Ciprofloxacin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYPROFLOXACIN (CIPROFLOXACIN)

Composition:

Active substance: ciprofloxacin;

1 ml of solution contains 3 mg of ciprofloxacin;

Excipients: benzalkonium chloride; disodium edetate (Trilon B); sodium chloride; purified water.

Pharmaceutical form. Ophthalmic and otic drops.

Main physicochemical properties: clear liquid with a greenish-yellow tint.

Pharmacotherapeutic group. Agents for ophthalmological and otological use. Antimicrobial agents. ATC code S03AA07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Ciprofloxacin is an antimicrobial agent belonging to the class of quinolones. 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.

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).

Otological 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 (minimum inhibitory concentrations MIC90s ≤2 µg/mL) against pathogenic microorganisms isolated from patients with acute external otitis in recent clinical studies.

Type of bacteria	Isolates N =	Minimum MIC (μg/ml)	MIC50 (μg/ml)	MIC90 (μg/ml)	Maximum 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

Breakpoints for zone diameters of microbial growth inhibition

Ophthalmic use

Ciprofloxacin has demonstrated in vitro activity against most strains of the microorganisms listed below; 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 tested using systemic breakpoints for zone diameters of microbial growth inhibition. However, the correlation between systemic in vitro microbial growth inhibition zone diameter values and ophthalmic efficacy has not been established. In vitro, ciprofloxacin demonstrates an MIC of 1 µg/mL or less (systemic breakpoints for microbial growth inhibition zone diameters) against most (90%) strains of the following ocular pathogenic microorganisms.

Aerobic gram-positive microorganisms: species of Bacillus.

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.

Other

The minimal bactericidal concentration (MBC) is generally not more than two-fold higher than the MIC.

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 external otitis caused by these microorganisms have not been established in adequate and well-controlled clinical trials.

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 microbial growth inhibition zone diameter values and efficacy in otological use has not been established. In vitro, ciprofloxacin demonstrates an MIC of 1 µg/mL or less (systemic breakpoints for microbial growth inhibition zone diameters) against most (90%) strains of the following pathogenic microorganisms.

Aerobic gram-positive microorganisms: species of Bacillus, species of Corynebacterium, 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, genomic species 3 of Acinetobacter, 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 has been observed within this group of gyrase inhibitors.

Most microorganisms resistant to ciprofloxacin have been confirmed to be resistant to other fluoroquinolones as well. 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 still be susceptible to ciprofloxacin.

Pharmacokinetics.

After topical ocular administration in humans, ciprofloxacin is well absorbed. The concentrations of ciprofloxacin detected in the tear film, cornea, and anterior chamber of the eye are 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 ocular use ranged from below the limit of quantification (<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 otitis media with tympanostomy tubes or tympanic membrane perforation, plasma concentrations of ciprofloxacin after topical otic application were below the limit of quantification, 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 distributes well into 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% 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 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 infections of the eye (eyes) 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 use, 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.

The medicinal product is intended for topical use (in the conjunctival sac or in the external auditory canal).

Ophthalmic drops

Clinical experience with use in children under 1 year of age, especially in newborns, is very limited.

The use of the drug is not recommended in newborns with gonococcal or chlamydial neonatal ophthalmia, as it has not been evaluated in patients of this category. Newborns with neonatal ophthalmia should receive treatment appropriate to their condition.

When using the drug, the risk of its penetration into the nasopharynx should be considered, which may contribute to the development and spread of bacterial resistance.

In patients with corneal ulceration, white ocular precipitates (drug residues) have been observed with frequent use of ophthalmic drops containing ciprofloxacin; these precipitates disappear after discontinuation of the eye drops. The occurrence of precipitates does not preclude further use of the ophthalmic drops and has no negative impact on the course of the disease.

Wearing contact lenses during treatment of ocular infection is not recommended.

Otic drops

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

When administering into the ear, frequent medical monitoring should be performed to allow timely implementation of additional therapeutic measures.

General precautions

In patients treated with quinolones, serious and sometimes fatal (anaphylactic) hypersensitivity reactions have been observed, some occurring after the first dose. Some of these reactions were accompanied by cardiovascular collapse, loss of consciousness, tinnitus, swelling of the throat or face, dyspnea, urticaria, and pruritus. Only some of these patients had a history of hypersensitivity reactions.

Severe cases of acute hypersensitivity to ciprofloxacin may require emergency treatment. Oxygen therapy should be administered and airway patency restored as clinically indicated.

Ciprofloxacin should be discontinued at the first signs of skin rash or any other manifestations of hypersensitivity.

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

Tendon inflammation and rupture are possible during systemic therapy with fluoroquinolones, including ciprofloxacin, particularly in elderly patients and in patients receiving concomitant corticosteroids. Therefore, treatment with ciprofloxacin should be discontinued at the first signs of tendon inflammation.

