Managing Chronic Panuveitis Manifesting in a Patient with Vogt-Koyanagi-Harada Syndrome

Managing Chronic Panuveitis Manifesting in a Patient With Vogt-Koyanagi-Harada Syndrome

SPONSORED BY BAUSCH + LOMB ™ RETISERT ® PATIENT CASE STUDY SERIES

Vogt-Koyanagi-Harada syndrome (VKH) is a granulomatous inflammatory disorder affecting ocular, auditory, meningeal, and integumentary systems, and features the development of a vision- threatening noninfectious bilateral panuveitis on a chronic course. 1-3 The exact cause of VKH is not fully understood,1,2 but the mechanism is generally agreed to be autoimmune in nature, involving the targeting of melanocytes by cytotoxic T cells in those with a genetic susceptibility. 4 VKH predominantly affects people of more-pigmented groups, such as those of Hispanic, Asian, Native American, Middle Eastern, or Asian Indian descent (but not those of sub-Saharan African descent), 1,2 and cases appear to predominate in women over men. 2 At the time of disease onset, most patients are in their second to fifth decades of life; in one study of 65 cases, the mean age was 32 years (range, 7-71 years). 2 While Lisa J. Faia, MD VKH is a multisystem disorder and diagnosis of “complete” disease requires both neurological findings Vitreoretinal Surgeon (eg, early meningism or tinnitus) and integumentary involvement (eg, later vitiligo), signs and symptoms at Associated Retina vary greatly depending on disease stage. 1 Nevertheless, evidence of bilateral diffuse posterior uveitis Consultants, PC in Royal is essential, even for probable VKH diagnosis. 1 If the early inflammation is not adequately controlled, Oak, MI, and Associate subretinal fibrosis can develop, as can glaucoma. 2,5 Months or years after disease onset, uveitis becomes Professor of Ophthalmology more diffuse and presents in the anterior segment. 1,2 Differentiation from entities such as sarcoidosis at Oakland University William Beaumont School and sympathetic ophthalmia is needed.1 High-dose systemic corticosteroids are the standard first- of Medicine line treatment for VKH; if these are not tolerated, immunomodulatory agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, can be employed. 6 The following case study describes a patient with previously undiagnosed, long-standing VKH who over time developed glaucoma in each Lisa J. Faia, MD, is a paid eye. This patient had irreparable vision loss in her left eye and later developed blurred vision in her right consultant of Bausch + Lomb. eye. Having hypertension, she is not a good candidate for first-line systemic corticosteroid therapy. After alternative therapies failed, the patient was treated with RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg therapy for control of her posterior uveitis associated with VKH.

Case Report: Chronic Panuveitis Manifesting in Vogt-Koyanagi-Harada Syndrome

BACKGROUND: A 55-year-old African American woman with hypertension and a history of bilateral glaucoma was referred to me in 2015 for diagnosis after her general ophthalmologist suspected posterior uveitis in the right eye.

Indication RETISERT® (fluocinolone acetonide intravitreal implant) 0.59 mg is a corticosteroid indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. Important Safety Information • Surgical placement of RETISERT® (fluocinolone acetonide intravitreal implant) 0.59 mg is contraindicated in active viral, bacterial, mycobacterial or fungal infections of the eye. Please see additional Important Safety Information throughout and full Prescribing Information for RETISERT® on pages 5-7.

Identifying the Optimal Patient Type for RETISERT treatment Retina Today Nov/Dec 2018 Managing Chronic Panuveitis Manifesting in a November/December 2020 | Insert to Retina Today Patient With Vogt-Koyanagi-Harada Syndrome

