FIGHT THE FIGHT AGAINST ACUTE OTITIS EXTERNA (AOE)TOUGH ON INFECTION, GENTLE ON EARS: PRESERVATIVE-FREE AND NON-OTOTOXIC

WEAPONS Cetraxal: Steroid-free optionCetraxal Plus: Suitable for perforated eardrum

PERSONALITY Preservative-freeNon-ototoxicNo known sensitising agents Well tolerated

POWERSTargeted, effective treatment of AOESTRENGTH

Cetraxal: Ciprofloxacin 0.2%Cetraxal Plus: Ciprofloxacin 0.3%, Fluocinolone 0.025%

MISSIONTwice-daily dosing over 7 days

AGILITY Precise and accurate delivery

Prescribing information can be found on the last page. aspirepharma.co.uk

A HERO EARS DESERVE

For uncomplicated AOE with:

Intact eardrum

Pain

Absence of swelling

Ciprofloxacin showed non-inferior efficacy to neomycin-based treatment, PNH

Figure 1*: % Clinical cure for ciprofloxacin. PNH at the test of cure visit in the clinical per-protocol (CPP) population1 (Adapted from Drehobl et al 20081)

*Non-inferiority study comparing the efficacy and safety of ciprofloxacin otic solution 0.2% to polymyxin B-neomycin-hydrocortisone (PNH) otic solution in the treatmentof acute diffuse otitis externa in children, adolescents, and adults. 7 days treatment with Cetraxal solution 0.25ml twice-daily to PNH three-times-daily in the treatment of acute AOE. N=630

**Clinical cure was defined as absence of ear pain, swelling and discharge in patients who previously had these symptoms moderately or severely.

100

90

80

70

60

50

40

30

20

10

0Ciprofloxacin

Clin

ical

cur

e (%

)

PNH

86.6%n=247

81.1%n=243

• The only licensed ciprofloxacin-only ear drops for AOE

• Suitable for patients 1 year+

• Steroid-free option

• Ciprofloxacin was found to be non-inferior to PNH (polymyxin-b-neomycin-hydrocortisone) in achieving clinical cure** (Fig. 1)

• Ciprofloxacin was well tolerated with only mild adverse events recorded: ear pruritus (0.9%), headache (0.6%) and application site pain (0.6%)

For more symptomatic AOE with:

Known/suspected eardrum perforation

Swelling

Tympanostomy tubes

Ciprofloxacin & ciprofloxacin + fluocinolone may demonstrate equivalent efficacy for resolution of pain, but ciprofloxacin + fluocinolone may be more effective where swelling or otorrhea is present

Figure 2*: Resolution of otalgia, oedema and otorrhoea** with ciprofloxacin and fluocinolone acetonide compared to ciprofloxacin used alone. (Adapted from Lorente et al 20142)

P = 0.44

*Randomised, parallel-group clinical trial comparing the efficacy of ciprofloxacin otic solution 0.3% (4-6 drops every 8 hours for 8 days) with ciprofloxacin 0.3% and fluocinolone acetonide 0.025% otic solution (4-6 drops every 8 hours for 8 days)† in the treatment of diffuse otitis externa. Trial included children, adolescents and adults aged 7 plus. N=590 **Reduction of otalgia, oedema and otorrhoea based on visual analogue scale (VAS) score ranging from 0-10. A VAS score of 7-10 was classed as severe (or 3), 3.5-7 was classed as moderate (or 2), 0-3.5 was classed as mild (or 1) and 0 was classed as absent (or 0). The total symptom score was the sum of these three scores, ranging from 0-9.

