Ciprofarm®

INSTRUCTIONS for medical use of the medicinal product CYPROFARM® (CIPROFARM)

Composition:

Active substance: ciprofloxacin;

1 ml of the preparation contains 3 mg of ciprofloxacin hydrochloride calculated as ciprofloxacin;

Excipients: benzalkonium chloride; sodium dihydrogen phosphate dihydrate; sorbitol (E 420); water for injections.

Pharmaceutical form. Eye/ear drops.

Main physicochemical properties: clear slightly yellowish-green liquid.

Pharmacotherapeutic group.

Agents for ophthalmological and otological use. Antimicrobial agents.

ATC code S03A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Cyprofloxacin

Cipropharm® contains ciprofloxacin hydrochloride from the class of quinolones. The bactericidal action of quinolones, which primarily affects bacterial DNA synthesis, is expressed through inhibition of DNA gyrase.

Ciprofloxacin has 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.

Microorganism susceptibility

Ophthalmological use

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.

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

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 studies.

The following bacteria are considered susceptible when evaluated using systemic limiting values of diameters of microbial growth inhibition zones. 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 (MIC) of 1 µg/mL or less (systemic limiting values of susceptibility zone diameters for microbial growth inhibition) 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.

Additional information

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

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 studies.

The following bacteria are considered susceptible when evaluated using systemic limiting values of microbial growth inhibition zone diameters. 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 limiting values of susceptibility zone diameters for microbial growth inhibition) 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 iwoffii; 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.

Bacterial susceptibility testing has shown that most microorganisms resistant to ciprofloxacin are also resistant to other fluoroquinolones. In clinical studies, 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.

Pharmacokinetics.

After topical application to the human eye, 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 use 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 times lower than that observed after a single 250 mg oral dose of ciprofloxacin.

In children with otitis media with tympanostomy tubes or tympanic membrane perforation, topical application of ciprofloxacin to the ear 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.

The systemic pharmacokinetic properties of ciprofloxacin are well studied.

Ciprofloxacin is well distributed 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 generally 300–479 mL/min. Approximately 20–40% of the dose is eliminated in feces as unchanged drug and metabolites over 5 days.

Clinical characteristics.

Indications.

Corneal ulcers and superficial ocular infections 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 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 ophthalmology or otology, interaction with other medicinal products is unlikely. If several topical ophthalmic products are used simultaneously, at least 5 minutes should be waited between their administration. Ocular ointments should be applied last.

Special precautions for use.

Use in patients with impaired liver or kidney function.

The use of Cipropharm® in this patient population has not been studied.

General

• Serious and sometimes 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 immediately.
• Administration of ciprofloxacin should be discontinued at the first signs of skin rash or any other signs of hypersensitivity reaction.
• As with the use of 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 tendon rupture may occur during systemic therapy with fluoroquinolones, including ciprofloxacin, particularly in elderly patients and in patients receiving concomitant corticosteroid therapy. Therefore, treatment with Cipropharm® eye/ear drops should be discontinued at the first signs of tendon inflammation.

Eye drops

• Clinical experience with use in children under 1 year of age, especially neonates, is very limited.
• The use of Cipropharm® eye drops in neonates for neonatal gonococcal or chlamydial ophthalmia is not recommended, as such use has not been evaluated in this patient population. Neonates with ophthalmia neonatorum should receive treatment appropriate to their condition.
• When using Cipropharm® eye drops, the risk of drug drainage into the nasopharynx should be considered, as this may promote the development and spread of bacterial resistance.
• Cipropharm® eye 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 Cipropharm® eye drops.

Ear drops

• The efficacy and safety of use in children under 1 year of age have not been established.
• Frequent medical monitoring is required during ear instillation 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 Cipropharm® have not been conducted.

Pregnancy

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

It is advisable to avoid using Cipropharm® during pregnancy.

Breastfeeding

Ciprofloxacin has been detected in breast milk following oral administration. It is unknown whether ciprofloxacin passes into breast milk after topical ocular or otic administration. Cipropharm® 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 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 Cipropharm® ear drops on the ability to drive or operate machinery.

Method of Administration and Dosage

Caution! Do not tightly screw the bottle cap before first use! Before the first application, screw the cap on tightly to allow the spike on the inner side of the cap to pierce the seal. Immediately before use, hold the bottle in the palm of the hand to warm the solution to body temperature. Unscrew and remove the cap, then instill the solution into the eye by gently pressing on the bottle. After instillation, tightly screw the cap back on and store the medication according to the recommendations provided in the instructions. Ophthalmic drops should be used with strict adherence to hygiene rules. Do not touch any surface with the dropper tip.