Untitled-5 1 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 1 11/6/20 10:07 AM BACKGROUND (CONT’D): In 2002, she underwent trabeculectomy and cataract surgery in her left eye; vision in this eye was later reduced WHY RETISERT? (CONT’D) The patient experienced an unacceptable to hand motion, which her doctor believed to be caused by uncontrolled, surgically exacerbated inflammation and glaucoma. In 2010, she received the adverse event following the first intraocular therapy, and there were apparently A same two surgeries in her right eye—and when the patient came to see me, she had begun to experience vision loss in her right eye. Her specialist believed diminishing outcomes from the second therapy. her glaucomatous damage was secondary to an uncontrolled posterior uveitis and response to topical ophthalmic corticosteroids, but the etiology of the The patient’s right-eye BCVA had fallen to 20/200, and uveitis of the posterior inflammation was unknown. segment was manifesting chronically in secondary macular edema. When we DIAGNOSIS: The patient’s left eye had only hand-motion vision and was soft in applanation tonometry. Band keratopathy, which has been observed in discussed RETISERT once again, the patient was more engaged, and her glaucoma B cases of VKH,7 was present, and the pseudophakic lens had dense posterior capsule opacification. Color fundus imaging showed subretinal fibrosis and optic specialist agreed that the treatment was viable. We talked through the risks disc pallor in a “sunset glow” effect (Figure 1), consistent with VKH.2 The right eye had a BCVA of 20/150 and an IOP of 13 mm Hg; the anterior chamber had associated with RETISERT. The patient had been unhappy with the blurred vision trace cell and flare, and the vitreous had grade 1 + haze and cell. Fluorescein angiography (FA) revealed diffuse leakage in the macula and around the optic that occurred after her preservative-free triamcinolone acetonide injection; and nerve (Figure 2A-B), and macular edema shown in OCT (Figure 2C), which has been reported in cases of VKH,7 suggested a posterior uveitis. while her vision was already so reduced, I advised her that nearly all RETISERT C patients experience a temporary decrease in visual acuity in the implanted eye The patient reported a previous case of hearing loss. She also had ongoing headaches (managed with over-the-counter drugs) and vitiligo (managed with immediately after surgery.11 Corticosteroids should also be used with caution in a steroid cream). Of note regarding ancestry, the patient mentioned that she has Native American relatives. Laboratory findings from a combination of patients with glaucoma; after RETISERT placement, eyes must be monitored for treponemal and non-treponemal tests were negative for syphilis, and an interferon gamma release assay for tuberculosis also returned a negative result— elevated IOP.11 Corticosteroids can also cause cataracts; based on RETISERT lowering the probability of uveitis secondary to such infections.8 Unremarkable serum levels of lysozyme and angiotensin converting enzyme helped D clinical trials, nearly all phakic eyes are expected to develop cataracts.11 My differentiate the patient’s condition from sarcoidosis.9 The patient also denied a history of ocular trauma or penetrating ocular surgery prior to the onset of patient’s eyes, however, had been pseudophakic since 2002 (left eye) and 2010 her earliest symptoms. Coupled with her glaucoma specialist’s belief that uncontrolled posterior uveitis was one of the causes of her glaucoma (for which (right eye). Caution needs to be exercised to ensure completeness of healing, if she later received trabeculectomies), this history permitted a differentiation from sympathetic ophthalmia.1,10 Based on the summary of findings, I diagnosed placing RETISERT following cataract surgery, as the use of steroids may delay my patient’s posterior uveitis as a feature of VKH. Figure 3. OCT scans following first RETISERT placement. healing and increase the incidence of bleb formation.11 Imaging demonstrates resolution of macular edema and improvement TREATMENT: Aggressive treatment with systemic corticosteroids was not FOLLOW-UP: One month following placement of her first RETISERT implant in the ellipsoid zone 1 month (A), 12 months (B), 24 months (C), and advised given the patient’s hypertension, so we tried low-dose corticosteroids with in the right eye, the patient began a slow taper off methotrexate, which was 34 months (D) after implantation. The patient was slowly tapered off an immunomodulator, oral mycophenolate mofetil—but therapeutic effect was methotrexate from the beginning of month 2 through month 12. completed 12 months post surgery. To manage the anterior portion of her panuveitis, not seen. She then began treatment with oral methotrexate 25 mg per week. In the patient took prednisolone acetate ophthalmic suspension, 1%, twice daily for follow-up, there were some improvements in the patient’s visual acuity as well as her 36 months following RETISERT placement. IOP-lowering medications were considered as well. RETISERT is designed to release fluocinolone acetonide neurological and integumentary symptoms, but she was not tolerating the therapy over approximately 30 months, initially at a rate of 0.6 µg per day, then decreasing to a steady state of between 0.3 and 0.4 µg after the first month.11 In well and admitted to lapses in regimen adherence. clinical trials, IOP-lowering medications were required in 77% of RETISERT patients, and filtration surgeries were needed in 37%.11 My patient had previously The patient wanted to stop taking systemic medications, so while continuing received a trabeculectomy. After RETISERT placement, she also took an IOP-lowering medication (dorzolamide hydrochloride, 2%, and timolol maleate, Figure 1. Color fundus photographs of right and left eye. methotrexate therapy, we began discussing potential options in intraocular 0.5%) until the end of the first month, when the rate of drug release is at its highest,11 on orders from her general ophthalmologist. Following implantation with The right eye shows significant glaucomatous and pigmentary damage treatments. Following one dose of preservative-free triamcinolone acetonide RETISERT, the patient’s IOP was carefully monitored. while the left eye shows subretinal fibrosis and “sunset glow” in the injectable suspension, the patient experienced blurred vision for multiple days macula (white arrows). Follow-up OCT imaging (Figure 3A-D) showed resolution of the patient’s right-eye macular edema through 34 months post RETISERT surgery. After and refused subsequent triamcinolone injections. Her flare-ups had become less 1 month, her BCVA improved to 20/80, which further increased, gradually, to 20/50 after 34 months. During the 34 months, there were no reports of frequent, and with the uveitis now in a chronic-smoldering phase, we discussed uveitic flare-ups, either from the patient’s general ophthalmologist or in her visits to my office. At 38 months following implantation, there was grade 1+ a dexamethasone intravitreal implant. The patient received three injections with anterior cell and flare, and the patient’s BCVA fell to 20/70. Her prednisone acetate regimen was increased to three times per day. A month later, her anterior A B 3-month intervals between injections. After the first two injections, her BCVA inflammation had not improved, her BCVA had decreased to 20/80, and her macular edema had resurfaced. As a result of consultation with me, the patient improved to 20/60, and her IOP remained between 11 and 17 mm Hg. However, wanted to receive a second RETISERT and had no interest in returning to previous therapies. the patient’s vision did not improve following the third injection, and 3 months later, her BCVA fell to 20/200. Important Safety Information (cont’d) WHY RETISERT? Hypertension precluded the patient’s ability to enter first-line ® therapy for VKH (high doses of systemic corticosteroids). Steroid-sparing therapies • Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. were tried, but were either poorly tolerated or resulted in an inadequate outcome. With methotrexate, the patient saw some improvements in visual acuity and some • As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT® into the vitreous alleviation of her headaches and vitiligo—however, she was barely tolerating and cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, endophthalmitis, hypotony, increased intraocular was at times missing weekly doses. She stated that her headaches were not a severe pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous C burden, and her steroid cream had been successful in controlling her vitiligo. The hemorrhage, vitreous loss, and wound dehiscence. patient wanted to find an option that did not involve systemic medications, and we • Following implantation of RETISERT®, nearly all patients will experience an immediate Figure 2. Early (A) and late phase (B) fundus FAs and OCT scan discussed RETISERT, but she was at the time reluctant because of a belief that surgical and temporary decrease in visual acuity in the implanted eye which lasts for approximately (C) of the right eye. FA demonstrates diffuse leakage in the macula complications had been the primary mechanism in losing her left-eye vision. In an one to four weeks post-operatively. and around the optic nerve. OCT shows diffuse intraretinal fluid (blue arrow) and disrupted ellipsoid zone (green arrows). attempt to minimize invasiveness, the patient chose to pursue a preservative-free Please see additional Important Safety Information throughout and triamcinolone acetonide injection, and later, dexamethasone intravitreal implants. full Prescribing Information for RETISERT® on pages 5-7.

