Cipro nex®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYPRONEX® (CIPRONEX)

Composition:

Active substance: ciprofloxacin;

1 ml of solution contains 3 mg of ciprofloxacin in the form of ciprofloxacin hydrochloride monohydrate 3.5 mg;

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

Pharmaceutical form. Eye and ear drops, solution.

Main physicochemical properties: almost colorless, light yellow or light green transparent liquid.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Cipronex® contains ciprofloxacin hydrochloride, a member of the quinolone class. The bactericidal action of quinolones, which primarily affects bacterial DNA synthesis, occurs 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 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 exhibits 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 Table 1, ciprofloxacin demonstrates a broad spectrum of in vivo activity (MIC₉₀s ≤2 µg/mL) against pathogenic microorganisms isolated from patients with acute external otitis.

Table 1

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

Table 2

Breakpoints for zone diameters of microbial growth inhibition

Ophthalmic use

Ciprofloxacin has shown 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 tested against systemic breakpoints for zone diameters of microbial growth inhibition. However, the relationship between systemic in vitro microbial growth inhibition zone diameter values and ophthalmic efficacy has not been established. In vitro, ciprofloxacin demonstrates minimum inhibitory concentrations (MICs) of 1 µg/mL or less (systemic breakpoints for zone diameters of microbial susceptibility) 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 certain anaerobic bacteria, particularly Bacteroides fragilis.

Additional information

The minimum bactericidal concentration (MBC) is usually no more than two-fold higher than the MIC.

Otic use

Ciprofloxacin has shown 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 tested against systemic breakpoints for zone diameters of microbial growth inhibition. However, the relationship between systemic in vitro microbial growth inhibition zone diameter values and efficacy in otic use has not been established. In vitro, ciprofloxacin demonstrates MICs of 1 µg/mL or less (systemic breakpoints for zone diameters of microbial susceptibility) 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 shown 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 the group of gyrase inhibitors.

Bacterial susceptibility testing has shown that most microorganisms resistant to ciprofloxacin are also resistant to other fluoroquinolones. The frequency of isolation of strains with acquired resistance to ciprofloxacin has been 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. Therefore, microorganisms resistant to these drugs may still be susceptible to ciprofloxacin.

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 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 7 days of topical ocular administration ranged from undetectable levels (<1.25 ng/mL) to 4.7 ng/mL. The mean maximum plasma concentration of ciprofloxacin after topical ocular administration was approximately 450-fold lower than that observed after a single 250 mg oral 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 limit of quantification, with a detection limit of 5 ng/mL. In animals, 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 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% to 43%. The serum half-life of ciprofloxacin is 3–5 hours. After a single oral dose of 250–750 mg administered to 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 in unchanged form and as metabolites over 5 days.

Clinical characteristics.

Indications.

Corneal ulcers and superficial ocular infections of the 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 or to other quinolones, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Since ciprofloxacin has low systemic concentrations following topical ophthalmic or otic administration, interaction with other medicinal products is unlikely. If several locally applied ophthalmic medicinal products are used simultaneously, at least 5 minutes should elapse between their administration. Ocular ointments should be administered last.

Special precautions for use

For ophthalmic use only.

General

• Serious and occasionally fatal (anaphylactic) hypersensitivity reactions have been reported in patients receiving quinolones, some following the first dose. Some of these reactions were accompanied by cardiovascular collapse, loss of consciousness, ringing in the ears, throat or facial swelling, dyspnea, urticaria, and pruritus. Hypersensitivity reactions have been observed in only a few patients.
• Severe cases of acute hypersensitivity to ciprofloxacin may require emergency treatment. Oxygen therapy and airway maintenance should be initiated as clinically indicated.
• 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 lead to overgrowth of antibiotic-resistant bacterial strains or fungi. If superinfection occurs, appropriate therapy should be instituted.
• Tendon inflammation and rupture may occur with systemic therapy of fluoroquinolones, including ciprofloxacin, particularly in elderly patients and in patients receiving concomitant corticosteroids. Therefore, treatment with ophthalmic/otic drops of Cipronex® should be discontinued at the first sign of tendon inflammation.

Ophthalmic solution

• Clinical experience with the use of the drug in children under 1 year of age, especially neonates, is limited.
• The use of Cipronex® ophthalmic drops is not recommended in neonates with neonatal conjunctivitis of gonococcal or chlamydial origin, as it has not been evaluated in this patient population. Neonates with neonatal conjunctivitis should receive treatment appropriate for their condition.
• When using Cipronex® ophthalmic drops, the risk of drug entry into the nasopharynx should be considered, as this may contribute to the development and spread of bacterial resistance.
• White ocular precipitates (drug residues) have been observed in patients with corneal ulceration and frequent use of ophthalmic drops containing ciprofloxacin. These precipitates disappear after discontinuation of the ophthalmic 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. Precipitates have been observed from 24 hours to 7 days after initiation of therapy. Complete disappearance of precipitates occurs immediately or within 13 days after therapy initiation.
• Cipronex® ophthalmic drops contain benzalkonium chloride, which may cause irritation and may discolor soft contact lenses.
• Wearing contact lenses during treatment of ocular infection is not recommended.