Ophthalmological Use

Dosage

Use in adolescents and adults, including elderly patients

Corneal ulcers:

Cipropharm® should be administered at the following intervals, including during nighttime:

• 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;
• Day 2: Instill 2 drops into the conjunctival sac(s) of the affected eye(s) every hour;
• Days 3–14: Instill 2 drops into the conjunctival sac(s) 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 are 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.

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

Treatment usually 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, thereby decreasing the likelihood of systemic adverse effects.

When using other topical ophthalmic medications concurrently, an interval of 10–15 minutes between administrations should be maintained.

Use in children

Dosage in children aged 1 year and older is the same as in adults.

Clinical studies in newborns and infants up to 1 month of age have shown that Cipropharm® 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 Cipropharm® 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 dropper tip.

Otological Use

Dosage

Use in adults, including elderly patients

The recommended dose for adults is 4 drops of Cipropharm® 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).

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

When using other topical medications concurrently, an interval of 10–15 minutes between administrations should be maintained.

Use in children

The dose is 3 drops of Cipropharm® into the ear canal twice daily. The safety and efficacy of Cipropharm® have been studied 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 Cipropharm® in this patient population has not been studied.

Method of administration

The external ear 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 gauze or cotton wool pledget 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 medication.

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

Children

Ophthalmic drops

The safety and efficacy of ophthalmic ciprofloxacin drops 3 mg/mL have been evaluated in children aged 0 to 12 years. No serious adverse reactions related to the use of the drug have been reported in this patient group.

Cipropharm® ophthalmic drops may be used in children from birth for the treatment of bacterial conjunctivitis.

Otic drops

The safety and efficacy of otic ciprofloxacin drops 3 mg/mL have been evaluated in children aged 1 to 12 years. No serious adverse reactions related to the use of the drug have been reported in this patient group.

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

Cipropharm® otic drops may be used in children aged 1 year and older.

Overdose

Due to the characteristics of this medication intended for topical use, no toxic effects are expected when used in ophthalmology/otology at recommended doses or following accidental ingestion of the contents of one bottle. In case of overdose with topical ocular administration of Cipropharm®, excess medication should be rinsed from the eye(s) with warm water.

Adverse reactions.

Adverse effects observed after ocular administration of Cipropharm®

Infections and infestations: stye, rhinitis.

Nervous system disorders: dysgeusia, headache, dizziness.

Immune system disorders: hypersensitivity.

Ophthalmic disorders: corneal deposits, eye discomfort, ocular hyperemia, 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, ocular discharge, scaling of eyelid margins, eyelid desquamation, conjunctival edema, eyelid erythema, ocular toxicity, punctate keratitis, keratitis, conjunctivitis, corneal function disorder, corneal epithelial defect, diplopia, ocular hypoesthesia, asthenopia, eye irritation, eye inflammation, conjunctival hyperemia.

Aural and labyrinth disorders: ear pain.

Respiratory, thoracic and mediastinal disorders: nasal sinus hypersecretion.

Gastrointestinal disorders: nausea, diarrhea, abdominal pain.

Skin and subcutaneous tissue disorders: dermatitis.

General disorders and administration site conditions: drug intolerance.

Investigations: laboratory test abnormalities.

Adverse reactions reported during otic use of Cipropharm®

Nervous system disorders: irritability, headache.

Aural and labyrinth disorders: ear pain, ear fullness, otorrhea, ear pruritus, tinnitus.

Skin and subcutaneous tissue disorders: dermatitis.

General disorders and administration site conditions: hyperthermia.

Description of the listed adverse reactions

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

Rarely, components of the drug may cause hypersensitivity reactions when used in 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 drug (for Cipropharm® 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 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 ruptures may increase in patients receiving corticosteroids, particularly elderly patients, and with excessive tendon stress, including the Achilles tendon. Currently, clinical and post-marketing data do not demonstrate a clear association between the use of Cipropharm® 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 Cipropharm®, which disappeared with continued administration. The presence of precipitate does not require discontinuation of Cipropharm® and has no negative impact on the clinical course of recovery.

Phototoxic effects of fluoroquinolones have been observed during systemic administration. However, phototoxicity of ciprofloxacin is not typical with topical ocular or otic use.

Shelf life.

3 years. The shelf life after first opening the bottle is 28 days.

Do not use the medication after the expiry date stated on the packaging.

Storage conditions.

Store in a light-protected place at a temperature between 8 °C and 25 °C. Keep out of reach of children. Do not freeze.

Packaging.

5 or 10 ml in a bottle. One bottle in a carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and location of manufacturing site.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.