Dear Prof. Lloyd Sansom and the Australian Pharmaceutical Formulary (APF) panel,

We are writing this letter on behalf of members and professional colleagues of Young Optometrists, a group representing optometry students and optometrists in their first decade of practice. We have recently been advised that there have been changes to the rules regarding the expiration dates of compounded eye drops following the release of APF25, for which the expiry of sterile compounded eye drops must comply with USP 797.(1) This unfortunately means that without a sterility test, the maximum time frame of expiry which can be assigned to a compounded eye drop is 1 day at room temperature or 3 days in the fridge if it is compounded from non-sterile raw ingredients.(1) We are aware that the previous expiry for eye drops was 28 days and up to 6 months (unopened) with chemical stability data. As such, we are concerned that these changes may negatively impact our patient outcomes.

Our priority as eye care practitioners is to ensure the safety and wellbeing of our patients as well as ensuring they receive appropriate access to cost-effective and affordable treatment and management options for their eye-related problems. Compounded eye drops play a significant role in the treatment and management of a myriad of eye conditions including, but not limited to, progressive myopia (shortsightedness), recurrent corneal erosions, corneal endothelial dystrophies and dry eyes. A number of these conditions affect our patients chronically, leading to an increased burden of cost associated with long-term treatment and management. In light of the recent changes proposed by you, the need to resupply compounded eye drops every 1 to 3 days will worsen the pre-existing burden of cost as well as bring forth attainment issues that are impractical for most of our patients.

​​Reasons as to why compounding of certain active ingredients in eye drops is needed in optometry and ophthalmology is outlined below.

Myopia is a major public health concern in many countries, including Australia. According to the Australian Bureau of Statistics, in 2016 approximately 1 in 4 Australians were myopic. Holden et al. (2016)(2) estimated that the prevalence of myopia would impact nearly 50% of the population by 2050, and 10% of these would have high myopia. In many parts of the world, high myopia is a major cause of visual impairment, being associated with an increased risk of retinal detachments, cataracts, glaucoma, and even blindness (Flitcroft 2012).(3)

A commonly prescribed medication for the management and control of myopia is low-dose atropine, serving to slow its progression in younger patients. Currently, the only commercially available concentration of atropine is 1%, which has visually significant side effects that can last up to 11 days and is impractical to dispense. Low concentration atropine eye drops  therefore need to be compounded by pharmacists who have appropriate sterile laboratories.(4) By compounding the atropine to a lower concentration, considerably fewer side effects are induced and the patients’ myopia is able to be appropriately managed whilst maintaining near-normal visual function. Several recent peer-reviewed studies have assessed the efficacy of low-dose atropine in controlling the progression of myopia whilst minimising unwanted side effects.(3, 5-7) Yam et al. (2019)7 demonstrated that 0.05%, 0.025% and 0.01% atropine eye drops were well tolerated without adverse effects on vision-related quality of life as well as reduced the rate of progression of both refractive power and axial elongation in myopic participants. Further, studies have shown efficacy and safety at least up to 5 years of atropine use in controlling myopic progression.(5,8-11)

With the changes to compounding proposed, the cost of low-dose atropine would greatly impact our patients given they would be using these eye drops once daily potentially over a period of years. It is unfeasible for patients to obtain eye drops from a compounding pharmacy every three days and it will become prohibitively costly to maintain treatment over the long term. The limitation in accessibility and complexity of obtaining the eye drops will be a hindrance to compliance leading to a negative impact on patient outcomes. Poorer outcomes and a rise in myopia progression are particularly prevalent in socio-economically disadvantaged children aged 6-15 years old whose' families struggle to meet the burden of cost associated with treatment.(12) By making these eye drops less affordable, this would simply be a further deterrent to best evidence-based provision of care to those who especially need it.

Another instance for the need of compounded eye drops is the application of hypertonic saline (e.g. 5% sodium chloride eye drops and eye ointment) in the management of corneal conditions such as corneal oedema, corneal dystrophies and recurrent corneal erosions. Corneal oedema have a number of causes ranging from mechanical, dystrophic, inflammatory or toxic in nature.(13) Possible aetiology of recurrent corneal erosions include history of eye injury, ocular surgery, dystrophies and contact lens wear.(14) These conditions may present acutely but may also be long-standing depending on the chronicity of disease. Symptoms of these conditions include eye pain, photophobia, and reduced visual acuity, and as such may have detrimental consequences on the individual’s quality of life. A retrospective case series from Sydney Eye Hospital showed that improvement in visual acuity was associated with the increased duration and frequency of use of hypertonic saline.(15) Therefore, timely access and affordable treatment is crucial.

Bausch & Lomb Muro 128 Solution 5% is a commercially available preparation of hypertonic saline, however, it requires Special Access Scheme (SAS) Approval via the Therapeutic Goods Administration (TGA) from an eye care practitioner. Supply of Muro 128 can be an issue as it is sourced from the US and is not readily available in Australian pharmacies. Compounded hypertonic saline solutions can often be accessed earlier from local compounding pharmacies as it does not require SAS approval, allowing for more timely treatment. Like the low-dose atropine, it is unfeasible for patients to obtain eye drops from a compounding pharmacy every three days and it will become prohibitively costly to maintain treatment over the long term.

