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CETRAXAL 2MG/ML EAR DROPS SOLUTION

Active substance(s): CIPROFLOXACIN HYDROCHLORIDE / CIPROFLOXACIN HYDROCHLORIDE / CIPROFLOXACIN HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Cetraxal 2 mg/ml ear drops solution in single-dose container.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 2 mg of ciprofloxacin as hydrochloride.
Each single-dose ampoule delivers 0.25 ml of solution that contains 0.58 mg of
ciprofloxacin hydrochloride monohydrate corresponding to 0.50 mg of ciprofloxacin.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Ear drops solution in single-dose container.
Clear, sterile, preservative-free aqueous solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Cetraxal 2 mg/ml ear drops solution is indicated for the treatment of acute otitis
externa in adults and children older than 1 year with an intact tympanic membrane,
caused by ciprofloxacin susceptible microorganisms (see sections 4.4 and 5.1).
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.

4.2

Posology and method of administration
Adults and children aged one year and older
Instil the contents of one single ampoule into the affected ear twice daily for
seven days.
Paediatric patients less than one year
The safety and efficacy of Cetraxal in children aged below 1 year of age have
not been established. No data are available. See section 4.4.

Method of administration
 Precautions to be taken before handling or administering the medicinal
product.
 The solution should be warmed, by holding the ampoule in the hand for
several minutes, to avoid the dizziness that may result from the instillation of
a cold solution into the ear canal.
 The patient should lie with the affected ear upward and then the drops
should be instilled, pulling several times on the auricle. This position should
be maintained for around 5 minutes to facilitate penetration of the drops into
the ear. Repeat, if necessary, for the opposite ear.
 The patient should be advised to discard the single-dose container after the
use, and not keep it for subsequent use.
 In case an otowick/tampon is used to facilitate administration, the first dose
should be doubled (2 ampoules instead of 1).
Renal/ hepatic impairment
Since the drug plasma concentration is anticipated to be undetectable, no dosage
adjustment for these patient groups is deemed necessary.

4.3

Contraindications
Hypersensitivity to the active substance ciprofloxacin or any member of the
quinolone class of antimicrobial agents or to any of the excipients listed in section
6.1.

4.4

Special warnings and precautions for use
This medicinal product is for auricular use, not for ophthalmic use, inhalation
or injection.
In otic use meticulous medical monitoring is required in order to be able to
determine in a timely manner the possible necessity of other therapeutic
measures.
Paediatric population
The safety and efficacy of this product have been established in paediatric
patients 1 year and older in controlled clinical trials. Although very limited
data are available in patients less than age 1 year treated for acute otitis
externa, there are no differences in the disease process itself, in this patient
population, which would preclude use of this product in patients less than one
year of age. Based upon the very limited data, the prescribing physician should
weigh the clinical benefits of use against the known and possibly unknown
risks when prescribing in patients less than age 1 year.

The safety and efficacy of Cetraxal have not been studied in the presence of a
perforated tympanic membrane. Therefore, Cetraxal should be used with
caution in patients with known or suspected perforation, or where there is a
risk of perforation of the tympanic membrane.
Cetraxal should be discontinued at the first appearance of a skin rash or any
other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity
(anaphylactic) reactions, some following the first dose, have been reported in
patients receiving systemic quinolones. Serious acute hypersensitivity
reactions may require immediate emergency treatment.
As with other antibiotic preparation, the use of this product may result in
overgrowth of non-susceptible organisms, including bacterial strains, yeast and
fungi. If superinfection occurs, appropriate therapy should be initiated.
If after one week of therapy some signs and symptoms persist, further
evaluation is recommended to reassess the disease and the treatment.
Some patients taking systemic quinolones have shown moderate to severe skin
sensitivity to sun. Due to the site of administration, it is unlikely that this
product may show photoallergic reactions.
4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with Cetraxal.
Due to low plasma level anticipated after application in the ear, it is unlikely that
ciprofloxacin may show systemic interaction with other drugs.
It is recommended not to use other ear preparations concomitantly.

4.6

Fertility, pregnancy and lactation

Pregnancy
There are no data on the use of ciprofloxacin otic solution 0.2% in pregnant women.
There are moderate amount of data from the use oral ciprofloxacin in pregnant
women. No reproductive toxicity has been performed after otic administration.
However after systemic exposure, animal studies do not indicate direct or indirect
harmful effects with respect to reproductive toxicity (see section 5.3).
Since systemic exposure to ciprofloxacin is negligible after otic administration, thus
no effects are anticipated during pregnancy. Cetraxal can be used during pregnancy.
Lactation
Ciprofloxacin is excreted in human milk after systemic use. It is not known whether
ciprofloxacin is excreted in human milk after otic use. No effects on the breast-fed
newborn are anticipated since the systemic exposure of the breast-feeding woman to
ciprofloxacin is negligible. Cetraxal can be used during breast-feeding.

Fertility
Studies in animals with oral administration of ciprofloxacin do not indicate any
effects on fertility.

