Ciprofloxacin, ear drops, 3 mg per mL (0.3%), 5 mL Ciloxan®, July 2006
Page last updated: 27 October 2006
Public Summary Document
Product: Ciprofloxacin, ear drops, 3 mg per mL (0.3%), 5 mL Ciloxan®
Sponsor: Alcon Laboratories (Australia) Pty Ltd
Date of PBAC Consideration: July 2006
1. Purpose of Application
The submission requested an authority required listing for the treatment of chronic
suppurative otitis media (CSOM).
A submission for ciprofloxacin ear drops had not been considered previously by the
PBAC, although ciprofloxacin eye drops are PBS listed (Authority required for bacterial
keratitis) and a combination ear drop of ciprofloxacin with hydrocortisone is listed
on the Repatriation PBS (Restricted benefit for acute bacterial otitis externa where
first-line treatment has failed or is inappropriate).
A central issue in the consideration of these earlier submissions had been the public health concern over adding to antibiotic resistance in the community. General advice from the Expert Advisory Group on Antimicrobial Resistance was that it was prudent to limit topical use of antibiotics to those products that are not used systemically.
The EAGAR’s advice to the Committee for ciprofloxacin ear drops, was that the group remains reluctant to support widespread use of quinolones to treat ear infections. The EAGAR also raised the issue of limited topical options for the treatment of CSOM. Those which are available are based on aminoglycosides and these are problematic in perforated membranes, particularly for those patients in whom the condition frequently relapses. The EAGAR advice concluded that if the PBAC were inclined to list, use be restricted to the Aboriginal and Torres Strait Islander (ATSI) population population.
3. Registration Status:
Ciprofloxacin ear drops (Ciloxan) was registered by the TGA on 17 May 2006 for the
treatment of chronic suppurative otitis media caused by organisms susceptible to ciprofloxacin
in adults and children 1 month and older. The product is identical to the currently
registered eye drop formulation.
4. Requested Listing and PBAC’s view
Treatment of chronic suppurative otitis media.
The PBAC’s view was that, taking into account the clinical data, the prevalence of the condition in the ATSI population, the advice from EAGAR, and noting also the 2004-05 Budget measure “Improving the capacity of the PBS to meet the needs of Indigenous Australians”, a recommendation restricting treatment to the ATSI population was more appropriate.
5. Clinical place for the proposed therapy
An alternative treatment for chronic suppurative otitis media (CSOM).
The submission nominated Sofradex® (dexamethasone with framycetin sulfate and gramicidin
= DFG) as the main comparator and oral antibiotics as a secondary comparator.
7. Clinical trials
The submission presented a single randomised trial (Couzos et al. 2003) comparing
ciprofloxacin 0.3% with Sofradex 5 drops/day for 9 days in 8 Aboriginal communities
in children under 15 years with CSOM in Western Australia and Queensland. The trial
was published at the time of the submission, as follows:
|Couzos et al
|Effectiveness of ototopical antibiotics for chronic suppurative otitis media in Aboriginal children: A community-based, multicentre, double-blind randomised controlled trial
|Medical Journal of Australia, 2003. 179(4): p. 185-190.
Also presented were 19 supplementary trials of ciprofloxacin vs other comparators
and other doses of ciprofloxacin, and two Cochrane reviews: MacFayden (2006) Systemic
antibiotics versus topical treatments for chronically discharging ears with underlying
eardrum perforations (9 trials) and; MacFayden (2005) Topical antibiotics without
steroids (quinolone, non-quinolone) for chronically discharging ears with underlying
eardrum perforations (14 trials).
8. Results of Trials
There was a statistically significant difference in the proportion with clinical cure,
favouring ciprofloxacin in the key trial’s primary analysis. There were no statistically
significant differences in the secondary outcomes, including perforation and hearing
impairment, between treatments. There was no association between clinical cure and
any assessed confounders: age, sex, history of exposure to cigarette smoke inside
dwellings, crowding, other children with CSOM in household, duration and grade of
discharge, prior ear infection, swimming, and number of visits by the Aboriginal Health
Worker. Children who were not cured (31 of the 83 with baseline audiometry) were more
likely to be those with poor hearing at baseline (average hearing threshold, 36.2dB
compared with 23.7dB p=0.01).
In general, there were no major adverse events associated with ciprofloxacin.
