905 Form

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Medical Policy Corneal Collagen Cross-linking Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 905 BCBSA Reference Number: 9.03.28 (For Plan internal use only) Related Policies
None Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

Corneal collagen cross-linking using riboflavin and ultraviolet A may be considered MEDICALLY NECESSARY under the following conditions:
• as a treatment of progressive keratoconus, OR • as a treatment of corneal ectasia resulting from refractive surgery in individuals who have failed conservative treatment (eg spectacle correction, rigid contact lens).

Two corneal collagen cross-linking products were available for treatment of progressive keratoconus and corneal ectasia – Photrexa and Epioxa. Photrexa products are planned to be discontinued from the market effective January 20, 2026 with manufacturing set to end February 2026.

Corneal collagen cross-linking using riboflavin and ultraviolet A is considered INVESTIGATIONAL for all other indications.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

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Outpatient Commercial Managed Care (HMO and POS) Prior authorization is not required. Commercial PPO and Indemnity Prior authorization is not required. CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity: CPT Codes
CPT codes: Code Description 0402T Collagen cross-linking of cornea, including removal of the corneal epithelium and intraoperative pachymetry, when performed (Report medication separately) HCPCS Codes HCPCS codes: Code Description J2787 Riboflavin 5'-phosphate, ophthalmic solution, up to 3 mL The following ICD Diagnosis Codes are considered medically necessary when submitted with the CPT and/or HCPCS codes above if medical necessity criteria are met:

ICD-10 Diagnosis Codes ICD-10-CM Diagnosis codes: Code Description H18.601 Keratoconus, unspecified, right eye H18.602 Keratoconus, unspecified, left eye H18.603 Keratoconus, unspecified, bilateral H18.609 Keratoconus, unspecified, unspecified eye H18.611 Keratoconus, stable, right eye H18.612 Keratoconus, stable, left eye H18.613 Keratoconus, stable, bilateral H18.619 Keratoconus, stable, unspecified eye H18.621 Keratoconus, unstable, right eye H18.622 Keratoconus, unstable, left eye H18.623 Keratoconus, unstable, bilateral H18.629 Keratoconus, unstable, unspecified eye H18.711 Corneal ectasia, right eye H18.712 Corneal ectasia, left eye H18.713 Corneal ectasia, bilateral H18.719 Corneal ectasia, unspecified eye

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Description Treatment of Keratoconus and Ectasia The initial treatment for keratoconus often consists of hard contact lenses. A variety of keratorefractive procedures have also been attempted, broadly divided into subtractive and additive techniques. Subtractive techniques include photorefractive keratectomy or laser in situ keratomileuses, although generally, results of these techniques have been poor. Implantation of intrastromal corneal ring segments is an additive technique in which the implants are intended to reinforce the cornea, prevent further deterioration, and potentially obviate the need for penetrating keratoplasty. Penetrating keratoplasty (ie, corneal grafting) is the last line of treatment. About 20% of patients with keratoconus will require corneal transplantation. All of these treatments attempt to improve the refractive errors but are not disease-modifying.

Treatment options for ectasia include intraocular pressure-lowering drugs and intracorneal ring segments. Frequently, penetrating keratoplasty is required.

None of the currently available treatment options for keratoconus and corneal ectasia halt the progression of the disease, and corneal transplantation is the only option available when functional vision can no longer be achieved.

Corneal collagen cross-linking has the potential to slow the progression of the disease. It is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet A irradiation. There are 2 protocols for corneal collagen cross-linking:

1. Epithelium-off corneal collagen cross-linking (also known as “epi-off”): In this method, about 8 mm of the central corneal epithelium is removed under topical anesthesia to allow better diffusion of the photosensitizer riboflavin into the stroma. Following de-epithelialization, a solution with riboflavin is applied to the cornea (every 1-3 minutes for 30 minutes) until the stroma is completely penetrated. The cornea is then irradiated for 30 minutes with ultraviolet A 370 nm, a maximal wavelength for absorption by riboflavin, while the riboflavin continues to be applied. The interaction of riboflavin and ultraviolet A causes the formation of reactive oxygen species, leading to additional covalent bonds (cross-linking) between collagen molecules, resulting in stiffening of the cornea. Theoretically, by using a homogeneous light source and absorption by riboflavin, the structures beyond a 400-mm thick stroma (endothelium, anterior chamber, iris, lens, retina) are not exposed to an ultraviolet dose that is above the cytotoxic threshold.

2. Epithelium-on corneal collagen cross-linking (also known as “epi-on” or transepithelial): In this method, the corneal epithelial surface is left intact (or may be partially disrupted) and a longer riboflavin loading time is needed.