2 November/December 2020 | Insert to Retina Today November/December 2020 | Insert to Retina Today 3

Untitled-5 2 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 2-3 11/6/20 10:09 AM BACKGROUND (CONT’D): In 2002, she underwent trabeculectomy and cataract surgery in her left eye; vision in this eye was later reduced WHY RETISERT? (CONT’D) The patient experienced an unacceptable to hand motion, which her doctor believed to be caused by uncontrolled, surgically exacerbated inflammation and glaucoma. In 2010, she received the adverse event following the first intraocular therapy, and there were apparently A same two surgeries in her right eye—and when the patient came to see me, she had begun to experience vision loss in her right eye. Her specialist believed diminishing outcomes from the second therapy. her glaucomatous damage was secondary to an uncontrolled posterior uveitis and response to topical ophthalmic corticosteroids, but the etiology of the The patient’s right-eye BCVA had fallen to 20/200, and uveitis of the posterior inflammation was unknown. segment was manifesting chronically in secondary macular edema. When we DIAGNOSIS: The patient’s left eye had only hand-motion vision and was soft in applanation tonometry. Band keratopathy, which has been observed in discussed RETISERT once again, the patient was more engaged, and her glaucoma B cases of VKH,7 was present, and the pseudophakic lens had dense posterior capsule opacification. Color fundus imaging showed subretinal fibrosis and optic specialist agreed that the treatment was viable. We talked through the risks disc pallor in a “sunset glow” effect (Figure 1), consistent with VKH.2 The right eye had a BCVA of 20/150 and an IOP of 13 mm Hg; the anterior chamber had associated with RETISERT. The patient had been unhappy with the blurred vision trace cell and flare, and the vitreous had grade 1 + haze and cell. Fluorescein angiography (FA) revealed diffuse leakage in the macula and around the optic that occurred after her preservative-free triamcinolone acetonide injection; and nerve (Figure 2A-B), and macular edema shown in OCT (Figure 2C), which has been reported in cases of VKH,7 suggested a posterior uveitis. while her vision was already so reduced, I advised her that nearly all RETISERT C patients experience a temporary decrease in visual acuity in the implanted eye The patient reported a previous case of hearing loss. She also had ongoing headaches (managed with over-the-counter drugs) and vitiligo (managed with immediately after surgery.11 Corticosteroids should also be used with caution in a steroid cream). Of note regarding ancestry, the patient mentioned that she has Native American relatives. Laboratory findings from a combination of patients with glaucoma; after RETISERT placement, eyes must be monitored for treponemal and non-treponemal tests were negative for syphilis, and an interferon gamma release assay for tuberculosis also returned a negative result— elevated IOP.11 Corticosteroids can also cause cataracts; based on RETISERT lowering the probability of uveitis secondary to such infections.8 Unremarkable serum levels of lysozyme and angiotensin converting enzyme helped D clinical trials, nearly all phakic eyes are expected to develop cataracts.11 My differentiate the patient’s condition from sarcoidosis.9 The patient also denied a history of ocular trauma or penetrating ocular surgery prior to the onset of patient’s eyes, however, had been pseudophakic since 2002 (left eye) and 2010 her earliest symptoms. Coupled with her glaucoma specialist’s belief that uncontrolled posterior uveitis was one of the causes of her glaucoma (for which (right eye). Caution needs to be exercised to ensure completeness of healing, if she later received trabeculectomies), this history permitted a differentiation from sympathetic ophthalmia.1,10 Based on the summary of findings, I diagnosed placing RETISERT following cataract surgery, as the use of steroids may delay my patient’s posterior uveitis as a feature of VKH. Figure 3. OCT scans following first RETISERT placement. healing and increase the incidence of bleb formation.11 Imaging demonstrates resolution of macular edema and improvement TREATMENT: Aggressive treatment with systemic corticosteroids was not FOLLOW-UP: One month following placement of her first RETISERT implant in the ellipsoid zone 1 month (A), 12 months (B), 24 months (C), and advised given the patient’s hypertension, so we tried low-dose corticosteroids with in the right eye, the patient began a slow taper off methotrexate, which was 34 months (D) after implantation. The patient was slowly tapered off an immunomodulator, oral mycophenolate mofetil—but therapeutic effect was methotrexate from the beginning of month 2 through month 12. completed 12 months post surgery. To manage the anterior portion of her panuveitis, not seen. She then began treatment with oral methotrexate 25 mg per week. In the patient took prednisolone acetate ophthalmic suspension, 1%, twice daily for follow-up, there were some improvements in the patient’s visual acuity as well as her 36 months following RETISERT placement. IOP-lowering medications were considered as well. RETISERT is designed to release fluocinolone acetonide neurological and integumentary symptoms, but she was not tolerating the therapy over approximately 30 months, initially at a rate of 0.6 µg per day, then decreasing to a steady state of between 0.3 and 0.4 µg after the first month.11 In well and admitted to lapses in regimen adherence. clinical trials, IOP-lowering medications were required in 77% of RETISERT patients, and filtration surgeries were needed in 37%.11 My patient had previously The patient wanted to stop taking systemic medications, so while continuing received a trabeculectomy. After RETISERT placement, she also took an IOP-lowering medication (dorzolamide hydrochloride, 2%, and timolol maleate, Figure 1. Color fundus photographs of right and left eye. methotrexate therapy, we began discussing potential options in intraocular 0.5%) until the end of the first month, when the rate of drug release is at its highest,11 on orders from her general ophthalmologist. Following implantation with The right eye shows significant glaucomatous and pigmentary damage treatments. Following one dose of preservative-free triamcinolone acetonide RETISERT, the patient’s IOP was carefully monitored. while the left eye shows subretinal fibrosis and “sunset glow” in the injectable suspension, the patient experienced blurred vision for multiple days macula (white arrows). Follow-up OCT imaging (Figure 3A-D) showed resolution of the patient’s right-eye macular edema through 34 months post RETISERT surgery. After and refused subsequent triamcinolone injections. Her flare-ups had become less 1 month, her BCVA improved to 20/80, which further increased, gradually, to 20/50 after 34 months. During the 34 months, there were no reports of frequent, and with the uveitis now in a chronic-smoldering phase, we discussed uveitic flare-ups, either from the patient’s general ophthalmologist or in her visits to my office. At 38 months following implantation, there was grade 1+ a dexamethasone intravitreal implant. The patient received three injections with anterior cell and flare, and the patient’s BCVA fell to 20/70. Her prednisone acetate regimen was increased to three times per day. A month later, her anterior A B 3-month intervals between injections. After the first two injections, her BCVA inflammation had not improved, her BCVA had decreased to 20/80, and her macular edema had resurfaced. As a result of consultation with me, the patient improved to 20/60, and her IOP remained between 11 and 17 mm Hg. However, wanted to receive a second RETISERT and had no interest in returning to previous therapies. the patient’s vision did not improve following the third injection, and 3 months later, her BCVA fell to 20/200. Important Safety Information (cont’d) WHY RETISERT? Hypertension precluded the patient’s ability to enter first-line ® therapy for VKH (high doses of systemic corticosteroids). Steroid-sparing therapies • Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. were tried, but were either poorly tolerated or resulted in an inadequate outcome. With methotrexate, the patient saw some improvements in visual acuity and some • As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT® into the vitreous alleviation of her headaches and vitiligo—however, she was barely tolerating and cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, endophthalmitis, hypotony, increased intraocular was at times missing weekly doses. She stated that her headaches were not a severe pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous C burden, and her steroid cream had been successful in controlling her vitiligo. The hemorrhage, vitreous loss, and wound dehiscence. patient wanted to find an option that did not involve systemic medications, and we • Following implantation of RETISERT®, nearly all patients will experience an immediate Figure 2. Early (A) and late phase (B) fundus FAs and OCT scan discussed RETISERT, but she was at the time reluctant because of a belief that surgical and temporary decrease in visual acuity in the implanted eye which lasts for approximately (C) of the right eye. FA demonstrates diffuse leakage in the macula complications had been the primary mechanism in losing her left-eye vision. In an one to four weeks post-operatively. and around the optic nerve. OCT shows diffuse intraretinal fluid (blue arrow) and disrupted ellipsoid zone (green arrows). attempt to minimize invasiveness, the patient chose to pursue a preservative-free Please see additional Important Safety Information throughout and triamcinolone acetonide injection, and later, dexamethasone intravitreal implants. full Prescribing Information for RETISERT® on pages 5-7.

