® eye/ear drops should be discontinued at the first sign of tendon inflammation.

Eye drops

• Clinical experience with use in children under 1 year of age, especially neonates, is limited.
• Use of ЦІЛОКСАН® eye drops is not recommended in neonates with gonococcal or chlamydial ophthalmia neonatorum, as it has not been evaluated in this patient population. Neonates with ophthalmia neonatorum should receive treatment appropriate for their condition.
• When using ЦІЛОКСАН® eye drops, the risk of drug drainage into the nasopharynx should be considered, as this may contribute to the development and spread of bacterial resistance.
• ЦІЛОКСАН® eye drops contain benzalkonium chloride, which may cause irritation and may discolor soft contact lenses.
• Wearing contact lenses during treatment of an ocular infection is not recommended.

Therefore, patients should be advised not to wear contact lenses during treatment with ЦІЛОКСАН® eye drops.

Ear drops

• The efficacy and safety of use in children under 1 year of age have not been established.
• When administering drops into the ear, frequent medical monitoring is recommended to allow timely implementation of additional therapeutic measures.

Use during pregnancy or breastfeeding.

Reproductive function

Studies to evaluate the effect on reproductive function following topical administration of ЦІЛОКСАН® have not been conducted.

Pregnancy

There are no adequate data on the use of ЦІЛОКСАН® in pregnant women. Animal studies do not indicate a direct harmful effect via reproductive toxicity.

Use of ЦІЛОКСАН® during pregnancy is not recommended.

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. ЦІЛОКСАН® should be used with caution in women who are breastfeeding.

Ability to influence the speed of reactions when driving or operating machinery.

This medicinal product has no or negligible effect on the ability to drive or operate machinery. However, transient blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs after instillation, the patient should wait until vision clears before driving or operating machinery.

There are no data on the effect of ЦІЛОКСАН® ear drops on the ability to drive or operate machinery.

Method of Administration and Dosage

Use in Ophthalmology

Dosage

Use in adolescents and adults, including elderly patients

Corneal ulcers:

CILKOSAN® 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 for the remainder of 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.

For corneal ulcers, treatment may last longer than 14 days; the dosage regimen and duration of therapy should be determined by the 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) four 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.

After instillation, it is recommended to close the eyelids tightly or perform nasolacrimal occlusion. This reduces systemic absorption of ophthalmically administered drugs and lowers the risk of systemic adverse effects.

If concomitant therapy with other topical ophthalmic agents is required, an interval of 10–15 minutes should be maintained between administrations.

Use in 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 CILKOSAN® is clinically and microbiologically effective in treating bacterial conjunctivitis in this patient group when administered 3 times daily for 4 days.

Use in patients with hepatic or renal impairment

The use of CILKOSAN® in patients with hepatic or renal impairment 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 any other surfaces with the tip of the dropper bottle.

Use in Otology

Dosage

Use in adults, including elderly patients

For adults, the dose is 4 drops of CILKOSAN® into the ear canal twice daily.

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

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

If concomitant therapy with other topical medicinal products is required, an interval of 10–15 minutes should be maintained between administrations.

Use in children

The dose is 3 drops of CILKOSAN® into the ear canal twice daily. The safety and efficacy of CILKOSAN® have been evaluated in children aged 1 to 12 years. Safety and efficacy in children under 1 year of age have not been established.

Use in patients with hepatic or renal impairment

The use of CILKOSAN® in patients with hepatic or renal impairment 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 or body temperature.

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

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

Children.

Ophthalmic drops

The safety and efficacy of CILKOSAN® ophthalmic drops 3 mg/g 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 group.

Otic drops

The safety and efficacy of CILKOSAN® otic drops 3 mg/mL 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 group.

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

Overdose.

Given 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 following accidental ingestion of the contents of one bottle.

Adverse reactions

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 (cannot be estimated from the available data). Within each group, adverse reactions are listed in order of decreasing severity. Data on adverse effects were obtained from clinical trials and post-marketing use.

Adverse effects observed after ocular administration of CYLOKSAN®

System organ classes	Adverse reactions according to MedDRA classification
Infections and infestations	Isolated: hordeolum, rhinitis
Immune system disorders	Isolated: hypersensitivity
Nervous system disorders	Common: dysgeusia Uncommon: headache Isolated: dizziness
Eye disorders	Common: corneal deposits, eye discomfort, ocular hyperemia Uncommon: keratopathy, corneal infiltrates, corneal staining, photophobia, decreased visual acuity, eyelid edema, blurred vision, eye pain, dry eye, eye swelling, eye pruritus, foreign body sensation in eye, increased lacrimation, eye discharge, scaling of eyelid margins, eyelid desquamation, conjunctival edema, eyelid erythema Isolated: ocular toxicity, punctate keratitis, keratitis, conjunctivitis, corneal function disorder, corneal epithelial defect, diplopia, ocular hypoesthesia, asthenopia, eye irritation, eye inflammation, conjunctival hyperemia
Ear and labyrinth disorders	Isolated: ear pain
Respiratory, thoracic and mediastinal disorders	Isolated: hypersecretion of nasal sinuses
Gastrointestinal disorders	Uncommon: nausea Isolated: diarrhea, abdominal pain
Skin and subcutaneous tissue disorders	Isolated: dermatitis
General disorders and administration site conditions	Isolated: drug intolerance
Investigations	Isolated: laboratory test abnormal

Adverse reactions reported during the use of CILoxan® in the ear

System organ classes	Adverse reactions according to MedDRA classifier
Nervous system disorders	Uncommon: tearfulness, headache
Ear and labyrinth disorders	Uncommon: ear pain, ear fullness, otorrhea, ear pruritus Unknown: tinnitus
Skin and subcutaneous tissue disorders	Uncommon: dermatitis
General disorders and administration site conditions	Uncommon: hyperthermia

Description of the reported adverse reactions

Very rarely, topical application of fluoroquinolones has been associated with reactions such as (generalized) rash, toxic epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, and urticaria.

In isolated cases, administration of ciprofloxacin into the eye has been associated with episodes of blurred vision, decreased visual acuity, and signs of drug residue.

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 component of the product (for CILUXAN® ear drops only).

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 repair or leading to prolonged disability have been reported in patients receiving systemic fluoroquinolones. Clinical studies and post-marketing experience with systemic fluoroquinolones suggest that the risk of such ruptures may be increased in patients receiving corticosteroids, particularly in elderly patients, and in those with high stress on tendons, including the Achilles tendon. To date, clinical and post-marketing data have not demonstrated a clear association between the use of CILUXAN® and adverse reactions affecting the musculoskeletal and connective tissue.

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

Shelf life. 2 years.

Storage period after first opening of the bottle – 4 weeks.

Storage conditions.

Do not store in the refrigerator and do not freeze. Keep out of reach and sight of children.

Packaging. 5 ml in a dropper bottle; 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Novartis Manufacturing NV / Novartis Manufacturing NV.

Manufacturer's address and place of business.

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.