   Historically, the only corneal collagen cross-linking treatment approved by the U.S. Food and Drug Administration (FDA) was the epithelium-off method. In 2025, the first epithelium-on corneal collagen cross- linking treatment was approved (riboflavin 5'-phosphate ophthalmic solution, 0.177% and 0.239%; Epioxa™). Epoxia is anticipated to enter the market during quarter 1 of 2026. Corneal collagen cross-linking is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning, such as keratoconus and corneal ectasia following refractive surgery. Corneal collagen cross-linking may also have anti-edematous and antimicrobial properties.

   Summary Description Corneal collagen cross-linking is a photochemical procedure approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive keratoconus and corneal ectasia following refractive surgery. Keratoconus is a dystrophy of the cornea characterized by progressive deformation (steepening) of the cornea, while corneal ectasia is keratoconus that occurs following refractive surgery. Both conditions can lead to functional loss of vision and need for corneal transplantation.

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Summary of Evidence For individuals who have progressive keratoconus who receive corneal collagen cross-linking using riboflavin and ultraviolet A, the evidence includes randomized controlled trials (RCTs), systematic reviews, and nonrandomized studies. Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. For epithelium-on corneal collagen cross-linking, 2 RCTs showed a significant difference between corneal cross-linking and sham treatment in maximum corneal curvature, but visual acuity results are lacking. Based on RCT evidence used to inform U.S. Food and Drug Administration (FDA approval, epithelium-off corneal collagen cross-linking was associated with significant improvements in corneal curvature score and corrected distance visual acuity and non-significant improvement in uncorrected distance visual acuity compared with sham treatment after 1 year of follow-up. Long-term RCT follow-up is needed. Several non-randomized studies measured visual acuity and found significant and lasting improvements in corrected visual acuity and other measures with corneal collagen cross-linking. The adverse events associated with epithelium-off corneal collagen cross-linking include corneal opacity (haze), corneal epithelial defects, and other ocular findings. Most adverse events resolved in the first month but continued in a few (1% to 6%) patients for 6 to 12 months. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have corneal ectasia after refractive surgery who receive corneal collagen cross-linking using riboflavin and ultraviolet A, the evidence includes systematic reviews and RCTs. Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. Systematic reviews demonstrate that corneal collagen cross-linking is effective in reducing the progression of keratoconus and post-laser refractive surgery ectasia. RCT evidence, used to inform FDA approval, found that corneal collagen cross-linking was associated with significant improvements in corneal curvature score, corrected distance visual acuity and uncorrected distance visual acuity after 1 year follow-up when compared with sham treatment. Another trial that followed patients up to 3 years saw continued improvement in visual acuity with corneal collagen cross-linking. Five-year follow-up in a prospective single-arm study found sustained improvement in uncorrected and corrected distance visual acuity scores and steep keratometry from baseline levels with no significant change in spherical equivalent. Additional long-term follow-up for visual acuity outcomes is needed. The adverse events associated with corneal collagen cross-linking were the same for the ectasia trials as for the keratoconus trials. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 4/2026 Annual policy review. Policy updated with literature review through December 26, 2025; references added. Policy statement unchanged. Addition of epithelium-on corneal collagen product (Epioxa HD and Epioxa).
5/2025 Annual policy review. Policy updated with literature review through January 15, 2025; references added. Policy statement unchanged. 5/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 5/2023 Annual policy review. Minor editorial refinements to policy statements, intent unchanged. 4/2022 Annual policy review. Policy statements unchanged. 4/2021 Annual policy review. Policy statements unchanged. 1/2021 Medicare information removed. See MP #132 Medicare Advantage Management for local coverage determination and national coverage determination reference. Clarified coding information.
7/2020 Medically necessary statement clarified. 5/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2020 Clarified coding information. 4/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2019 Clarified coding information.

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8/2018 Medically necessary statement clarified.
4/2018 Annual policy review. New references added. Summary clarified. 8/2017 Annual policy review. New medically necessary indications described. Investigational indications clarified. Clarified coding information. Effective 8/1/2017. 4/2016 Annual policy review. New references added. 1/2016 Clarified coding information. 6/2015 Annual policy review. New references added. 7/2014 Annual policy review. New references added. 5/2013 Annual policy review. New references added. 2/2013 New policy describing ongoing non-coverage. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