Another group of patients who will be negatively affected by the proposed changes are sufferers of dry eye disease. Dry eye disease (DED) is defined as a “multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles”.(16) It is a highly prevalent and often chronic condition which affects up to 50% of the global population,(17, 18) and has been shown to negatively impact vision, have a negative psychological and physical impact associated with pain, reduce work productivity, increase economic burden and reduce overall quality of life.(18)

For many patients, the application of commercially available ocular lubrication is not sufficient in alleviating these symptoms. Patients suffering from severe dry eye disease can benefit from other pharmacological agents in addition to ocular lubricants. Research shows the efficacy of ciclosporin for both clinical signs and symptoms of dry eye disease as an immunomodulatory agent.(19-21) Cequa (ciclosporin 0.9 mg/mL) has been approved by the TGA for prescribing as indicated to increase tear production in patients with moderate-to-severe dry eye where prior use of artificial tears has not been sufficient. Ciclosporin drops are dosed twice daily (every 12 hours) on an ongoing basis. Unfortunately, Cequa is currently unavailable to Australians due to supply issues. This therefore has to be made by a compounding pharmacist. As mentioned previously, dry eyes can significantly compromise quality of life. Limitations to accessibility as well as increasing costs associated with compounding ciclosporin eye drops will unfortunately negatively impact these patients leading to poorer patient outcomes.

As eye care practitioners, we feel that the changes to compounded eye drops expiry dates will have a significant negative impact on our patients accessing treatments. We ask that you and the panel consider reviewing your decision on the expiry date of compounded eye drops. We understand that compounding of eye drops is considered a ‘complex’ process of compounding. We ask you to consider reinstating previous expiry dates with added safeguards as set out by the national pharmaceutical guidelines such as ensuring certified compounding facilities meet Australian Standards and for the certified compounding pharmacist to be adequately trained and meet competencies in compounding eye drops. By having standardised processes/protocols for compounding eye drops in certified sterile facilities, this would limit the risk of error and ensure compounded eye drops supplied by Australian compounding pharmacies are sterile and safe to use for our patients.

Thank you for your consideration.

Yours sincerely,

Young Optometrists

References:

1. United States Pharmacopeia and National Formulary. Pharmaceutical Compounding - Sterile Preparations (797): The United States Pharmacopeial Convention; 2008.

2. Holden BA, Fricke TR, Wilson DA et al. (2016): Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology 123: 1036–1042.

3. Flitcroft DI. The complex interactions of retinal, optical and environmental factors in myopia aetiology. Prog Retin Eye Res. 2012;31(6):622-60.

4. Gifford KL, Richdale K, Kang P, Aller TA, Lam CS, Liu YM, et al. IMI - Clinical Management Guidelines Report. Invest Ophthalmol Vis Sci. 2019;60(3):M184-M203.

5. Chia A, Lu QS, Tan D. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology. 2016;123(2):391-9.

6. Fu A, Stapleton F, Wei L, Wang W, Zhao B, Watt K, et al. Effect of low-dose atropine on myopia progression, pupil diameter and accommodative amplitude: low-dose atropine and myopia progression. Br J Ophthalmol. 2020;104(11):1535-41.

7. Yam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, et al. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology. 2019;126(1):113-24.

8. Myles W, Dunlop C, McFadden SA. The Effect of Long-Term Low-Dose Atropine on Refractive Progression in Myopic Australian School Children. J Clin Med. 2021;10(7).

9. Yam JC, Li FF, Zhang X, Tang SM, Yip BHK, Kam KW, et al. Two-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 2 Report. Ophthalmology. 2020;127(7):910-9.

10. Chia A, Chua WH, Cheung YB, Wong WL, Lingham A, Fong A, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119(2):347-54.

11. Chia A, Chua WH, Wen L, Fong A, Goon YY, Tan D. Atropine for the treatment of childhood myopia: changes after stopping atropine 0.01%, 0.1% and 0.5%. Am J Ophthalmol. 2014;157(2):451-7 e1.

12. Fu A, Watt K, M. Junghans B, Delaveris A, Stapleton F (2020) Prevalence of myopia among disadvantaged Australian schoolchildren: A 5-year cross-sectional study. PLoS ONE 15(8): e0238122. https://doi.org/10.1371/journal.pone.0238122

13. Costagliola C, Romano V, Forbice E, Angi M, Pascotto A, Boccia T, et al. Corneal oedema and its medical treatment. Clin Exp Optom. 2013;96(6):529-35.

14. Diez-Feijoo E, Grau AE, Abusleme EI, Duran JA. Clinical presentation and causes of recurrent corneal erosion syndrome: review of 100 patients. Cornea. 2014;33(6):571-5.

15. Leung V, Watson S. Clinical use of topical hypertonic saline eye drops in a quaternary referral eye care centre over 5 years in Sydney, Australia. Clin Exp Ophthalmol. 2019. 47(5):673-675

16. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276-83.

17. Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II Epidemiology Report. Ocul Surf. 2017;15(3):334-65.

18. McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology. 1998;105(6):1114-9.

19. Straub M, Bron AM, Muselier-Mathieu A, Creuzot-Garcher C. Long-term outcome after topical ciclosporin in severe dry eye disease with a 10-year follow-up. Br J Ophthalmol. 2016;100(11):1547-50.

20. Sacchetti M, Mantelli F, Lambiase A, Mastropasqua A, Merlo D, Bonini S. Systematic review of randomised clinical trials on topical ciclosporin A for the treatment of dry eye disease. Br J Ophthalmol. 2014;98(8):1016-22.

21. Jones L, Downie LE, Korb D, Benitez-Del-Castillo JM, Dana R, Deng SX, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf. 2017;15(3):575-628.