2 November/December 2020 | Insert to Retina Today November/December 2020 | Insert to Retina Today 3

Untitled-5 3 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 2-3 11/6/20 10:09 AM Retisert ® FOLLOW-UP (CONT’D): I increased her prednisone acetate drops to 4 times daily as we looked to authorize a second RETISERT surgery. (fluocinolone acetonide Seven weeks later, the anterior uveitis had shown no improvement, the patient’s macular edema had worsened, her BCVA was down to 20/200, and an intravitreal implant) 0.59 mg STERILE increasing IOP (18 mm Hg, which was relatively high for this patient) suggested association with the persistent uveitic activity. The patient then received a second RETISERT implant. After 1 week, her BCVA was 20/80, and her IOP was 17 mm Hg. After 2 months, there was only trace anterior cell, BCVA HIGHLIGHTS OF PRESCRIBING INFORMATION ------CONTRAINDICATIONS ------These highlights do not include all the information needed to use RETISERT safely • Surgical placement of RETISERT is contraindicated in active viral, bacterial, was maintained at 20/80, and the IOP was 15 mm Hg. OCT imaging showed an improved macula. In our latest visit (September 1, 2020), the patient told and effectively. See full prescribing information for RETISERT. mycobacterial and fungal infections of ocular structures. (4.1) me she had stopped taking her prednisone acetate drops, and exams and imaging showed retrogression in her VA and aggravation of her uveitis. She was RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg for intravitreal use ------WARNINGS AND PRECAUTIONS ------Initial U.S. Approval: 1963 encouraged to return to a 3-times-daily regimen with a reminder that complete management of her panuveitis during the period when she had experienced • Cataract formation: Nearly all phakic patients are expected to develop cataracts and positive outcomes had involved assistance for her anterior inflammation. require cataract surgery. (5.1) ------INDICATIONS AND USAGE ------• Endophthalmitis: Late onset endophthalmitis has been observed. (5.2) RETISERT is a corticosteroid indicated for the treatment of chronic noninfectious uveitis • Increase in intraocular pressure: Use of corticosteroids may result in elevated IOP affecting the posterior segment of the eye. (1) and/or glaucoma. (5.3) IOP lowering medications were required in > 75% of patients; filtering surgeries were required in > 35% of patients. (6.1) • Separation of implant components: Physicians should periodically monitor the ------DOSAGE AND ADMINISTRATION ------Conclusions integrity of the implant by visual inspection. (5.4) • RETISERT is surgically implanted into the posterior segment of the affected eye through a pars plana incision. (2.1) This case study describes a patient with previously undiagnosed, long-standing VKH, a systemic autoimmune disorder featuring ------ADVERSE REACTIONS ------• RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of • Ocular adverse events included procedural complications, and eye pain (> 50%). 1,2,4 0.6 mcg/day, decreasing over the first month to a steady state between 0.3-0.4 mcg/day a diffuse posterior uveitis that develops into a panuveitis throughout a chronic course. The patient had lost her left-eye vision Thirty-five to forty percent of patients reported ocular/conjunctival hyperemia, over approximately 30 months. (2.1) reduced visual acuity, and conjunctival hemorrhage. (6.1) from secondary glaucoma, and her right-eye vision was imperiled by glaucoma and macular edema secondary to posterior • Aseptic technique should be maintained at all times prior to and during the surgical • The most common non-ocular event reported was headache (33%). (6.2) uveitis. Hypertension precluded aggressive treatment with systemic corticosteroids, and the patient tolerated immunomodulators implantation procedure. (2.2) ------DOSAGE FORMS AND STRENGTHS ------To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated poorly. After her first RETISERT implant, the signs of her posterior segment inflammation resolved for 34 months. After the • 0.59 mg fluocinolone acetonide intravitreal implant. (3) at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. implant’s intended period of drug release had ended and the patient’s uveitis returned, a second implant was placed. In the most See 17 for PATIENT COUNSELING INFORMATION. recent visit, an adherence stoppage in her additional therapy for anterior conditions has been attended by uveitic aggravation, the Revised: 05/2019 exact causes of which need evaluation through further monitoring. However, in the first two follow-ups following placement of the FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS second RETISERT implant, the patient’s uveitis showed renewed signs of improvement. 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.3 Nursing Mothers 2.1 Dosing Information 8.4 Pediatric Use 2.2 Handling of Implant 8.5 Geriatric Use 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION Important Safety Information (cont’d) 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY Use of corticosteroids may result in elevated IOP and/or glaucoma. Based on clinical trials with RETISERT®, within 3 years post-implantation, 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures 12.1 Mechanism of Action • 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures 5.1 Cataract Formation 13 NONCLINICAL TOXICOLOGY to control intraocular pressure. 5.2 Endophthalmitis and Surgical Complications 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.3 Increase in Intraocular Pressure 14 CLINICAL STUDIES • Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of RETISERT®. 5.4 Separation of Implant Components 16 HOW SUPPLIED/STORAGE AND HANDLING Physicians should periodically monitor the integrity of the implant by visual inspection. 5.5 Other Corticosteroid Induced Adverse Reactions 17 PATIENT COUNSELING INFORMATION 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience - Ocular Events • Ocular administration of corticosteroids has been associated with delayed wound healing and perforation of the globe where there is thinning of the sclera. *Sections or subsections omitted from the full prescribing information are not listed 6.2 Clinical Trials Experience - Non-Ocular Events • The most frequently reported ocular adverse events in clinical trials with RETISERT® occurring in 50-90% of patients included: cataract, increased intraocular pressure, procedural complications and eye pain. The most common non-ocular event reported was headache (33%). FULL PRESCRIBING INFORMATION 3 DOSAGE FORMS AND STRENGTHS Please see additional Important Safety Information throughout and full Prescribing Information for RETISERT® on pages 5-7. 1 INDICATIONS AND USAGE 0.59 mg fluocinolone acetonide intravitreal implant. RETISERT is indicated for the treatment of chronic non-infectious uveitis affecting the 4 CONTRAINDICATIONS posterior segment of the eye. References: 1. Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures 2001;131(5):647-652. 2. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol. 1995;39(4):265-292. 3. Baltmr A, Lightman S, Tomkins-Netzer O. Vogt– 2 DOSAGE AND ADMINISTRATION Surgical placement of RETISERT is contraindicated in active viral diseases of the cornea Koyanagi–Harada syndrome – current perspectives. Clin Ophthalmol. 2016;10:2,345-2,361. 4. Damico FM, Bezerra Gaspar Carvalho da Silva FT, Gasparin F, Yamamoto JH. New insights into 2.1 Dosing Information and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg is implanted into the and varicella, and also in active bacterial, mycobacterial or fungal infections of the eye. Vogt-Koyanagi-Harada disease. Arq Bras Oftalmol. 2009;72(3):413-420. 5. Zhao C, Dong F, Gao F, et al. Longitudinal observation of subretinal fibrosis in Vogt-Koyanagi-Harada disease. posterior segment of the affected eye through a pars plana incision. BMC Ophthalmol. 2018;18(1):6. 6. Rao NA, Inomata H. Vogt-Koyanagi-Harada disease. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Saint Louis, MO: Mosby Elsevier; 2009:861-863. 5 WARNINGS AND PRECAUTIONS The implant contains one tablet of 0.59 mg of fluocinolone acetonide. RETISERT is 5.1 Cataract Formation 7. Lavezzo MM, Sakata VM, Morita C, et al. Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes. Orphanet J Rare Dis. 2016;11:29. 8. Lin P. designed to release fluocinolone acetonide at a nominal initial rate of 0.6 mcg/day, Use of corticosteroids may result in posterior subcapsular cataract formation. Infectious uveitis. Curr Ophthalmol Rep. 2015;3(3):170-183. 9. Majumder PD, Sudharshan S, Biswas J. Laboratory support in the diagnosis of uveitis. Indian J Ophthalmol. 2013;61(6):269-276. decreasing over the first month to a steady state between 0.3-0.4 mcg/day over Based on clinical trials with RETISERT, during the 3-year post-implantation period, approximately 30 months. Following depletion of fluocinolone acetonide as evidenced 10. Rao NA, Marak GE Jr. Sympathetic uveitis. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Saint Louis, MO: Mosby Elsevier; 2009:854-856. 11. RETISERT Prescribing Information. nearly all phakic eyes are expected to develop cataracts and require cataract surgery. Bausch & Lomb Incorporated. by recurrence of uveitis, RETISERT may be replaced. 5.2 Endophthalmitis and Surgical Complications 2.2 Handling of Implant Late onset endophthalmitis has been observed. These events are often related to the Caution should be exercised in handling RETISERT in order to avoid damage to the integrity of the surgical wound site. Careful attention to assure tight closure of the scleral implant, which may result in an increased rate of drug release from the implant. Thus, wound and the integrity of the overlying conjunctiva at the wound site is important. RETISERT should be handled only by the suture tab. Care should be taken during implantation and explantation to avoid sheer forces on the implant that could disengage Potential complications accompanying intraocular surgery to place RETISERT into the the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the vitreous cavity may include, but are not limited to, the following: cataract formation, suture tab. Aseptic technique should be maintained at all times prior to and during the choroidal detachment, endophthalmitis, hypotony, increased intraocular pressure, surgical implantation procedure. exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. RETISERT should not be resterilized by any method.