P = 0.004 P = 0.002100

90

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0Otalgia Oedema Otorrhoea

Reso

luti

on o

f sym

ptom

s (%

)

End of treatment

Ciprofloxacin Ciprofloxacin + fluocinolone acetonide

86.10%

75.20%77.90%

88.20%84.80%

87.50%

• Suitable for patients 6 months+

• Significantly higher resolution of oedema and otorrhoea in patients receiving ciprofloxacin + fluocinolone vs ciprofloxacin alone2 (Fig. 2)

• Comparable resolution of otalgia between ciprofloxacin and ciprofloxacin + fluocinolone

– Steroid use may be reserved for more symptomatic AOE with swelling or known/suspected eardrum perforation

• Well tolerated: common adverse effects: ear pain, ear discomfort, ear pruritus, dysgeusia

SINGLE-DOSE AMPOULES ENABLE:• Accurate dosing

– Under-dosing may prevent resolution of AOE

– Over-dosing may predispose to fungal infection3

• Low risk of cross-contamination1

• Easy, targeted administration1

– A study showed 94.4% of patients found it easy to administer a single dose into the ear1

• Preservative-free and no known sensitising agents

• Support of treatment adherence1

– One ampoule per ear

– Bi-daily dosing regimen

FIGHTING AOE, ONE DOSE AT A TIME

The use of a single-dose ampoule helps improve adherence to treatment, which may help improve therapeutic efficacy compared with a standard bottle.1

NICE Recommendations

Group Chemicals

Antibiotics Neomycin, Gentamicin sulphate, Framycetin, Polymyxin B sulphate, Chloramphenicol, Bacitracin

Corticosteroids Hydrocortisone

Excipients A range of preservatives:Benzalkonium chloride 0.1% (BAK), Benzethonium chloride, Methyl-p-oxybenzoate, Propyleneglycol, Thimerosal merthiolateOthers: Caine mix, Methyl-methacrylate, Methylrosaniline (Gentian violet), Nickel sulphate 5%, Quinolone mix 6%

Status of eardrum (perforated or intact) Cetraxal Plus can be used with a perforated tympanic membrane

Personal preference The Cetraxal range allows for a tailored treatment choice

Cost £6.01 per treatment course5

Dosing The Cetraxal range uses single dose ampoules for bi-daily dosing

Risk of adverse events:• Fungal super-infection• Aminoglycoside-induced:

– Ototoxicity – Skin sensitization (Fig. 3)

The Cetraxal range is non-ototoxic and preservative-free with no known sensitising agents

NICE advises consideration of the following factors when prescribing a topical antibiotic4:

Figure 3: List of NICE recognised sensitisers in ear drop preparations. (Adapted from NICE CKS Sensitisers Table)4

WHEN AOE STRIKES, DEPLOY CETRAXAL

SUPPORTS PATIENT OUTCOMES AND COMPLIANCE

Single dose ampoules and twice-daily dosing offer precision, accuracy and convenience

with low risk of contamination1,6,7.

IN LINE WITH NICE GUIDANCE

Offers well tolerated steroid and steroid-free options that can be tailored to the patient, with low-dosing

frequency at a non-prohibitive price point.

TAILORED TREATMENT

Cetraxal is the only licensed ciprofloxacin-only ear drop, offering a steroid-free option. Cetraxal Plus can be used

for AOE with tympanic membrane perforation.

EFFICACIOUS AND WELL-TOLERATED

Ciprofloxacin had non-inferior efficacy when compared with PNH1. Non-ototoxic and preservative free

with no known sensitising agents.