4.7

Effects on ability to drive and use machines
Cetraxal has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects
In a Phase III clinical trial, a total of 319 patients were treated with Cetraxal.
The most commonly reported adverse reactions are: ear pruritus occurring in 0.9% of
patients treated with ciprofloxacin, and headache and application site pain, both
occurring in approximately 0.6 % of patients.
All treatment related adverse reactions are uncommon (≥1/1000 to <1/100) and are
listed below.
Ear and Labyrinth Disorders
Uncommon: Ear pruritus, tinnitus
Nervous System Disorders
Uncommon: Dizziness, headache
Skin and subcutaneous disorders
Uncommon: Dermatitis
General Disorders and Administration Site Conditions
Uncommon: Application Site Pain
With locally applied fluoroquinolones (generalized) rash, toxic epidermolysis,
dermatitis exfoliative, Stevens-Johnson syndrome, and urticaria occur very rarely.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the national reporting system listed in Appendix V*.

4.9

Overdose
The potential risk of overdose with this single-dose preparation is negligible since the
total amount of ciprofloxacin per pack is 7.5 mg.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: S02AA15 Sensory organs. Otologicals. Antiinfectives.
Mechanism of action
As a fluoroquinolone antibacterial agent, the bactericidal action of ciprofloxacin
results from the inhibition of both type II topoisomerase (DNA gyrase) and
topoisomerase IV, which are required for bacterial DNA replication, transcription,
repair and recombination.
PK/PD relationship
No pharmacodynamic relationship has been described for topical administration.
With local pharmaceutical forms, the concentration attained in situ are far higher than
plasma concentrations.
Mechanism of resistance
In-vitro resistance to ciprofloxacin can be acquired through a stepwise process by
target site mutations in both DNA gyrase and topoisomerase IV. The degree of crossresistance between ciprofloxacin and other fluoroquinolones that results is variable.
Single mutations may not result in clinical resistance, but multiple mutations
generally result in clinical resistance to many or all active substances within the class.
Impermeability and/or active substance efflux pump mechanisms of resistance may
have a variable effect on susceptibility to fluoroquinolones, which depends on the
physiochemical properties of the various active substances within the class and the
affinity of transport systems for each active substance. All in-vitro mechanisms of
resistance are commonly observed in clinical isolates. Resistance mechanisms that
inactivate other antibiotics such as permeation barriers (common in Pseudomonas
aeruginosa) and efflux mechanisms may affect susceptibility to ciprofloxacin.
Plasmid-mediated resistance encoded by qnr-genes has been reported.
Breakpoints
For most topical agents there are limited pharmacological data and no data relating
treatment to outcome. For this reason EUCAST proposes that epidemiological cut-off
values (ECOFFs) are used to indicate susceptibility to topical agents.
Epidemiological cut-off values according to EUCAST. ECOFF ≤ mg/ml

-

Enterobacteriaceae
Staphylococcus spp.
Pseudomonas aeruginosa

0.125 mg/l
1 mg/l
0.5 mg/l

Prevalence of resistance may vary according to geographical zone and weather for the
selected microorganisms. Local information on resistance should be available,
particularly in the case of serious infections. This information only provides an
approximate orientation as to the probability of the microorganism being sensitive to
this antibiotic.
Based on present data the following table represents susceptibility of ciprofloxacin to
the leading pathogens in the approved indication.
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram positive micro-organisms
Staphylococcus aureus

Aerobic Gram negative micro-organisms
Pseudomonas aeruginosa
NB: With local pharmaceutical forms, the concentrations attained in situ are far higher
than plasma concentrations. Some doubts remain as to the kinetics of concentrations
in situ, the local physical and chemical conditions which may modify the activity of
the antibiotic and the stability of the product in situ.
5.2

Pharmacokinetic properties
The plasma concentrations of ciprofloxacin were not measured following
administration of 0.25 ml Cetraxal 0.2% (total dose: 0.5 mg ciprofloxacin). It is
expected that systemic plasma levels will be no detectable or very low, although no
significant systemic passage of ciprofloxacin is expected under normal condition of
use. Even if the entire amount of ciprofloxacin was absorbed following bilateral ear
administration (1mg total dose) it is doubtful that a detectable plasma concentration
of this drug would result in a human considering 180L as volume of distribution of
ciprofloxacin (EUCAST information) and 5ng/ml as the detection limit.

5.3

Preclinical safety data

No significant findings were seen in carcinogenicity or reproductive and
developmental toxicity studies. Ciprofloxacin is well tolerated when applied to both
intact and abraded skin in the external ear canal.

In test animals, toxicity was only observed at doses which are high above compared
to the highest dose used in the ear.
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 30
mg/kg ciprofloxacin the effect on the joint was minimal.
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Povidone-K-90-F (E1201)
Glycerol (E422)
Purified water
Sodium hydroxide (E524) and lactic acid (E270) (for pH-adjustment).

6.2

Incompatibilities
Not applicable.

6.3
Shelf life
2 years.
The ampoule contents should be used immediately after opening the single dose
ampoule. Any unused contents should be discarded.
Shelf-life after first opening of the pouch: 8 days.

6.4

Special precautions for storage
Store below 30ºC. Store in the original packaging in order to protect from light.

6.5

Nature and contents of container
The solution 0.2% is contained within a formed low-density polyethylene (LDPE)
ampoule. Each single ampoule delivers 0.25 ml dropwise. The ampoules are
contained in an aluminium foil overwrap pouch for protection.
Each pack contains 15 ampoules.

6.6

Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Laboratorios SALVAT, S.A.
Gall, 30-36 – 08950 Esplugues de Llobregat
Barcelona (Spain)

8

MARKETING AUTHORISATION NUMBER(S)
PL 17156/0003

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/09/2015

10

DATE OF REVISION OF THE TEXT
30/09/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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