Therefore, patients should be advised not to wear contact lenses during treatment with Cipronex® ophthalmic drops. If patients are permitted to wear contact lenses, they should be removed before instillation of the ophthalmic drops and reinserted no sooner than 15 minutes after administration.

Otic solution

• The efficacy and safety of the drug in children under 1 year of age have not been established.
• Although data are very limited in patients under 1 year of age treated for acute otitis externa, there are no differences in the disease course in this patient population that would contraindicate the use of this medicinal product. Based on very limited data, the physician prescribing the drug to children under 1 year of age should weigh the clinical benefits against the known and potential unknown risks. The safety and efficacy of Cipronex® have not been studied in the presence of a perforated tympanic membrane; therefore, it should be used with caution in patients with known or suspected perforation or when there is a risk of tympanic membrane perforation.
• If signs and symptoms of infection do not resolve after one week of treatment, a reassessment of the treatment regimen is recommended.
• Photosensitivity reactions of varying severity have been reported in patients receiving systemic quinolones. Since this medicinal product is applied locally, photosensitivity reactions are unlikely.
• Frequent medical monitoring is required during otic administration 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 Cipronex® have not been conducted.

Pregnancy

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

Use of the drug during pregnancy should be avoided.

Breastfeeding

Ciprofloxacin has been detected in breast milk following oral administration. It is unknown whether ciprofloxacin is excreted into breast milk following topical administration to the eye or ear. Cipronex® should be used with caution in women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery

This 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 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 Cipronex® otic drops on the ability to drive or operate machinery.

Method of Administration and Dosage

Ophthalmological Use

Adults, including elderly patients, and children

Corneal ulcers

Cipronex® 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.

For corneal ulcers, treatment may last longer than 14 days; the dosing 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) 4 times daily.

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

Treatment typically lasts 7–14 days.

After instillation, it is recommended to firmly close the eyelids or perform nasolacrimal occlusion. This reduces systemic absorption of the drug administered into the eye, thereby decreasing 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.

Children

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

A clinical study demonstrated that Cipronex® is clinically and microbiologically effective in treating bacterial conjunctivitis in neonates and infants up to one month of age when administered 3 times daily for 4 days.

Patients with hepatic or renal impairment

The use of Cipronex® in these patient populations has not been studied.

Precautions for Use

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

Otological Use

Dosage

Adults, including elderly patients

The recommended dose for adults is 4 drops of Cipronex® into the ear canal twice daily.

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

Generally, treatment duration should not exceed 5–10 days. In some cases, treatment may be extended; however, in such instances, 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.

Children

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

Patients with hepatic or renal impairment

The use of Cipronex® in these patient populations has not been studied.

Precautions for Use

The external auditory canal should be carefully cleaned. To avoid vestibular stimulation, the solution should be administered at room temperature or body temperature.

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

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

Children

Ophthalmic drops

May be used in children from birth (see section "Special Instructions").

Otic drops

May be used in children aged 1 year and older.

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 administration in ophthalmology/otology at recommended doses, or after 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, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), or not known (cannot be estimated from available data). Within each group, adverse effects are listed in order of decreasing severity. Data on adverse effects were obtained from clinical studies and from the post-marketing period of use.

Adverse effects observed after ophthalmic administration of Cipronex®

Table 3

Adverse reactions reported during the use of Cipronex® ear preparation

Table 4

Description of the reported adverse reactions

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

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

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 the possibility of an allergic reaction to any component of the product (for Cipronex® ear drops only).

Serious, and in some cases fatal (anaphylactic) hypersensitivity reactions, sometimes after the first dose, have been reported in patients treated with systemic quinolones. 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 indicate that the risk of such tendon ruptures may be increased in patients receiving corticosteroids, particularly elderly patients, and in those with high levels of physical activity affecting tendons, including the Achilles tendon. To date, clinical and post-marketing data have not demonstrated a clear association between the use of Cipronex® and adverse musculoskeletal or connective tissue reactions.

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

Shelf life. 3 years. Do not use after the expiry date stated on the packaging.

The shelf life of the medicinal product after first opening is 4 weeks.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

5 mL of the medicinal product in a 5 mL polyethylene dropper bottle with a cap and tamper-evident ring. One bottle per cardboard box.

Prescription status. Prescription only.

Marketing Authorization Holder.

Pharmaceutical Works “POLPHARMA” S.A.

Address of the Marketing Authorization Holder and location of its operations.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland

Manufacturer.

JADRAN GALENSKI LABORATORIJ d.d.

Address of the Manufacturer and location of its operations.

Svilno 20, Rijeka, 51000, Croatia