4 November/December 2020 | Insert to Retina Today November/December 2020 | Insert to Retina Today 5

Untitled-5 4 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 4-5 11/6/20 10:09 AM Retisert ® FOLLOW-UP (CONT’D): I increased her prednisone acetate drops to 4 times daily as we looked to authorize a second RETISERT surgery. (fluocinolone acetonide Seven weeks later, the anterior uveitis had shown no improvement, the patient’s macular edema had worsened, her BCVA was down to 20/200, and an intravitreal implant) 0.59 mg STERILE increasing IOP (18 mm Hg, which was relatively high for this patient) suggested association with the persistent uveitic activity. The patient then received a second RETISERT implant. After 1 week, her BCVA was 20/80, and her IOP was 17 mm Hg. After 2 months, there was only trace anterior cell, BCVA HIGHLIGHTS OF PRESCRIBING INFORMATION ------CONTRAINDICATIONS ------These highlights do not include all the information needed to use RETISERT safely • Surgical placement of RETISERT is contraindicated in active viral, bacterial, was maintained at 20/80, and the IOP was 15 mm Hg. OCT imaging showed an improved macula. In our latest visit (September 1, 2020), the patient told and effectively. See full prescribing information for RETISERT. mycobacterial and fungal infections of ocular structures. (4.1) me she had stopped taking her prednisone acetate drops, and exams and imaging showed retrogression in her VA and aggravation of her uveitis. She was RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg for intravitreal use ------WARNINGS AND PRECAUTIONS ------Initial U.S. Approval: 1963 encouraged to return to a 3-times-daily regimen with a reminder that complete management of her panuveitis during the period when she had experienced • Cataract formation: Nearly all phakic patients are expected to develop cataracts and positive outcomes had involved assistance for her anterior inflammation. require cataract surgery. (5.1) ------INDICATIONS AND USAGE ------• Endophthalmitis: Late onset endophthalmitis has been observed. (5.2) RETISERT is a corticosteroid indicated for the treatment of chronic noninfectious uveitis • Increase in intraocular pressure: Use of corticosteroids may result in elevated IOP affecting the posterior segment of the eye. (1) and/or glaucoma. (5.3) IOP lowering medications were required in > 75% of patients; filtering surgeries were required in > 35% of patients. (6.1) • Separation of implant components: Physicians should periodically monitor the ------DOSAGE AND ADMINISTRATION ------Conclusions integrity of the implant by visual inspection. (5.4) • RETISERT is surgically implanted into the posterior segment of the affected eye through a pars plana incision. (2.1) This case study describes a patient with previously undiagnosed, long-standing VKH, a systemic autoimmune disorder featuring ------ADVERSE REACTIONS ------• RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of • Ocular adverse events included procedural complications, and eye pain (> 50%). 1,2,4 0.6 mcg/day, decreasing over the first month to a steady state between 0.3-0.4 mcg/day a diffuse posterior uveitis that develops into a panuveitis throughout a chronic course. The patient had lost her left-eye vision Thirty-five to forty percent of patients reported ocular/conjunctival hyperemia, over approximately 30 months. (2.1) reduced visual acuity, and conjunctival hemorrhage. (6.1) from secondary glaucoma, and her right-eye vision was imperiled by glaucoma and macular edema secondary to posterior • Aseptic technique should be maintained at all times prior to and during the surgical • The most common non-ocular event reported was headache (33%). (6.2) uveitis. Hypertension precluded aggressive treatment with systemic corticosteroids, and the patient tolerated immunomodulators implantation procedure. (2.2) ------DOSAGE FORMS AND STRENGTHS ------To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated poorly. After her first RETISERT implant, the signs of her posterior segment inflammation resolved for 34 months. After the • 0.59 mg fluocinolone acetonide intravitreal implant. (3) at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. implant’s intended period of drug release had ended and the patient’s uveitis returned, a second implant was placed. In the most See 17 for PATIENT COUNSELING INFORMATION. recent visit, an adherence stoppage in her additional therapy for anterior conditions has been attended by uveitic aggravation, the Revised: 05/2019 exact causes of which need evaluation through further monitoring. However, in the first two follow-ups following placement of the FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS second RETISERT implant, the patient’s uveitis showed renewed signs of improvement. 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.3 Nursing Mothers 2.1 Dosing Information 8.4 Pediatric Use 2.2 Handling of Implant 8.5 Geriatric Use 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION Important Safety Information (cont’d) 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY Use of corticosteroids may result in elevated IOP and/or glaucoma. Based on clinical trials with RETISERT®, within 3 years post-implantation, 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures 12.1 Mechanism of Action • 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures 5.1 Cataract Formation 13 NONCLINICAL TOXICOLOGY to control intraocular pressure. 