CILOXAN 3mg/g Eye Ointment

Ciprofloxacin 3 mg/g hydrochloride equivalent to 3 mg/g ciprofloxacin.

For excipients, see 6.1

Eye ointment

White to off-white ointment.

CILOXAN eye ointment will be indicated for adults and children as follows:

Adults and children 1 year and above

For the treatment of the following infections when known or suspected to be caused by ciprofloxacin-susceptible bacteria.

• Corneal ulcers

• Conjunctivitis

• Blepharitis

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Adults and children 1 year and above

The recommended dosage regimens for adults (including the elderly) and children over the age of one year of age are as follows:

• Corneal ulcers: 1.25 cm ointment ribbon applied into the conjunctival sac every 1-2 hours around the clock for two days, then every 4 hours for a further 12 days. The dosing may be extended at the discretion of the physician.

• Bacterial conjunctivitis (and blepharitis): 1.25 cm ointment ribbon applied into the conjunctival sac (or on the lid margin, respectively) three times daily for two days, then twice daily for a further five days. The dosing may be extended at the discretion of the physician.

Do not touch tube tip to any surface, as this may contaminate the contents.

Use in elderly

Clinical studies have indicated dosage modifications are not required for the elderly.

Use in children

Safety and effectiveness of CILOXAN 3mg/g Eye Ointment were determined in 192 children between the ages of one to 12 years. No serious adverse event was reported in these patients. These clinical studies have indicated that dosage modifications are not required for children.

Use in hepatic and renal impairment

No studies have been performed using CILOXAN 3mg/g Eye Ointment in patients with kidney or liver problems.

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity to quinolones.

There is no experience in children less than 1 year old.

When using CILOXAN eye ointment one should take into account the risk of a rhinopharyngeal passage which can contribute to the occurrence and the diffusion of bacterial resistance.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, were observed in patients receiving treatment based on systematically administered quinolones. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions.

As with all antibacterial preparations prolonged use may lead to overgrowth of non-susceptible bacterial strains or fungi. If superinfection occurs, appropriate therapy should be initiated.

Ciprofloxacin should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity

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 has been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.

Pregnancy

For CILOXAN 3mg/g Eye Ointment no clinical data from well-controlled studies in pregnant women are available.

Animal studies do not indicate direct or indirect harmful effects with respect to fertility and embryonic / foetal development. Studies in rabbits have shown an increased risk of abortion due to maternal weight loss. The relevance of these data for humans is unknown (see section 5.3).

CILOXAN 3mg/g Eye Ointment should not be used during pregnancy unless clearly necessary and only if the potential benefit justifies the potential risk to the foetus.

Women of child-bearing potential

No special recommendations for women of childbearing potential.

Lactation

It is not known whether topically applied Ciprofloxacin is excreted in human milk, although it has been reported in human breast milk after a single 500 mg dose. Caution should be exercised when CILOXAN 3mg/g Eye Ointment is administered to a nursing mother.

Fertility

No special recommendations (see section 5.3).

As with any ocular medication, if transient, blurred vision occurs at application, the patient should wait until the vision clears before driving or using machinery.

In clinical trials with CILOXAN 3mg/g Eye Ointment, the following treatment-related signs and symptoms were reported:

Common

Ocular: White precipitate (3.0%) and ocular discomfort (transient stinging and burning upon application) (1.4%). In patients with corneal ulcer or frequent administration of the drug, white precipitates have been observed which resolved after continuous application of CILOXAN 3mg/g Eye Ointment. The precipitate does not preclude continued use of CILOXAN 3mg/g Eye Ointment nor does it adversely affect the clinical course of the recovery process.

Uncommon

Ocular effects: Blurred vision (0.8%), hyperaemia (0.7%), pruritus (0.6%), decreased visual acuity (0.6%), pain (0.6%), tearing (0.4%), and photophobia (0.3%).

Special senses effects: Taste perversion (metallic taste) (0.5%).

Skin Effects: Dermatitis (0.2%).

With locally applied fluoroquinolones (generalized) rash, toxic epidermolysis, dermatitis exfoliative, Stevens-Johnson syndrome and urticaria occur very rarely

Safety and effectiveness of CILOXAN 3mg/g eye ointment were determined in 103 children between the ages of one and 12 years of age. No serious adverse drug reaction was reported in these patients.