1. American Academy of Ophthalmology. Corneal Collagen Cross-Linking. December 2, 2025. https://www.aao.org/eye-health/treatments/corneal-cross-linking-2. Accessed December 26, 2025.
2. Avedro Inc. Avedro Briefing Package for Joint Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Device Panel of the Medical Devices Advisory Committee NDA 203324: Photrexa Viscous and Photrexa (riboflavin ophthalmic solution) and KXL System (UVA light source) Avedro, Inc. 2016; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/203324Orig1s000TOC.cfm. Accessed December 26, 2025.
3. Davis LJ, Schechtman KB, Wilson BS, et al. Longitudinal changes in visual acuity in keratoconus. Invest Ophthalmol Vis Sci. Feb 2006; 47(2): 489-500. PMID 16431941
4. McMahon TT, Edrington TB, Szczotka-Flynn L, et al. Longitudinal changes in corneal curvature in keratoconus. Cornea. Apr 2006; 25(3): 296-305. PMID 16633030
5. Epioxa HD and Epioxa. Package insert. Glaukos Corporation; October
6. https://www.epioxa.com/wp-content/uploads/2025/10/epioxa-prescribing-information-final.pdf. Accessed January 7, 2026.
7. Cortina MS, Greiner MA, Kuo AN, et al. Safety and Efficacy of Epithelium-Off Corneal Collagen Cross- Linking for the Treatment of Corneal Ectasia: A Report by the American Academy of Ophthalmology. Ophthalmology. Oct 2024; 131(10): 1234-1242. PMID 38935041
8. McAnena L, Doyle F, O'Keefe M. Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmol. May 2017; 95(3): 229-239. PMID 27678078
9. Hersh PS, Stulting RD, Muller D, et al. United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment. Ophthalmology. Sep 2017; 124(9): 1259-1270. PMID 28495149
10. Toprak I, Yaylali V, Yildirim C. Visual, Topographic, and Pachymetric Effects of Pediatric Corneal Collagen Cross-linking. J Pediatr Ophthalmol Strabismus. Mar 01 2017; 54(2): 84-89. PMID 27668869
11. Badawi AE. Accelerated corneal collagen cross-linking in pediatric keratoconus: One year study. Saudi J Ophthalmol. 2017; 31(1): 11-18. PMID 28337057
12. Knutsson KA, Paganoni G, Matuska S, et al. Corneal collagen cross-linking in paediatric patients affected by keratoconus. Br J Ophthalmol. Feb 2018; 102(2): 248-252. PMID 28655729
13. Papaioannou L, Miligkos M, Papathanassiou M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea. Jan 2016; 35(1): 62-71. PMID 26509768
14. Padmanabhan P, Rachapalle Reddi S, Rajagopal R, et al. Corneal Collagen Cross-Linking for Keratoconus in Pediatric Patients-Long-Term Results. Cornea. Feb 2017; 36(2): 138-143. PMID 28060058

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14. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. May 2008; 34(5): 796-801. PMID 18471635
15. Raiskup F, Theuring A, Pillunat LE, et al. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. Jan 2015; 41(1): 41-6. PMID 25532633
16. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. Apr 2010; 149(4): 585-93. PMID 20138607
17. Amaral DC, Menezes AHG, Vilaça Lima LC, et al. Corneal Collagen Crosslinking for Ectasia After Refractive Surgery: A Systematic Review and Meta-Analysis. Clin Ophthalmol. 2024; 18: 865-879. PMID 38525385
18. Hersh PS, Stulting RD, Muller D, et al. U.S. Multicenter Clinical Trial of Corneal Collagen Crosslinking for Treatment of Corneal Ectasia after Refractive Surgery. Ophthalmology. Oct 2017; 124(10): 1475-
19. PMID 28655538
20. Wittig-Silva C, Whiting M, Lamoureux E, et al. A randomized controlled trial of corneal collagen cross- linking in progressive keratoconus: preliminary results. J Refract Surg. Sep 2008; 24(7): S720-5. PMID 18811118
21. Wittig-Silva C, Chan E, Islam FM, et al. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. Apr 2014; 121(4): 812-21. PMID 24393351
22. Margines JB, Rabinowitz YS, Li X, et al. Results of corneal collagen cross-linking in patients with corneal ectasia after laser refractive surgery-A prospective study. Photodiagnosis Photodyn Ther. Jun 2023; 42: 103521. PMID 36931367
23. Center for Drug Evaluation and Research. Application Number 203324Orig2s000. Summary Review. 2015; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/203324Orig2s000SumR.pdf. Accessed December 26, 2025.
24. National Institute for Health and Care Excellence (NICE). Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia [IPG466]. 2013; https://www.nice.org.uk/guidance/ipg466. Accessed December 26, 2025.