At the completion of this article, the reader should be able to…
• Understand the immunomodulatory role of ciclosporin in managing ocular surface disease.
• Have the information needed to educate patients on dosing and expected treatment timelines.
• Advise patients on strategies to reduce instillation discomfort and improve adherence.
• Understand how topical CsA combined with artificial tears can be more effective at improving DED symptoms and signs than artificial tears alone.
Dr Ngozi Chidi-Egboka
FNCO, FAAO
Postdoctoral Research Associate, clinical trial
coordinator, sub-investigator, The University of Sydney
Corneal Research Group, Sydney Medical School,
Faculty of Medicine and Health, Sydney Eye Hospital,
Central Sydney (Patyegarang) Precinct.
Professor Chameen Samarawickrama
BSc(Med) MBBS, PhD, FRANZCO
Professor of Cornea and Cataract, Sydney University
Head of Cornea Unit, Westmead Hospital
Director, Translational Ocular Research and
Immunology Consortium (TORIC)
Faculty of Medicine and Health
Clinical Ophthalmology and Eye Health
Westmead Institute for Medical Research, Save Sight Institute
University of Sydney, Westmead and Central Clinical Schools.
Professor Stephanie Watson
OAM FARVO
Head of the speciality of ophthalmology and head of the
Corneal Research Group, The University of Sydney
Sydney Medical School, Faculty of Medicine and Health,
Central Sydney (Patyegarang) Precinct
Head of Corneal Unit, Sydney Eye Hospital
Chair, Australian Vision Research (formerly
Ophthalmic Research Institute of Australia)
Ciclosporin is transforming ocular surface disease by addressing underlying inflammation rather than just symptom relief. With ciclosporin use expanding, optometrists are influential in prescribing, monitoring and optimising treatment outcomes, as the authors explain.
Patients with ocular surface disease, particularly dry eye disease (DED), may benefit from topical ciclosporin.1 Increased apoptosis or programmed cell death in the ocular surface epithelium, particularly the conjunctiva, has been found in ocular surface diseases including dry eye. Topical ciclosporin A (CsA) exerts immunomodulatory effect by reducing T-cell activation and the release of pro-inflammatory cytokines that can trigger or exacerbate apoptosis.2 By inhibiting apoptosis (programmed cell death) of the ocular surface epithelium, topical CsA reduces inflammatory cell infiltration of the lacrimal gland.3
The efficacy and safety of CsA has been shown in multiple studies, including randomised controlled clinical trials1 and Cochrane systematic reviews,4,5 which have reported on the use of CsA for treating ocular surface disease. Use of topical CsA in varying concentrations, and in combination with other topical treatments, has been investigated more commonly for DED – the most common ocular surface disease.4,5
Most studies have found reduced ocular surface symptoms and improved clinical signs including tear production and ocular surface staining with CsA treatment over the course of four to 12 weeks treatment duration. Studies have also shown that patients may benefit from up to 12 months of treatment during which follow-up is required at the least every six months to monitor improvement and patient compliance, but the efficacy is unclear for longer term treatments.1
The treatment regimen consists of the instillation of an eyedrop of CsA once daily (Ikervis (CsA 0.1%)), twice daily (Cequa (CsA 0.09%)), Restasis (CsA 0.05%)), or four times daily (Restasis (CsA 0.05%)) to achieve a sustained immunomodulatory effect. Although the cost of treatment with a commercial formulation of CsA for DED may be higher than lubricants alone (0.05% CsA (Restasis, Allergan) has a calculated annual cost of US $1,276 per patient compared to treatment with
preservative-free artificial tears (for example, Refresh Lubricant Eye Drops, Allergan, Inc., Irvine, CA) costing US $96 per patient annually)),6 the benefit from improved treatment outcomes with CsA may out-weigh the costs.
What are the clinical indications for prescribing?
Topical CsA at concentrations ranging from 0.05% to 2% have been useful in treating ocular surface diseases. For DED, topical CsA has been indicated for the management of symptoms and/or signs of DED not adequately controlled by preservative- free artificial tear monotherapy. Topical CsA may be considered for moderate severity of DED – that is, in patients with dry eye symptoms (typically OSDI score ≥ 23 or an equivalent depending on the questionnaire scale) and at least one deficient ocular surface sign based on recommendation by the TFOS DEWS II management and therapy report.7
In Australia, the Therapeutic Goods Administration (TGA) approved product information and pharmaceutical benefits scheme (PBS) guidelines for initiating treatment with topical CsA (example, Ikervis (CsA 0.1%) and Cequa (CsA 0.09%) indicate that patients must have corneal fluorescein staining (CFS) at grade 4 at treatment initiation using the Oxford scale8 (or equivalent9) and an Ocular Surface Disease Index (OSDI) score of ≥ 23 (out of 100).10 If outside this guideline, CsA can still be prescribed using a private prescription.