5.2 Endophthalmitis and Surgical Complications 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.3 Increase in Intraocular Pressure 14 CLINICAL STUDIES • Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of RETISERT®. 5.4 Separation of Implant Components 16 HOW SUPPLIED/STORAGE AND HANDLING Physicians should periodically monitor the integrity of the implant by visual inspection. 5.5 Other Corticosteroid Induced Adverse Reactions 17 PATIENT COUNSELING INFORMATION 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience - Ocular Events • Ocular administration of corticosteroids has been associated with delayed wound healing and perforation of the globe where there is thinning of the sclera. *Sections or subsections omitted from the full prescribing information are not listed 6.2 Clinical Trials Experience - Non-Ocular Events • The most frequently reported ocular adverse events in clinical trials with RETISERT® occurring in 50-90% of patients included: cataract, increased intraocular pressure, procedural complications and eye pain. The most common non-ocular event reported was headache (33%). FULL PRESCRIBING INFORMATION 3 DOSAGE FORMS AND STRENGTHS Please see additional Important Safety Information throughout and full Prescribing Information for RETISERT® on pages 5-7. 1 INDICATIONS AND USAGE 0.59 mg fluocinolone acetonide intravitreal implant. RETISERT is indicated for the treatment of chronic non-infectious uveitis affecting the 4 CONTRAINDICATIONS posterior segment of the eye. References: 1. Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures 2001;131(5):647-652. 2. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol. 1995;39(4):265-292. 3. Baltmr A, Lightman S, Tomkins-Netzer O. Vogt– 2 DOSAGE AND ADMINISTRATION Surgical placement of RETISERT is contraindicated in active viral diseases of the cornea Koyanagi–Harada syndrome – current perspectives. Clin Ophthalmol. 2016;10:2,345-2,361. 4. Damico FM, Bezerra Gaspar Carvalho da Silva FT, Gasparin F, Yamamoto JH. New insights into 2.1 Dosing Information and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg is implanted into the and varicella, and also in active bacterial, mycobacterial or fungal infections of the eye. Vogt-Koyanagi-Harada disease. Arq Bras Oftalmol. 2009;72(3):413-420. 5. Zhao C, Dong F, Gao F, et al. Longitudinal observation of subretinal fibrosis in Vogt-Koyanagi-Harada disease. posterior segment of the affected eye through a pars plana incision. BMC Ophthalmol. 2018;18(1):6. 6. Rao NA, Inomata H. Vogt-Koyanagi-Harada disease. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Saint Louis, MO: Mosby Elsevier; 2009:861-863. 5 WARNINGS AND PRECAUTIONS The implant contains one tablet of 0.59 mg of fluocinolone acetonide. RETISERT is 5.1 Cataract Formation 7. Lavezzo MM, Sakata VM, Morita C, et al. Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes. Orphanet J Rare Dis. 2016;11:29. 8. Lin P. designed to release fluocinolone acetonide at a nominal initial rate of 0.6 mcg/day, Use of corticosteroids may result in posterior subcapsular cataract formation. Infectious uveitis. Curr Ophthalmol Rep. 2015;3(3):170-183. 9. Majumder PD, Sudharshan S, Biswas J. Laboratory support in the diagnosis of uveitis. Indian J Ophthalmol. 2013;61(6):269-276. decreasing over the first month to a steady state between 0.3-0.4 mcg/day over Based on clinical trials with RETISERT, during the 3-year post-implantation period, approximately 30 months. Following depletion of fluocinolone acetonide as evidenced 10. Rao NA, Marak GE Jr. Sympathetic uveitis. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. Saint Louis, MO: Mosby Elsevier; 2009:854-856. 11. RETISERT Prescribing Information. nearly all phakic eyes are expected to develop cataracts and require cataract surgery. Bausch & Lomb Incorporated. by recurrence of uveitis, RETISERT may be replaced. 5.2 Endophthalmitis and Surgical Complications 2.2 Handling of Implant Late onset endophthalmitis has been observed. These events are often related to the Caution should be exercised in handling RETISERT in order to avoid damage to the integrity of the surgical wound site. Careful attention to assure tight closure of the scleral implant, which may result in an increased rate of drug release from the implant. Thus, wound and the integrity of the overlying conjunctiva at the wound site is important. RETISERT should be handled only by the suture tab. Care should be taken during implantation and explantation to avoid sheer forces on the implant that could disengage Potential complications accompanying intraocular surgery to place RETISERT into the the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the vitreous cavity may include, but are not limited to, the following: cataract formation, suture tab. Aseptic technique should be maintained at all times prior to and during the choroidal detachment, endophthalmitis, hypotony, increased intraocular pressure, surgical implantation procedure. exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. RETISERT should not be resterilized by any method.

