Alcon Laboratories (U.K) Limited

CILOXAN 3 mg/ml ear drops, solution

Each ml contains 3mg ciprofloxacin as ciprofloxacin hydrochloride.

Excipients: contains benzalkonium chloride 0.06mg/ml.

For a full list of excipients, see section 6.1.

Ear drops, solution.

Clear, colourless to pale yellow solution.

Adults and Children 1 year and above

CILOXAN is indicated for acute otitis externa due to susceptible strains of bacterial species shown to be responsive to ciprofloxacin as listed in section 5.1.

Use should be under the supervision of a specialist ENT service having the facilities for regular monitoring of clinical and microbiological effects during and after administration.

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

Adults and children 1 year and above:

The dose is 4 drops of CILOXAN in the ear canal twice daily for adults.

For patients requiring use of an otowick, the dose can be doubled for the first administration only (i.e., 6 drops for paediatric patients and 8 drops for adult patients).

Use in elderly

No dosage alteration in elderly patients is necessary.

In clinical studies conducted with CILOXAN, the probability of having an adverse reaction was independent of age. No difference in patients experiencing adverse reactions was noted in patients less than 65 years of age, between 65 and 75 years of age, and greater than 75 years of age.

Use in children

The dose is 3 drops of CILOXAN in the ear canal twice daily for children. Safety and effectiveness of CILOXAN was determined in 139 children between the ages of one and 12 years. No serious adverse events were reported in these patients. Safety and effectiveness in children below 1 year of age have not been established.

Use in hepatic and renal impairment

CILOXAN has not been studied in patients with hepatic or renal impairment and is therefore not recommended in such patients.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the auricle or the external ear canal, and surrounding areas, or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.

Hypersensitivity to ciprofloxacin, to other quinolones or any of the excipients.

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 epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

Likewise CILOXAN should be suspended immediately at the first appearance of a skin rash or any other sign of hypersensitivity reaction and medical advice should be sought.

Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.

As with all antibacterial preparations prolonged use of Ciprofloxacin may result in overgrowth of non-susceptible organisms, including fungi. If super infection occurs, appropriate therapy should be initiated.

Benzalkonium chloride, used as a preservative in this medicine is an irritant, may cause skin reactions when used topically.

Specific drug interaction studies have not been conducted with otic 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

No adequate and well-controlled studies were performed in pregnant women.

Animal studies conducted with 100 mg/kg ciprofloxacin 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 at 100 mg/kg ciprofloxacin due to maternal weight loss. The relevance of these data for humans is unknown (see section 5.3), however it is known that the dose causing weight loss in the treated animal was greater than 900 fold higher than the proposed otic dose if a 10 kg child or 50 kg adult is treated with 0.27 mg or 0.36 mg of ciprofloxacin, respectively, into each ear twice a day.

CILOXAN 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.

Nursing mothers

Oral ciprofloxacin has been reported in human breast milk after a single 500-mg dose. It is not known whether topically applied ciprofloxacin is excreted in human milk. Caution should, therefore, be exercised when CILOXAN is administered to a nursing mother (see section 5.3).

Fertility

No special recommendations (see section 5.3).

There are no known effects of CILOXAN on the ability to drive and use machines. It is unlikely to have an effect.

In well-controlled clinical studies involving over 300 patients, CILOXAN was administered twice daily in the affected ear(s). No serious otic or systemic undesirable effects related or not related to CILOXAN were reported in clinical studies. The most frequently reported treatment-related undesirable effect was otic pruritus (1.3%).

The following undesirable effects assessed as definitely, probably or possibly related to treatment were reported during clinical trials with CILOXAN. Their incidence was either common (1.3%) or uncommon (0.3%). No events were reported in the frequency categories of very common, rare, or very rare.

Paediatric population

Safety and efficacy of CILOXAN 3mg/ml ear drops was determined in 193 children between the ages of one and 12 years of age. No serious adverse drug reaction was reported in this group of patients.

In otic use the ingredients rarely are sensitising. However as with any substance that is applied to the skin, an allergic reaction to any of the ingredients of the preparation can always occur. With locally applied fluoroquinolones (generalized) rash, toxic epidermolysis, dermatitis exfoliative, Stevens-Johnson syndrome and urticaria occur very rarely.

Otic effects

Common: otic pruritus.

Uncommon: tinnitus.

Systemic effects

Body As A Whole:

Uncommon: headache.

Skin and Appendages:

Uncommon: dermatitis.

No case of overdose has been reported. No data are available in humans regarding overdosage by accidental or deliberate ingestion. The risk of overdosage by ingestion of ear drops is minimal.

Pharmacotherapeutic group: Otological; Antiinfectives.

ATC Code: S02A A

Mechanism of Action:

Ciprofloxacin

CILOXAN contains the quinolone ciprofloxacin hydrochloride. The primary site of action of quinolones is bacterial DNA synthesis. These compounds exert their bactericidal effect by inhibiting DNA gyrase.