The optometrist’s role in ciclosporin therapy
In Australia, the Therapeutic Goods Administration approved topical CsA products (Ikervis and Cequa) are prescription-only medicine, for prescription by ophthalmologists and
therapeutically-qualified optometrists.
Ikervis and Cequa may be prescribed under the PBS subsidy scheme or as a private prescription. Restasis is available in Australia via the authorised prescriber or special access schemes (SAS) of the TGA.11
Eligible patients for PBS subsidy must meet the criteria for moderate to severe DED symptoms and signs criteria for initial treatment, and an improvement in corneal fluorescein staining by
≥ 3 grades and OSDI score by ≥ 30% for continuing treatment with no more than five scripts repeats at a time. Patients do not need to meet the PBS criteria for a private prescription.
The prescription of Restasis requires a government special authority approval after prior consideration of other appropriate treatment options by the clinician. Such that the optometrists have a key role in assessing which patients may be eligible for CsA and if therapeutically-qualified prescribing CsA and then reviewing the response to treatment. Optometrists are also able to work closely with a prescribing ophthalmologist to manage patients on topical CsA.
Available compounded formulations in Australia are typically prepared in varying concentrations (0.02%, 0.05%, 0.2%, 0.5%, and occasionally 1% or 2%) by only a handful of pharmacies, with ophthalmologists exclusively eligible to prescribe. Compounded CsA can be considered if a higher concentration (0.5%, 1% or 2%) is needed, if there is no response to a low dose, or if there is intolerance/sensitivity to excipients or adverse reactions to commercially available products. Use of compounded topical CsA with preservative-free artificial tears, allowing five 15 minutes interval between drops is still recommended.
Patient education
It is important for clinicians to explain the mechanism of action of topical CsA, treatment timelines and possible side effects of use to patients. Topical CsA is an anti-inflammatory agent used to treat inflammatory ocular surface diseases including mostly DED. DED is a common inflammatory ocular surface condition associated with disruption in the tear film function and may develop due to an underlying health problem, eye treatment, after eye surgery, environmental exposure, lifestyles or for no apparent reason.
Treatment with topical CsA is aimed to improve tear production by treating the ocular inflammation. Patients should understand the dosing in accordance with the relevant product information (Ikervis once daily as final medication at bedtime, Cequa twice daily, Restasis twice daily), the concomitant use with preservative-free artificial tears, and timeline to improvement usually up to 12 weeks which may inform the follow-up schedule.
Currently available CsA products are
preservative-free where each ampoule is intended for single use; patients should be advised to discard the ampoule immediately after a single dose.
Topical ciclosporin drops may be prescribed in varying concentrations and combinations with other topical treatments such as corticosteroids in the presence of moderate to severe inflammation. Lower potency topical corticosteroids (for example, fluorometholone 0.1%, loteprednol etabonate 0.5%) may be considered and commenced concurrently with topical CsA for short term (two to four weeks).
Topical corticosteroid eyedrops provide fast relief of ocular inflammation signs and symptoms. However, long-term use of topical steroids is known to be associated with adverse effects such as cataracts, high intraocular pressure and delayed corneal wound healing which may increase the risk of developing an infectious keratitis.12 Close monitoring is required to mitigate the risks if topical corticosteroids are used concurrently.
Patients should be educated on a risk of ocular side effects with topical CsA such as stinging, irritation or transient blurring of vision on instillation. Adverse effects are mostly mild and primarily relate to local reactions upon eye drop instillation and do not usually require treatment discontinuation. Adverse effects may be more frequent with topical CsA in oil formulation (Restasis, Compounded CsA) or higher concentrations of CsA e.g., 1%, 2%.4
Managing instillation discomfort due to topical ciclosporin A
Managing topical CsA instillation discomfort is vital to improve patient adherence to treatment. Evidence from randomised clinical trials showed the proportion of participant reporting instillation discomfort with topical CsA ranged from 7.6% to 38%1 indicating a significant proportion of patients at risk for treatment discontinuation.
A recent study13 found that refrigerating topical CsA reduced instillation discomfort in up to 60% of patients with DED, lasting up to nine minutes, compared with instillation of warm CsA. Thus, refrigerating CsA prior to instillation may improve patient experience. Although there may be concern that refrigeration could potentially impact the stability of the product, given the recommended CsA storage at room temperature of 20 to 25°C, though this study found that 30 days of storage at 4°C did not significantly alter its pH or nanoparticle size.13 The results were consistent with previous investigations that reported stability in CsA encapsulated in lipid nanoparticles over three to six months of refrigeration at 4°C,14 5°C,15 or −20°C.16 These studies suggest that refrigeration for a duration under six months may have minimal effect on the physical properties of CsA products.