1. Drehobl, M. et al. (2008) Comparison of efficacy and safety of ciprofloxacin otic solution 0.2% versus polymyxin B-neomycin-hydrocortisone in the treatment of acute diffuse otitis externa. Current Medical 5,6(12): pp. 3531-3542. 2. Lorente, J. et al. (2014) Ciprofloxacin plus fluocinolone acetonide versus ciprofloxacin alone in the treatment of diffuse otitis externa. Journal of Laryngology & Otology,128: pp. 591-598. 3. Anwar, K. et al. (2014) Otomycosis; clinical features, predisposing factors and treatment implications. Pak J Med Sci, 30(3): pp.564-567. 4. NICE. Clinical Knowledge Summary: Otitis Externa. February 2018.Available at: https://cks.nice.org.uk/otitis-externa. 5. Mims.co.uk (accessed May 2020) 6. Cetraxal Plus Summary of Product Characteristics. 7. Cetraxal Summary of Product Characteristics. 8. Ganesan, P. et al. (2018) Ototoxicity: A Challenge in Diagnosis and Treatment. JAudiol Otol. 2018 Apr; 22(2): 59–68 9. Bitner-Glindzicz, M. et al. Ototoxicity caused by aminoglycosides. BMJ. 2007 Oct 20; 335(7624): 784–785. 10. Huth, M.E. et al. (2011) Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection. Int J Otolaryngol. 2011: 937861. 11. Coates, H. Ear drops and ototoxicity. Aust Prescr 2008; 31:40-1. 12. Ninkovic, G. et al, Microbiology of otitis externa in the secondary care in United Kingdom and antimicrobial sensitivity, Auris Nasus Larynx 35 (2008) 480

The Cetraxal range provides a non-ototoxic treatment option and may offer an alternative where antibiotic resistance is a complication

OtotoxicityPharmacological adverse reaction affecting the inner ear or auditory nerve, characterized by cochlear or vestibular dysfunction8

• Increased risk where there is tympanic membrane perforation

Aminoglycosides are well known to cause ototoxicity9

• Gentamicin: vestibulotoxic10

– Can result in dizziness, ataxia and nystagmus

• Neomycin: cochleotoxic10

– Can lead to permanent hearing loss

Fluoroquinolones eg. Cetraxal range are considered to be non-ototoxic11

Antibiotic resistance• In a study of 144 swabs taken from patients with AOE12:

– All pseudomonas infections were resistant to neomycin

– All pseudomonas infections were sensitive to ciprofloxacin eg. Cetraxal range

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Aspire Pharma Ltd on 01730 231148.

Cetraxal (ciprofloxacin) 2mg/ml ear drops solution in a single-dose container. Prescribing Information (please refer to the full SmPC before prescribing)

Indication: Acute otitis externa in adults and children older than 1 year with an intact tympanic membrane, caused by ciprofloxacin susceptible microorganisms. Available strength 0.50 mg ciprofloxacin as hydrochloride, contained in 0.25ml of solution. See the Summary of Product Characteristics (SmPC) for a full list of excipients. Dosage and method of use: Adults and children aged one year and older: Instil the contents of a single ampoule into the affected ear twice daily for seven days. Children aged less than one year: Safety and efficacy not established. Warm the ampoule in the hand for several minutes. Patient should lie with affected ear upward and instil drops, pulling on auricle several times. Maintain position for 5 minutes to facilitate penetration. For further administration details, please see SmPC. If otowick/tampon is used for administration, double the first dose to two ampoules. Use immediately after opening the ampoule. Discard any unused contents. No dose adjustment required in those with renal or hepatic impairment. Contraindications: Hypersensitivity to ciprofloxacin, any member of the quinolone class or listed excipients. Special warnings and precautions for use: Not for ophthalmic use, inhalation or injection. Monitor use carefully to determine if other therapy may be required. If after one week of therapy, signs and symptoms persist, re-evaluate further. Safety and efficacy not established under 1 year of age. Weigh benefits against known and unknown risks of prescribing in those under 1. Use with caution if known or suspected perforated tympanic membrane and where there is a risk of perforation. Discontinue use at first appearance of a skin rash or any other sign of hypersensitivity. Some patients taking systemic quinolones have shown moderate to severe skin sensitivity to the sun. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported, some after the first dose of a systemic quinolone. Serious acute hypersensitivity reactions may require immediate emergency treatment. Overgrowth of non-susceptible organisms may occur from use including bacterial strains, yeast and fungi. If superinfection occurs, treat as appropriate. Interactions with other medicinal products: No interaction studies performed. Due to low plasma levels, systemic interactions unlikely. Recommendation not to use other ear preparations concomitantly. Pregnancy and breast-feeding: Can be used during pregnancy and breast-feeding. Effects on ability to drive and use machines: None or negligible. Side effects: For full list of side effects consult the SmPC. Ear pruritis, headache, application site pain, tinnitus, dizziness, dermatitis. Very rarely with locally applied fluoroquinolones: rash, toxic epidermolysis, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria. MAH: Aspire Pharma Ltd, Unit 4, Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, United Kingdom MA number: PL35533/0130. Cost: Per pack of 15 ampoules £6.01 Legal Category: POM. Date reviewed: September 2021Version number: 1010385675 v 3.0