The medicinal product contains benzalkonium chloride, which may cause irritation. Contact with soft contact lenses should be avoided (remove contact lenses before instilling eye drops and reinsert no sooner than 15 minutes after instillation). Benzalkonium chloride may discolor soft contact lenses. Therefore, patients should be advised not to wear contact lenses during treatment with ophthalmic drops.

When applied topically, benzalkonium chloride may cause skin reactions.

Use during pregnancy or breastfeeding.

Fertility

Studies to assess the effect on fertility following topical administration of ciprofloxacin have not been conducted.

Pregnancy

There are no data on the 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 drug should be used with caution in women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has no effect or has a negligible effect on the ability to drive or operate machinery. Transient blurred vision or other visual disturbances may impair 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

Ciprofloxacin 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 for the remainder of 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.

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 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 firmly or perform nasolacrimal occlusion. This reduces systemic absorption of ophthalmically administered drugs 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.

Ciprofloxacin has been shown to be clinically and microbiologically effective in treating bacterial conjunctivitis in newborns and infants under 1 month of age when administered 3 times daily for 4 days.

Use in patients with hepatic or renal impairment

The use of ciprofloxacin 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 any other surfaces with the tip of the dropper bottle.

Use in Otorhinolaryngology (Otolaryngology)

Dosage

Use in adults, including elderly patients

The dose for adults is 4 drops of the medication instilled 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, it is recommended to reassess the sensitivity of the local flora.

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 the medication instilled into the ear canal twice daily. The safety and efficacy of ciprofloxacin 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 ciprofloxacin 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 the affected ear. It is advisable to remain in this position for 5–10 minutes. After local cleansing, a moistened gauze or absorbent cotton pledget may be inserted into the ear canal for 1–2 days, but it 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 ophthalmic drops have been established in 230 children aged 0 to 12 years. No serious adverse reactions related to the use of the drug have been reported in this patient population.

Otic drops

The safety and efficacy of otic drops have been established in 193 children aged 1 to 12 years. No serious adverse reactions related to the use of the drug have been reported in this patient population.

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

Overdose.

Due to the characteristics of this medicinal product intended for topical use, no toxic effects are expected following ophthalmic or otic administration at recommended doses, or even after accidental ingestion of the contents of one bottle.

Side effects

The adverse reactions listed below are classified by frequency of occurrence 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 frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity. The data on adverse effects were obtained from clinical trials and post-marketing experience.

Adverse effects observed after ocular administration of ciprofloxacin

Infections and infestations: rare: hordeolum, rhinitis.

Immune system disorders: rare: hypersensitivity.

Nervous system disorders: common: dysgeusia; uncommon: headache; rare: dizziness.

Eye disorders: common: corneal deposits, eye discomfort, ocular hyperemia; uncommon: keratopathy, corneal infiltrates, corneal pigmentation, photophobia, decreased visual acuity, eyelid edema, blurred vision, eye pain, dry eye, eye swelling, eye pruritus, foreign body sensation in the eye, increased lacrimation, eye discharge, scaling along eyelid margins, eyelid desquamation, conjunctival edema, eyelid erythema; rare: 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: rare: ear pain.

Respiratory, thoracic and mediastinal disorders: rare: increased nasal secretion.

Gastrointestinal disorders: uncommon: nausea; rare: diarrhea, abdominal pain.

Skin and subcutaneous tissue disorders: rare: dermatitis.

General disorders and administration site conditions: rare: drug intolerance.

Investigations: rare: laboratory test abnormality.

Adverse reactions reported with otic administration of ciprofloxacin

Nervous system disorders: uncommon: irritability, headache.

Ear and labyrinth disorders: uncommon: ear pain, ear fullness, otorrhea, ear pruritus; frequency not known: tinnitus.

Skin and subcutaneous tissue disorders: uncommon: dermatitis.

General disorders and administration site conditions: uncommon: hyperthermia.

Description of selected adverse reactions

Very rarely, systemic 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, blurred vision, decreased visual acuity, and signs of drug residue have been observed during ocular use of ciprofloxacin.

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 (applies only to ear drops).

Severe, and in some cases fatal (anaphylactic) hypersensitivity reactions, sometimes after the first dose, have occurred 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 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 concomitant corticosteroid therapy, particularly in elderly patients, and with excessive physical strain on tendons, including the Achilles tendon. To date, clinical and post-marketing data have not demonstrated a clear association between ciprofloxacin use and adverse musculoskeletal or connective tissue reactions.

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

Shelf life. 3 years.

Storage period of the solution after opening the bottle – 28 days.

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

Do not refrigerate.

Keep out of reach of children.

Packaging. 5 ml or 10 ml in a bottle with a dropper cap in a box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Experimental Plant 'GNCLS'".

Limited Liability Company "FARMEKS GROUP".

Address of manufacturer and location of business activity.

8 Vorobiova Street, Kharkiv, Kharkiv region, 61057, Ukraine.

(Limited Liability Company "Experimental Plant 'GNCLS')

100 Shevchenka Street, Boryspil, Kyiv region, 08301, Ukraine.

(Limited Liability Company "FARMEKS GROUP")