Role of artificial tears as adjunct therapy
Topical CsA combined with artificial tears can be more effective at improving DED symptoms and signs than artificial tears alone and/or vehicle eye drops.1 Topical CsA has been mostly trialled in patients with the aqueous-deficient DED subtype of which typical treatment involves primarily using artificial tears as the first-line therapy.
Monotherapy with artificial tears can be sufficient to treat symptoms in milder cases of DED that may not require CsA.1 However, in moderate-to-
severe DED, topical anti-inflammatory medications such as CsA or corticosteroids may be added to manage ocular surface inflammation.
Safety indications
Ocular side effects with topical CsA such as stinging and irritation on instillation have been reported in some high evidence trials with no risk of serious adverse events. Evidence is limited on CsA use in individuals <18 years however, some topical CsA eyedrops are used as steroid sparing agent for non-infective severe conjunctivitis for children >3 years in the in-house medication resource called Meds4Kids under the Sydney Children’s Hospital Network.
The use of topical CsA has not satisfied the TGA categories A, B, C, D and X system for prescribing in pregnancy therefore the potential risk of prescribing CsA during pregnancy or planning pregnancy or lactating, based primarily on preclinical evidence should be carefully weighed against the expected benefit.
Topical CsA should not be used while wearing contact lenses; patients should be advised to remove contact lenses prior to administering topical CsA and have contact lenses re-inserted at least 15 minutes following administration. Topical CsA should not be prescribed for patients with active or suspected ocular or peri-ocular infection, peri-ocular malignancies or premalignant conditions; and should not be prescribed for patients with known hypersensitivity to the active substance or to any of the excipients. Patients should be advised not to touch the ampoule tip to the eye during instillation to avoid potential for eye injury.
Gaps in knowledge
There is a need for evidence-based recommendations for prescribing topical CsA in various ocular surface diseases to inform clinicians and support improvements in care and research. To meet this need, a systematic review with meta-analysis involving 48 randomised controlled clinical trials1 and a review of Australian CsA prescribing guidelines, formulations, TGA-approved product information, TFOS DEWS II Diagnostic Methodology and Management and Therapy reports,17,18 was used to inform an expert-led consensus of ophthalmologists and optometrists from across Australia.
The consensus aligned with the TGA approved product information that topical CsA can be used for patients with moderate to severe DED symptoms (OSDI score ≥ 23)10 and at least grade 4 corneal fluorescein staining (using the Oxford scale 8 or equivalent9), where artificial tears monotherapy was not providing adequate disease control, at treatment initiation.
Concomitant treatment with preservative-free artificial tears substitute allowing at least five minutes interval between drops was also recommended. The clinical response to treatment was recommended to be reassessed at least every six months to determine further prescription.
Overall, it was noted that topical CsA can be used for treatment of a variety of ocular surface diseases with most evidence for aqueous-
deficient DED and may lead to improvements in symptoms and signs.
A knowledge gap remains on the coherency of benefits and the magnitude of treatment effect of the various CsA treatment options. Translation of the clinical studies into guidelines and then clinical practice for ocular surface disease is lacking. Currently, translating results from research to routine clinical practice is an important challenge in medicine. The framework of guidelines developed will support the translation of clinical evidence into practice on the use of topical CsA in ocular surface disease that will ultimately improve patient safety and care. The framework developed by our consensus approach will provide insight to some clinical questions including evidence of superiority of CsA in clinical effectiveness of ocular surface disease treatment compared to other conventional treatments, dosage, concentration and duration of treatment effect, the best clinical outcome and patient reported outcome effect, and the safety of use.
There is also a need for robust clinical real word data to provide evidence-based patient reported outcomes data and long-term follow-up data. Ophthalmic registries yield knowledge that complements randomised clinical trials which may have generalisability and applicability issues due to their controlled testing conditions and strict participant selection criteria.19
The real world data collected by clinicians in routine clinical practice and entered into the Save Sight Dry Eye Registry (SSDER) (Fight Corneal Blindness! – Save Sight Registries) is a valuable means of tracking patient reported outcomes from the use of topical CsA in DED and can be used to monitor patients’ disease status by tracking their DED symptoms and signs.20,21
Conclusion
Therapeutically-endorsed optometrists are now able to prescribe ciclosporin in Australia, but its integration into routine clinical practice will require enhanced patient assessment, long-term follow-up, and a deeper understanding of treatment efficacy. While ciclosporin has shown significant benefits, factors such as cost, patient adherence and potential side effects must be carefully managed.
Future advancements, including improved formulations and real-world data collection through registries, will further refine prescribing guidelines for ciclosporin and strengthen the role of optometry in delivering targeted, evidence-based care for ocular surface disease.
NOTE: This article has been supported by CSL Seqirus.
More reading
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