Cetraxal Plus (ciprofloxacin and fluocinolone acetonide) 3mg/ml + 0.25mg/ml ear drops solution in a single-dose container. Prescribing Information (please refer to the full SmPC before prescribing)

Indication: Acute otitis externa and acute otitis media in patients with tympanostomy tubes, in adults and children aged 6 months and older, caused by ciprofloxacin susceptible microorganisms. Available strength: 0.75 mg ciprofloxacin as hydrochloride and 0.0625 mg of fluocinolone acetonide, contained in 0.25ml of solution. Please refer to the Summary of Product Characteristics (SmPC) for a full list of excipients. Dosage and method of use: Adults, elderly and children aged 6 months and older: Instil the contents of one single-dose container into the affected ear canal every 12 hours for 7 days. Renal/hepatic impairment: no dose adjustment necessary. Warm bottle by holding in hand for several minutes. Lie with affected ear upwards - for patients with otitis externa, pull the auricle several times during instillation. For patients with acute otitis media with tympanostomy tubes, pump the tragus 4 times by pushing inward to facilitate penetration. This position should be maintained for around 1 minute. For further details, please refer to the SmPC. Contraindications: Hypersensitivity to ciprofloxacin, any member of the quinolone class, fluocinolone acetonide or listed excipients. Viral infections of the external ear canal, including varicella and herpes simplex infections and fungal otic infections. Special warnings and precautions for use: Not for ophthalmic use, inhalation or injection. Should not be swallowed. If otorrhea persists after full course of therapy or if two or more episodes occur within six months, evaluate further. If after treatment signs and symptoms persist, evaluate further. Discontinue at first appearance of a skin rash or any other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported, some after the first dose of a systemic quinolone. Serious acute hypersensitivity reactions may require immediate emergency treatment. Overgrowth of non-susceptible organisms may occur from use including bacterial strains, yeast and fungi. If superinfection occurs, treat appropriately. Some patients taking systemic quinolones have shown moderate to severe skin sensitivity to the sun. Corticosteroids may reduce resistance to, and aid in, the establishment of bacterial, viral or fungal infections and mask the clinical signs of an infection, ineffectiveness of the antibiotic or suppress hypersensitivity reactions. If patient presents with blurred vision or other visual disturbances, consider referral to ophthalmologist for evaluation of causes e.g. cataract, glaucoma, central serous chorioretinopathy. Safety and efficacy not established in children under 6 months – only use after very careful benefit/risk evaluation. Interactions with other medicinal products: No interaction studies performed. Due to low plasma levels, systemic interactions unlikely. Systemic administration of some quinolones may enhance the effects of warfarin and its derivatives and has been associated with transient serum creatinine elevations in patients receiving concomitant cyclosporine. Recommendation not to use other ear preparations concomitantly; if more than one is needed, administer them apart. Pregnancy and breast-feeding: For full details please refer to the SmPC. Pregnancy – Assess whether benefits of the treatment outweigh the possible risk. Caution when administered to a nursing woman. Effects on ability to drive and use machines: None or negligible. Side effects: For full list of side effects consult SmPC. ‘Very Common’ ‘Common’ and ‘Serious’ side effects included in prescribing information: dysgeusia, ear pain, ear discomfort, ear pruritus, skin exfoliation. MAH: Aspire Pharma Ltd, Unit 4, Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, United Kingdom MA number: PL35533/0133. Cost: Per pack of 15 ampoules £6.01 Legal Category: POM. Date reviewed September 2021. Version Number: 1010385676 v 3.0

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