Citicom

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

Composition:

Active substance: ciprofloxacin;

5 ml of solution contain ciprofloxacin hydrochloride equivalent to ciprofloxacin 15 mg;

Excipients: sodium chloride, disodium edetate, benzalkonium chloride solution, hydrochloric acid, water for injections.

Pharmaceutical form. Ear/eye drops, solution.

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

Pharmacotherapeutic group. Agents for ophthalmological and otological use. Antimicrobial agents. ATC code S03A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Cyprofloxacin

The drug contains ciprofloxacin hydrochloride, a member of the quinolone class. The bactericidal effect 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.

Susceptibility of microorganisms

Ophthalmological 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 species, 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.

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

Limits of inhibition zone diameters for microbial growth

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

Aerobic Gram-Positive Microorganisms

• Bacillus species.

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 Otorology

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

Aerobic Gram-Positive Microorganisms

• Bacillus species;
• Corynebacterium species;
• 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. In 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 remain susceptible to ciprofloxacin.

Preclinical Safety Data

Ciprofloxacin and other quinolones cause arthropathy in young animals of most species studied following oral administration. Joint effects were minimal at a dose of 30 mg/kg ciprofloxacin. This dose is 270 times higher than the recommended clinical dose for otic use in a 10 kg child, using 0.27 mg of ciprofloxacin in each ear twice daily. In a one-month study in young dogs (beagles), topical application of ophthalmic drops did not reveal any joint lesions. There was also no evidence that topical application had any effect on joints. Furthermore, in 634 children who received oral ciprofloxacin, no toxic effects on the skeleton were detected by clinical or radiological examination.

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 10 kg child or a 50 kg adult receiving 0.27 mg or 0.36 mg ciprofloxacin, respectively, in each ear twice daily), showed no evidence of impaired fertility or fetal harm caused by ciprofloxacin.

Oral administration of ciprofloxacin 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 use 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 application to the middle ear.

Systemic pharmacokinetic properties of ciprofloxacin are well studied.

Ciprofloxacin is widely distributed in body tissues, with tissue concentrations generally exceeding plasma concentrations. The steady-state volume of distribution is 1.7–2.71 L/kg. Protein binding to serum proteins ranges from 16–43%. The serum half-life of ciprofloxacin is 3–5 hours. After a single oral dose of 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 excreted 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 has low systemic concentration when administered topically in ophthalmological or otological indications, 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.

For ophthalmic use only.

General

• Serious and occasionally fatal (anaphylactic) hypersensitivity reactions have been reported in patients receiving quinolone therapy, some after administration of the first dose. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tinnitus, swelling of the throat or face, dyspnea, urticaria, and pruritus.
• Severe acute hypersensitivity reactions to ciprofloxacin may require emergency treatment. In clinical emergencies, 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.
• 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 otic/ophthalmic drops should be discontinued at the first sign of tendon inflammation.

Ophthalmic solution

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

Otic solution

• The efficacy and safety of use in children under 1 year of age have not been established.
• Frequent medical monitoring is required during administration into the ear to allow timely implementation of additional therapeutic interventions.

Use during pregnancy or breastfeeding.

Reproductive function

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

Pregnancy

There are no adequate data on the use of this medicinal product in pregnant women. Animal studies do not indicate a direct harmful effect related to reproductive toxicity.

Use of the 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. Caution should be exercised when administering to women who are breastfeeding.

Effect on ability to drive or operate 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, patients should wait until vision clears before driving or operating machinery.

There are no data on the effect of otic 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

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

• On Day 1: instill 2 drops into the conjunctival sac 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 of the affected eye(s) every hour;
• From Day 3 to Day 14: instill 2 drops into the conjunctival sac 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 into the conjunctival sac 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.

After instillation, it is recommended to close the eyelids firmly or perform nasolacrimal occlusion. This reduces systemic absorption of ophthalmic medications and decreases the likelihood 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 the drug 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 this medication 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

The recommended dose for adults is 4 drops of the medication 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).

In general, 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 into the ear canal twice daily. The safety and efficacy of the medication 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 this medication 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 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 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 saturated with the medication twice daily.

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

Children

Ophthalmic drops

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

Otic drops

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

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

Overdose

Due to the characteristics of this medication intended for topical use, no toxic effects are expected when used in ophthalmology/otology at the recommended doses, or even in case of 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 (≥1/10,000 to <1/1000), very rare (<1/10000), or not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity. Data on adverse reactions were obtained from clinical trials and post-marketing experience.

Adverse reactions observed after ophthalmic administration of the medicinal product

Adverse reactions reported during use of the drug in the ear

Description of the adverse reactions listed

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

In isolated cases, use of ciprofloxacin in the eye has been associated with transient 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 any substance applied to the skin, there is always a possibility of an allergic reaction to any component of the product (for 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, throat or facial swelling, dyspnea, urticaria, and pruritus.

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 fluoroquinolones. Clinical studies and post-marketing experience with systemic fluoroquinolones suggest that the risk of such tendon ruptures may be increased in patients receiving concomitant corticosteroids, particularly in elderly patients, and in those with high physical stress on tendons, including the Achilles tendon. Currently, clinical and post-marketing data have not demonstrated a clear association between the use of this medicinal product 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 the product, which resolved upon continued administration. The presence of precipitate does not require discontinuation of the product and has no negative impact on the clinical course of recovery.

Reporting of adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Do not freeze.

Packaging.

5 mL solution in a plastic bottle with a cap and dropper plug, one bottle per carton.

Prescription status.

Prescription only.

Manufacturer.

Eurolife Healthcare Pvt. Ltd.

Manufacturer's address and location of operations.

Plot No. 520, Bhagwanpur, Roorkee, Haridwar, Uttarakhand, India.

Marketing authorization holder.

Ananta Medicare Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.