Ciprofloxacin is active in vitro against most aerobic Gram-negative bacteria including Pseudomonas aeruginosa. It is also effective against aerobic Gram-positive bacteria, such as Staphylococci and Streptococci. Anaerobes are less susceptible. As shown in the following table, ciprofloxacin demonstrates an extended spectrum of activity in vivo (MIC₉₀s < 2.0 µg/ml) against pathogens isolated from patients with acute otitis externa, in recent clinical studies:

In vitro, ciprofloxacin has been shown to be active against most strains of the following organisms; however, the clinical significance of these data in otic infections is unknown. The safety and effectiveness of ciprofloxacin in treating acute otitis externa due to these microorganisms have not been established in adequate and well-controlled clinical trials.

The following bacteria are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitro systemic breakpoint and otic efficacy has not been established. Ciprofloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 1 µg/ml or less (systemic susceptible breakpoint) against most (90%) strains of the following pathogens:

Aerobic Gram-Positive Microorganisms:

Bacillus species

Corynebacterium species

Enterococcus faecalis

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus caprae

Staphylococcus capitis

Staphylococcus haemolyticus

Streptococcus pneumoniae

Viridans group Streptococcus

Aerobic Gram-Negative Microorganisms:

Achromobacter xylosoxidans subsp. xylosoxidans

Acinetobacter baumanii

Acinetobacter junii

Acinetobacter lwoffi

Acinetobacter radioresistans

Acinetobacter genospecies 3

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas stutzeri

Stenotrophomonas maltophilia

Serratia marcescens

Resistance development against ciprofloxacin occurs infrequently. 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 anti-bacterial compounds with different chemical structures, such as beta-lactam antibiotics, aminoglycosides, tetracyclines, macrolide and peptide antibiotics as well as sulfonamides, trimethoprim and nitrofuran derivatives.

Bacterial susceptibility studies demonstrate that most micro-organisms resistant to ciprofloxacin are resistant to other fluoroquinolones as well. In clinical trails, the isolation frequency of strains with acquired resistance to ciprofloxacin was low (<3%).

The systemic pharmacokinetic properties of ciprofloxacin have been well studied. Ciprofloxacin widely distributes to tissues of the body, with tissue levels typically greater than levels in plasma. The apparent volume of distribution at steady state is 1.7-2.7 l/kg. Serum protein binding is 16 43%. The half life of ciprofloxacin in serum is 3-5 hours. Following oral administration of single doses ranging from 250 to 750 mg to adults 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 faeces. Renal clearance of ciprofloxacin is typically 300-479 ml/minute. Approximately 20-40% of the dose is excreted in faeces as unchanged drug and metabolites within 5 days.

In children with otitis media with tympanostomy tubes treated with ciprofloxacin 3mg/ml solution (3 drops three times daily for 14 days), plasma concentrations of ciprofloxacin were not detected (limit of quantification 5ng/ml). In children with suppurative otitis with perforated tympanic membrane, treated by ciprofloxacin 2mg/ml solution (twice daily for 7-10 days), no circulating plasma concentration of ciprofloxacin up to the limit of quantification 5ng/ml was detected. No significant systemic passage of ciprofloxacin is expected under the normal conditions of use.

Reproduction studies have been performed in rats and mice at 100 mg/kg ciprofloxacin (900 times the proposed otic dose if a 10 kg child is treated with 0.27 mg of ciprofloxacin into each ear twice a day) 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.

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, species and dosage. With 30mg/kg ciprofloxacin the effect on joint was minimal. The dose is greater than 270 times the proposed otic clinical dose if a 10-kg child is treated with 0.27 mg ciprofloxacin into each ear twice a day.

While the joints of some species of juvenile animals are sensitive to the degenerative effects of fluoroquinolones (primarily the dog), young adult guinea pigs dosed in the middle ear with ciprofloxacin for one month exhibited no drug related structural or functional changes of the cochlear hair cells and no lesions in the ossicles.

Benzalkonium chloride

Sodium acetate (trihydrate) (E262)

Acetic acid (E260)

Mannitol (E421)

Disodium edetate

Hydrochloric acid/sodium hydroxide (for pH adjustment)

Purified water.

Not applicable.

Unopened: 2 years

Discard 4 weeks after first opening.

This medicinal product does not require any special storage precautions.

Low-density polyethylene bottle and polypropylene screw cap.

Content: 5 ml

No special requirements.

Alcon Laboratories (UK) Ltd.

Pentagon Park,

Boundary Way,

Hemel Hempstead,

Hertfordshire, HP2 7UD,

United Kingdom

PA 290/69/3

Date of first authorisation: 03 February 2006

Date of last renewal: 03 February 2011

February 2011