INFORMATION FOR HEALTH PROFESSIONALS
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
CILOXAN Eye Drops contain the equivalent of 3 mg/mL ciprofloxacin base, and have been formulated as a sterile, multiple-dose product, for topical ophthalmic use. The pH of CILOXAN Eye Drops is approximately 4.5 and the osmolality is approximately 300 m0sm.
CILOXAN Eye Drops also contain sodium acetate, acetic acid, mannitol, disodium edetate, hydrochloric acid and/or sodium hydroxide (to adjust pH), purified water and benzalkonium chloride (0.06 mg/mL) as preservative.
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms, possessing the greatest antibacterial activity of all quinolones.
The bactericidal action of ciprofloxacin results from interference with the enzyme DNA gyrase which is needed for the synthesis of bacterial DNA.
Ciprofloxacin has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS):
Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains)
Staphylococcus epidermidis
Streptococcus pneumoniae
Viridans group of Streptococcus
Pseudomonas aeruginosa
Serratia marcescens
Haemophilus influenzae
Most strains of Pseudomonas cepacia and some strains of Pseudomonas maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2. Resistance to ciprofloxacin in vitro usually develops slowly (multiple-step mutation). A plasmid-mediated bacterial resistance does not appear to occur with the fluoroquinolone class of antibiotics, however, parallel resistance is seen with this group of gyrase inhibitors.
Due to its special mode of action there is no cross-over resistance between ciprofloxacin and other antibacterial compounds with different chemical structures, such as β-lactam antibiotics, aminoglycosides, tetracyclines, macrolide and peptide antibiotics as well as sulfonamides, trimethoprim and nitrofuran derivatives.
A systemic absorption study was performed in which CILOXAN Eye Drops were administered in each eye every two hours while awake for two days followed by every four hours while awake for an additional 5 days. The maximum reported plasma concentration of ciprofloxacin was 4.7 ng/mL (some 450-fold less than levels observed following simple 250 mg oral administration). The mean concentration was usually less than 2.5 ng/mL.
Ciprofloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested following oral administration. However, a one-month topical ocular study using immature Beagle dogs did not demonstrate any articular lesions.
Acute topical ocular toxicology studies performed in rabbits employing an exaggerated topical ocular exposure to 0.3%, 0.75%, or 1.5% ciprofloxacin ophthalmic solution showed findings that were minimal and transient in nature, confined to the conjunctiva and generally comparable to those effects observed in the untreated control and vehicle control groups.
A subchronic, one-month topical ocular irritation study of 0.3% to 1.5% ciprofloxacin ophthalmic solution did not demonstrate any apparent systemic or ocular toxicity in rabbits.
Following therapy with CILOXAN Eye Drops 76% of the patients with corneal ulcers and positive bacterial cultures were clinically cured and complete re-epithelialization occurred in about 92% of the ulcers. In 3 and 7 day multicentre clinical trials, 52% of the patients with conjunctivitis and positive conjunctival cultures were clinically cured and 70-80% had all causative pathogens eradicated by the end of treatment.
Treatment of corneal ulcers, conjunctivitis and blepharitis caused by susceptible strains of bacteria in adults and children 12 months of age or older.
The recommended dosage regimen for the treatment of corneal ulcers is: Two drops into the affected eye every 15 minutes for the first six hours and then two drops into the affected eye every 30 minutes for the remainder of the first day. On the second day, instil two drops in the affected eye hourly. On the third through the fourteenth day, place two drops in the affected eye every four hours. Treatment may be continued after 14 days if corneal re-epithelialization has not occurred.
The recommended dosage regimen for the treatment of bacterial conjunctivitis is: One drop instilled into the conjunctival sac(s) every two hours while awake for two days and one drop every four hours while awake for the next five days.
A history of hypersensitivity to ciprofloxacin or any other component of the medication. A history of hypersensitivity to other quinolones, including nalidixic acid, may also contraindicate the use of ciprofloxacin.
FOR TOPICAL USE ONLY - NOT FOR INJECTION
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnoea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with adrenaline and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.
Moderate to severe phototoxicity manifested by an exaggerated sunburn reaction has been observed in some patients who were exposed to direct sunlight while receiving some members of the quinolone class of drugs, including oral ciprofloxacin. Excessive sunlight should be avoided.
As with other antibacterial preparations, prolonged use of ciprofloxacin may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. Whenever clinical judgment dictates, the patient's eye(s) should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction.
In clinical studies of patients with bacterial corneal ulcer a white crystalline precipitate located in the superficial portion of the corneal defect was observed in 35 (16.6%) of 210 patients. The onset of the precipitate was within 24 hours to 7 days after starting therapy. In one patient, the precipitate was immediately irrigated out upon its appearance. In 17 patients, resolution of the precipitate was seen in 1 to 8 days (seven within the first 24-72 hours); in five patients, resolution was noted in 10-13 days. In nine patients, exact resolution days were unavailable, however, at follow-up examinations, 18-44 days after onset of the event, complete resolution of the precipitate was noted. In three patients, outcome information was unavailable. The precipitate did not preclude continued use of ciprofloxacin, nor did it adversely affect the clinical course of the ulcer or visual outcome (see ADVERSE REACTIONS).