4 November/December 2020 | Insert to Retina Today November/December 2020 | Insert to Retina Today 5

Untitled-5 5 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 4-5 11/6/20 10:09 AM Following implantation of RETISERT, nearly all patients will experience an immediate and the daily clinical dose of RETISERT), during days 6 to 18 of pregnancy in the rabbit, Fluocinolone acetonide was not genotoxic in vitro in the Ames test, the mouse temporary decrease in visual acuity in the implanted eye which lasts for approximately induced abortion at the end of the third and at the beginning of the fourth gestational lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay. one to four weeks post-operatively. week. When administered subcutaneously to rats and rabbits during gestation at a 14 CLINICAL STUDIES maternal toxic dose of 50 mcg/kg/day (approximately 4,000 times the clinical dose 5.3 Increase in Intraocular Pressure In two randomized, double-masked, multicenter controlled clinical trials, 224 patients of RETISERT), fluocinolone acetonide caused abortions and malformations in a few Prolonged use of corticosteroids may result in elevated IOP and/or glaucoma with with chronic (a one year or greater history) non-infectious uveitis affecting the posterior surviving fetuses. damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should segment of one or both eyes were randomized to receive a 0.59 mg RETISERT. The be used with caution in the presence of glaucoma. Patients must be monitored for There are no adequate and well-controlled studies in pregnant women. RETISERT primary efficacy endpoint in both trials was the rate of recurrence of uveitis affecting elevated IOP. should be used during pregnancy only if the potential benefit justifies the potential risk the posterior segment of the study eye in the 34 week pre-implantation period to the fetus. compared to the rate of recurrence in the 34 week post-implantation period. Uveitis Based on clinical trials with RETISERT, within 3-years post-implantation, approximately recurrence rates at 1, 2, and 3 year post-implantation were also compared to the 34 77% of patients will require IOP lowering medications to control intraocular pressure 8.3 Nursing Mothers week pre-implantation period. and 37% of patients will require filtering procedures to control intraocular pressure [see It is not known whether ocular administration of corticosteroids could result in sufficient Adverse Reactions (6.1)]. systemic absorption to produce detectable quantities in human milk. Systemic Detailed results are shown in Table 1 below: steroids appear in human milk and could suppress growth, interfere with endogenous 5.4 Separation of Implant Components Table 1: Uveitis Recurrence Rates corticosteroid production, or cause other untoward effects. Caution should be exercised In vitro stability studies show that the strength of the adhesive bond between the when RETISERT is implanted in a nursing woman. STUDY 1 STUDY 2 silicone cup reservoir and the suture tab is reduced with prolonged hydration, indicating N=108 N=116 a potential for the separation of these components. The suture tab composition is a 8.4 Pediatric Use TIME POINT silicone elastomer reinforced with a polyester mesh. Physicians should periodically Safety and effectiveness in pediatric patients below the age of 12 years have not Uveitis Recurrence Rates1,2 monitor the integrity of the implant by visual inspection. been established. N (%) 5.5 Other Corticosteroid Induced Adverse Reactions 8.5 Geriatric Use 34 Weeks Pre-implantation 58 (53.7) 46 (39.7) RETISERT should be used with caution in patients with a history of a viral, bacterial, No overall differences in safety and effectiveness have been observed between elderly 34 Weeks Post-implantation 2 (1.8) 15 (12.9) mycobacterial or fungal infection of the cornea and conjunctiva including epithelial and younger patients. 1 Year Post-implantation 4 (3.7) 15 (12.9) herpes simplex keratitis (dendritic keratitis), vaccinia and varicella. Use of ocular steroids 11 DESCRIPTION 2 Years Post-implantation 11 (10.2) 16 (13.8) may prolong the course and may exacerbate the severity of many viral infections of RETISERT® (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant designed the eye (including herpes simplex). Employment of a corticosteroid medication in the 3 Years Post-implantation 22 (20.4) 20 (17.2) to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal treatment of patients with a history of herpes simplex requires great caution. 3 initial rate of 0.6 mcg/day, decreasing over the first month to a steady state between 3 Years Post-implantation 33 (30.6) 28 (24.1) Prolonged use of corticosteroids may suppress the host response and thus increase 0.3-0.4 mcg/day over approximately 30 months. The drug substance is the synthetic 1 the hazard of secondary ocular infections (bacterial, fungal, and viral). In acute purulent corticosteroid fluocinolone acetonide, represented by the following structural formula: Recurrence of uveitis for all post-implantation time points was compared to the conditions of the eye, steroids may mask infection or enhance existing infection. Fungal 34 weeks pre-implantation time point. 2 2 and viral infections of the cornea are particularly prone to develop coincidentally with p-value <0.01 from McNemar’s χ test. 3 long-term application of steroids. The possibility of fungal invasion should be considered Results presented include imputed recurrences. Recurrences were imputed when a in any persistent corneal ulceration where steroid treatment has been used. subject was not seen within 10 weeks of their final scheduled visit. Since resistance to infections is known to be reduced by corticosteroids, simultaneous 16 HOW SUPPLIED/STORAGE AND HANDLING bilateral implantation should not be carried out, in order to limit the potential for bilateral The implant consists of a tablet encased in a silicone elastomer cup containing a post-operative infection. release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The silicone elastomer cup assembly is attached to a silicone elastomer suture Ocular administration of corticosteroids has also been associated with delayed wound tab with silicone adhesive. Each RETISERT is approximately 3 mm x 2 mm x 5 mm. healing and perforation of the globe where there is thinning of the sclera. Each implant is stored in a clear polycarbonate case within a foil pouch within a Tyvek The use of steroids after cataract surgery may delay healing and increase the incidence peelable overwrap. Each packaged implant is provided in a carton which includes the of bleb formation. package insert.