A topical ocular overdose of CILOXAN 3mg/g Eye Ointment may be rinsed from the eye(s) with lukewarm tap water.

Pharmacotherapeutic group: Antiinfectives; Other antiinfectives.

ATC Code: S01A X 13

The bactericidal action of Ciprofloxacin results from the inhibition of bacterial topoisomerases II (DNA gyrase) and IV. These are essential enzymes for replication, transcription and repair of bacterial DNA.

Susceptibility

Ciprofloxacin has been shown to be active against most strains of the following organisms both in vitro and in clinical ocular infections.

Aerobic Gram-Positive Microorganisms:

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Other β-haemolytic Streptococci

Aerobic Gram-Negative Microorganisms:

Haemophilus influenzae

Pseudomonas aeruginosa

Moraxella catarrhalis

Neisseria gonorrhoeae

Breakpoints

The following bacteria are considered susceptible when evaluated using systemic breakpoints. For most organisms, BSAC MIC systemic breakpoints are: susceptible 1 mg/L; resistant 2 mg/L. Specifically for Pseudomonas aeruginosa, the BSAC MIC systemic breakpoints are 1 mg/L (Susceptible) and 8 mg/L (Resistant). Overall, ciprofloxacin exhibits in vitro MICs of 1 mg/L or less (BSAC systemic susceptible breakpoint) against most (90%) strains of the following ocular pathogens:

Aerobic Gram-Positive Microorganisms:

Bacillus species

Coryneform bacteria

Staphylococcus haemolyticus

Staphylococcus hominis

Aerobic Gram-Negative Microorganisms:

Acinetobacter calcoaceticus

Enterobacter aerogenes

Escherichia coli

Haemophilus parainfluenzae

Klebsiella pneumoniae

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Others (BSAC MIC 1 mg/L)

Peptococcus spp., Peptostreptococcus spp., Propionibacterium acnes, and Clostridium perfringens are susceptible.

Resistant (BSAC MIC 2 mg/L)

Ciprofloxacin exhibits in vitro MICs 2 mg/L against some strains of Burkholderia (Pseudomonas) cepacia, Stenotrophomonas (Pseudomonas) maltophilia and some anaerobic bacteria, particularly Bacteroides fragilis and Clostridium difficile.

Other information

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).

There is not usually cross-reaction between ciprofloxacin and other antimicrobial agents such as beta-lactams or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to Ciprofloxacin.

Bacterial susceptibility studies demonstrate that most microorganisms resistant to Ciprofloxacin are resistant to the other ophthalmic quinolones as well. In clinical trials, the isolation frequency of strains resistant to Ciprofloxacin was low (<3%).

Absorption studies in humans with the ointment have not been conducted. Two systemic absorption studies were performed with CILOXAN 3mg/g Eye Drops using the conjunctivitis or corneal ulcer dosing regimen. In the study involving the more intensive dosing regimen (i.e., corneal ulcer/abscess indication), two drops were administered in one eye every 15 minutes for six hours, every 30 minutes for 18 hours, then two drops hourly for one day, followed by two drops every four hours for five additional days. In each study, the maximum reported plasma concentration of Ciprofloxacin was less than 5 ng/ml. The mean concentrations in each of the studies were less than 2.5 ng/ml.

There are no pharmacokinetic data available in respect of use in children.

Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested following oral administration. The degree of cartilage involvement was found to be dependent on age, specieis and dosage. With 30mg/kg ciprofloxacin the effect on the joint was minimal.

A one month topical ocular study with ciprofloxacin 3mg/ml eye drops, solution in immature beagle dogs did not demonstrate any articular lesions. Likewise there is no evidence that the ophthalmic dosage form has any effect on the weight bearing joints.

In 634 children treated orally with Ciprofloxacin, clinical and radiological monitoring did not reveal any skeletal toxicity.

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 oral) 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.

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.

Liquid Paraffin

White Soft Paraffin

Not applicable.

24 months

One month after first opening

Do not store above 30˚C.

Epoxy-phenolic lined aluminum tube with polyethylene nozzle and screw cap. The tube contains 3.5 g of eye ointment.

Not applicable.

Alcon Laboratories (UK) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

Herts. HP2 7UD,

U.K.

PL 00649/0161

11/08/2008

28/10/2008

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)