Category B3 - Reproduction studies have been performed in rats and mice at doses up to six times the usual daily human oral dose and have revealed no evidence of impaired fertility or harm to the foetus due to ciprofloxacin. In rabbits, as with most antimicrobial agents, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion. No teratogenicity was observed at either dose. After intravenous administration at doses up to 20 mg/kg, no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. There are no adequate and well controlled studies in pregnant women. Ciprofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether topically applied ciprofloxacin is excreted in human milk, however, it is known that orally administered ciprofloxacin is excreted in the milk of lactating rats, and oral ciprofloxacin has been reported in human breast milk after a single 500 mg dose. Caution should be exercised when ciprofloxacin is administered to a nursing mother.
Safety and effectiveness in children below the age of 1 year have not been established. Although ciprofloxacin and other quinolones cause arthropathy in immature animals after oral administration, topical ocular administration of ciprofloxacin to immature animals did not cause any arthropathy, and there is no evidence that the ophthalmic dosage form has any effect on the weight-bearing joints.
Eight in vitro mutagenicity tests have been conducted with ciprofloxacin and the test results are listed below:
Salmonella Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay
(Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but the results of the following three in vivo test systems gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Carcinogenicity studies in mice (oral doses up to 1090 mg/kg/day and 1455 mg/kg/day in males and females, respectively) and rats (oral doses up to 241 mg/kg/day and 328 mg/kg/day in males and females, respectively) showed no evidence of carcinogenicity.
Special studies included a cataractogenic potential study of systemic ciprofloxacin in rats. The results indicated that ciprofloxacin was not co-cataractogenic. An intravenous study of ciprofloxacin at dose levels up to 20 mg/kg over a 6-month period in Rhesus monkeys indicated there were no signs of changes in lens transparency due to the administration of ciprofloxacin.
The arthropathogenic potential of some quinolones in immature animals after oral administration is recognised. Topical ocular administration of ciprofloxacin to immature animals did not cause any arthropathy and there is no evidence that the ophthalmic dosage form has any effect on the weight-bearing joints.
The most frequently reported drug related adverse reaction was local burning or discomfort. In corneal ulcer studies with frequent administration of the drug, white crystalline precipitates were seen in approximately 17% of patients (see PRECAUTIONS).
Tabulated adverse reaction data (considered to be related or possible related to treatment), providing comparisons to placebo (to an incidence of 1% or greater in the CILOXAN Eye Drops treatment group), which have been generated from all adult clinical studies with CILOXAN Eye Drops are provided below:
| Tabulated Adverse Reaction Data Comparing Incidence (%) Figures | ||
|---|---|---|
| Adverse Reaction | CILOXAN Eye Drops 0.3% (n = 950) |
Placebo (n = 202) |
| Ocular | ||
| Discomfort | 9.7 | 7.9 |
| White precipitate | 3.6 | - |
| Foreign body sensation | 2.0 | - |
| Hyperaemia/erythema/redness | 1.2 | 1.4 |
| Itching | 1.1 | 1.9 |
| Special Senses | ||
| Taste abnormality | 5.0 | - |
"-" Incidence less than 1%.
Uncommon ophthalmic events (occurring in less than 1% and greater than 0.1% of patients) included lid margin crusting, crystals/scales, dryness/dry eye, discharge, corneal staining, keratopathy/keratitis, tearing, photophobia, pain, vision decrease, chemosis, corneal infiltrates, inflammation, blurred vision, corneal toxicity, allergy, intolerance, lid oedema, heavy sensation, swelling, conjunctival reaction, numbing sensation, conjunctivitis, punctate epithelial erosion and progression of infiltrate.
Uncommon systemic events (occurring in less than 1% and greater than 0.1% of patients) included nausea and sinus drainage.
The most common adverse events reported in the Post-marketing period for CILOXAN Eye Drops were precipitate in the eye, eye discomfort, non-specific ocular irritation and foreign body sensation. No adverse events were reported at an incidence greater than 1:100, 000.
Specific drug interaction studies have not been conducted with ophthalmic ciprofloxacin. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, enhance the effects of the oral anticoagulant warfarin and its derivatives and have been associated with transient elevations in serum creatinine in patients receiving cyclosporin concomitantly.
A topical overdose of CILOXAN Eye Drops may be flushed from the eye(s) with warm tap water.
Store below 25°C. Do not freeze. Protect from light.
Discard container 4 weeks after opening.
Consumer Product Information is supplied with this product.
Incompatibilities
Alkaline solutions.
Prescription Medicine.
5 mL DROP-TAINER®
Ciprofloxacin, a faint to light yellow crystalline powder which is soluble in water, is a fluoroquinolone antibacterial.
Empirical formula: C17H18FN303.HCl.H20
Molecular weight: 385.8
Chemical name: The monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid.
CAS Registry Number: 86393-32-0
Alcon New Zealand Limited
c/- Pharmaco (NZ) Ltd
49 George Street
Newmarket AUCKLAND
1st December 2007
® Registered Trademark