9. Clinical Claim
The submission claimed that ciprofloxacin had significant advantages in effectiveness (clinical cure of discharge at 1-2 weeks) over topical DFG (Sofradex) and oral antibiotics and had similar or less toxicity. This was considered acceptable by the PBAC.
10. Economic Analysis
The submission presented a preliminary economic evaluation. The choice of the cost-effectiveness
approach was considered valid. The resources included were drug costs. Two modelled
economic evaluations were presented. Model 1: ciprofloxacin compared to Sofradex in
rural settings for 2 treatment courses (~20 days). A patient can have up to 2 courses
of Sofradex® or ciprofloxacin. If unsuccessful, 5% of patients are hospitalised. Only
includes direct medical costs associated with GP visits, specialist visits, audiograms,
drug costs and hospitalisation. Model 2: ciprofloxacin compared to systemic antibiotics
in urban settings. A patient can have up to 2 courses of systemic antibiotics or ciprofloxacin.
If unsuccessful, then treated with 1 course of Sofradex. If Sofradex treatment then
fails, 5% of patients are hospitalised.
The incremental cost-effectiveness ratios are $10.30 saved per week of earlier resolution gained and $23.40 saved per week of earlier resolution in the rural and urban environments, respectively.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was between 100,000 – 200,000 in Year 3 (some
patients will have bilateral disease), while the financial cost per year to the PBS
in Year 3 was < $10 million.
12. Recommendation and Reasons
The PBAC recommended listing on clinical and cost-effectiveness grounds for use in
chronic suppurative otitis media (CSOM) in an Aboriginal and Torres Strait Islander
The key evidence in the submission came from a single randomised trial (Couzos et al. 2003) comparing ciprofloxacin 0.3% with Sofradex (DFG) in ATSI children under 15 years with CSOM. Ciprofloxacin was statistically significantly better than Sofradex in the proportion with clinical cure [RD 24.6% (95%CI 15.8, 33.4)]. Although the ESC advised that this difference declines to 16% (p=0.06) when an ITT analysis is conducted, the PBAC considered it was not inappropriate to accept the data as presented in view of the difficulty in conducting such trials in the population studied.
The Committee also noted that the prevalence of CSOM in the ATSI population is extremely high at approximately 15%, compared to approximately 1% in the non-indigenous population. The PBAC also noted that there was a higher chronicity and relapse rate in the ATSI population with a greater potential for hearing loss.
Although, the sponsor has stated that it will conduct a post-listing evaluation of the development of resistant strains, the Committee noted that the use of fluoroquinolones in other indications has previously been restricted on advice from the Expert Advisory Group on Antibiotic Resistance (EAGAR). This has been done in an attempt to limit the potential for the development of resistant strains which could limit the usefulness of these agents. EAGAR’s advice to the Committee for ciprofloxacin ear drops, was that that group remains reluctant to support widespread use of fluoroquinolones to treat ear infections. EAGAR also raised the issue of limited topical options for the treatment of CSOM. Those which are available are based on aminoglycosides and are problematic in perforated membranes, particularly for those patients in whom the condition frequently relapses. The EAGAR advice concluded that if the PBAC is inclined to list, use be restricted to the ATSI population.
The Committee considered that economic analysis provided in the submission is adequate to provide confidence that the product would be of acceptable cost effectiveness. If the product is restricted to the ATSI population, then the total cost is anticipated to be less than $1million.
Taking into account the clinical data, the prevalence of the condition in the ATSI population, the advice from EAGAR, and noting also the 2004-05 Budget measure “Improving the capacity of the PBS to meet the needs of Indigenous Australians”, the Committee considered that a recommendation restricting treatment to the ATSI population was appropriate.
The Committee requested that the DUSC monitor usage.
The PBAC recommended the 20 day safety net rule should not apply.
Ciprofloxacin, ear drops, 3 mg per mL (0.3%), 5 mL
Restriction: Authority required
Treatment of chronic suppurative otitis media in an Aboriginal and Torres Strait Islander person aged one year and older.
Maximum quantity: 1
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia.
It considers submissions in this context. A PBAC decision not to recommend listing
or not to recommend changing a listing does not represent a final PBAC view about
the merits of the medicine. A company can resubmit to the PBAC or seek independent
review of the PBAC decision.
14. Sponsor’s Comment
In view of the limitations of other available therapies, Alcon will be working towards making Ciloxan Ear Drops accessible to all Australians with CSOM. Alcon did not believe there was adequate justification that the only medicine approved in Australia for CSOM should not be re-imbursed for non-ATSI Australians.