1 INDICATIONS AND USAGE PHOTREXA ® VISCOUS and PHOTREXA ® are indicated for use in corneal collagen cross-linking in combination with the KXL ® System for the treatment of PHOTREXA VISCOUS and PHOTREXA are photoenhancers indicated for use with the KXL System in corneal collagen cross-linking for the treatment of progressive keratoconus ( 1.1 ) and corneal ectasia following refractive surgery ( 1.2 ).

1.1 Progressive Keratoconus 1.2 Corneal Ectasia Following Refractive Surgery

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Ulcerative keratitis [ Warnings and Precautions (Section 5) ] In progressive keratoconus patients, the most common ocular adverse reactions in any CXL-treated eye were corneal opacity (haze), punctate keratitis, corneal striae, corneal epithelium defect, eye pain, reduced visual acuity, and blurred vision ( 6.1 ).

In corneal ectasia patients, the most common ocular adverse reactions were corneal opacity (haze), corneal epithelium defect, corneal striae, dry eye, eye pain, punctate keratitis, photophobia, reduced visual acuity, and blurred vision ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Avedro at 1-844-528-3376 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of the corneal collagen cross-linking procedure was evaluated in 3 randomized, parallel-group, open-label, sham-controlled trials; patients were followed up for 12 months.

Study 1 enrolled patients with progressive keratoconus or corneal ectasia following refractive surgery.

Study 2 enrolled only patients with progressive keratoconus, and Study 3 enrolled only patients with corneal ectasia following refractive surgery.

In each study, only one eye of each patient was designated as the study eye.

Study eyes were randomized to receive one of the two study treatments (CXL or sham) at the baseline visit and were followed up at Day 1, Week 1, and Months 1, 3, 6, and 12.

At Month 3 or later, sham study eyes and non-study eyes had the option of receiving CXL treatment, and were followed-up for 12 months from the time of receiving CXL treatment.

Each CXL treated eye received a single course of CXL treatment only.

Safety data were obtained from: 193 randomized CXL study eyes (102 keratoconus, 91 corneal ectasia), 191 control eyes, and 319 nonrandomized CXL non-study eyes (191 keratoconus, 128 corneal ectasia).

Overall, 512 eyes (293 keratoconus, 219 corneal ectasia) in 364 patients received CXL treatment.

In progressive keratoconus patients, the most common ocular adverse reactions in any CXL-treated eye were corneal opacity (haze), punctate keratitis, corneal striae, corneal epithelium defect, eye pain, reduced visual acuity, and blurred vision ( Table 1 ).

In corneal ectasia patients, the most common ocular adverse reactions were corneal opacity (haze), corneal epithelium defect, corneal striae, dry eye, eye pain, punctate keratitis, photophobia, reduced visual acuity, and blurred vision.

These events are expected sequelae following epithelial corneal debridement and occurred at a higher incidence than observed in control patients, who did not undergo debridement or exposure to UVA light ( Table 1 ).

Adverse events reported in non-study, non-randomized CXL treated were similar in terms of preferred terms and frequency to those seen in randomized study eyes.

The majority of adverse events reported resolved during the first month, while events such as corneal epithelium defect, corneal striae, punctate keratitis, photophobia, dry eye and eye pain, and decreased visual acuity took up to 6 months to resolve and corneal opacity or haze took up to 12 months to resolve.

In 1-2% of patients, corneal epithelium defect, corneal edema, corneal opacity and corneal scar continued to be observed at 12 months.

In 6% of corneal ectasia patients, corneal opacity continued to be observed at 12 months.

Table 1: Most Common (≥1%) Ocular Adverse Reactions in CXL-Treated Study Eye in the Pooled Randomized Safety Population – N (%) 1) Results are presented as the number (%) of patients with an event from baseline to Month 3.

2) Almost all cases of corneal opacity were reported as haze.

Progressive Keratoconus Studies Corneal Ectasia Studies Preferred Term CXL Group (N=102) 1 Control Group (N=103) 1 CXL Group (N=91) 1 Control Group (N=88) 1 Anterior chamber cell 2 (2) 0 2 (2) 1 (1) Anterior chamber flare 4 (4) 0 5 (6) 2 (2) Asthenopia 1 (1) 1 (1) 2 (2) 0 Blepharitis 0 0 0 1 (1) Corneal disorder 3 (3) 1 (1) 3 (3) 0 Corneal epithelium defect 24 (24) 1 (1) 26 (28) 3 (3) Corneal oedema 3 (3) 0 3 (3) 0 Corneal opacity 2 65 (64) 9 (9) 65 (71) 8 (9) Corneal striae 24 (24) 12 (12) 8 (9) 6 (7) Corneal thinning 1 (1) 2 (2) 0 0 Diplopia 2 (2) 1 (1) 1 (1) 0 Dry eye 6 (6) 2 (2) 13 (14) 4 (5) Eye complication associated with device 2 (2) 0 1 (1) 0 Eye discharge 2 (2) 1 (1) 0 0 Eye oedema 7 (7) 0 0 0 Eye pain 17 (17) 3 (3) 24 (26) 0 Eye pruritus 2 (2) 0 0 0 Eyelid oedema 5 (5) 0 5 (6) 1 (1) Foreign body sensation in eyes 15 (15) 1 (1) 13 (14) 2 (2) Glare 4 (4) 1 (1) 2 (2) 0 Halo vision 1 (1) 0 2 (2) 0 Keratitis 1 (1) 0 3 (3) 0 Lacrimation increased 5 (5) 0 9 (10) 1 (1) Meibomian gland dysfunction 1 (1) 1 (1) 3 (3) 2 (2) Ocular discomfort 0 0 8 (9) 0 Ocular hyperaemia 14 (14) 2 (2) 7 (8) 4 (5) Photophobia 11 (11) 0 17 (19) 0 Punctate keratitis 25 (25) 8 (8) 18 (20) 3 (3) Vision blurred 16 (16) 2 (2) 15 (17) 4 (5) Visual acuity reduced 10 (10) 9 (9) 10 (11) 1 (1) Visual impairment 3 (3) 2 (2) 4 (4) 1 (1) Vitreous detachment 2 (2) 0 0 0 Headache was reported in between 4 to 8% of treated patients.