6 ADVERSE REACTIONS C24H30F2O6 Mol. Wt. 452.50 NDC 24208-416-01 0.59 mg 1 count 6.1 Clinical Trials Experience - Ocular Events Chemical Name: Pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy-16,17-[(1- The available safety data includes exposure to RETISERT in patients with chronic Storage: Store in the original container at 15°-25°C (59°-77°F). Protect from freezing. methyl-ethylidene)bis(oxy)],(6α,11β ,16α)-. non-infectious uveitis affecting the posterior segment in two multicenter controlled 17 PATIENT COUNSELING INFORMATION clinical trials. Patients were randomized to dosage regimens of 0.59 mg or 2.1 mg Fluocinolone acetonide is a white crystalline powder, insoluble in water, and soluble in Patients should be advised to have ophthalmologic follow-up examinations of both eyes implants. methanol. It has a melting point of 265-266ºC. at appropriate intervals following implantation of RETISERT. The most frequently reported ocular adverse events were cataract, increased Each RETISERT consists of a tablet containing 0.59 mg of the active ingredient, As with any surgical procedure, there is risk involved. Potential complications intraocular pressure, procedural complication, and eye pain. These events occurred in Fluocinolone Acetonide, USP, and the following inactives: magnesium stearate, accompanying intraocular surgery to place RETISERT into the vitreous cavity may approximately 50 - 90% of patients. Cataract includes aggravated cataract, and posterior microcrystalline cellulose, and polyvinyl alcohol. include, but are not limited to, the following: cataract formation, choroidal detachment, capsular opacification. Procedural complications includes post-op complication, post-op 12 CLINICAL PHARMACOLOGY temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular wound complication, post-op wound site erythema, and wound dehiscense. 12.1 Mechanism of Action pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous Based on clinical trials with RETISERT, during the 3-year post-implantation period, Corticosteroids inhibit the inflammatory response to a variety of inciting agents and hemorrhage, vitreous loss, and wound dehiscence. nearly all phakic eyes are expected to develop cataracts and require cataract surgery. probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary Following implantation of RETISERT, nearly all patients will experience an immediate and IOP lowering medications to lower intraocular pressure were required in approximately dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of temporary decrease in visual acuity in the implanted eye which lasts for approximately 77% of patients; filtering surgeries were required to control intraocular pressure in collagen, and scar formation associated with inflammation. one to four weeks post-operatively. 37% of patients. Ocular adverse events occurring in approximately 10 - 40% of patients There is no generally accepted explanation for the mechanism of action of ocular in decreasing order of incidence were ocular/conjunctival hyperemia, reduced visual Based on clinical trials with RETISERT, within 3 years post-implantation, approximately corticosteroids. However, corticosteroids are thought to act by the induction of acuity, glaucoma, conjunctival hemorrhage, blurred vision, abnormal sensation in the eye, 77% of patients will require IOP lowering medications to control intraocular pressure phospholipase A inhibitory proteins, collectively called lipocortins. It is postulated that eye irritation, maculopathy, vitreous floaters, hypotony, pruritus, ptosis, increased tearing, 2 and 37% of patients will require filtering procedures to control intraocular pressure [see these proteins control the biosynthesis of potent mediators of inflammation such as vitreous hemorrhage, dry eye, eyelid edema, macular edema and visual disturbance. Adverse Reactions (6.1)]. prostaglandins and leukotrienes by inhibiting the release of their common precursor Ocular adverse events occurring in approximately 5 - 9% of patients in decreasing order arachidonic acid. Arachidonic acid is released from membrane phospholipids by Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. of incidence were eye discharge, photophobia, blepharitis, corneal edema, iris adhesions, phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure. choroidal detachment, diplopia, eye swelling, retinal detachment, photopsia, retinal 12.3 Pharmacokinetics Manufactured for: hemorrhage and hyphema. In a subset of patients who received the intravitreal implant, and had blood samples Bausch & Lomb Incorporated 6.2 Clinical Trials Experience - Non-Ocular Events taken at various times (weeks 1, 4 and 34) after implantation, plasma levels of Bridgewater, NJ 08807 USA The most frequently reported non-ocular adverse event was headache (33%). Other non- fluocinolone acetonide were below the limit of detection (0.2 ng/mL) at all times. Aqueous Manufactured by: ocular adverse events occurring in approximately 5-20% of patients in decreasing order of and vitreous humor samples were assayed for fluocinolone acetonide in a further Bausch Health Ireland Limited incidence were nasopharyngitis, arthralgia, sinusitis, dizziness, pyrexia, upper respiratory subset of patients. While detectable concentrations of fluocinolone acetonide were seen d/b/a Bausch & Lomb Ireland tract infection, influenza, vomiting, nausea, cough, back pain, limb pain, and rash. throughout the observation interval (up to 34 months), the concentrations were highly Waterford, Ireland variable, ranging from below the limit of detection (0.2 ng/mL) to 589 ng/mL. 8 USE IN SPECIFIC POPULATIONS Retisert is a trademark of Bausch & Lomb Incorporated or its affiliates. 8.1 Pregnancy 13 NONCLINICAL TOXICOLOGY © 2019 Bausch & Lomb Incorporated or its affiliates No adequate animal reproduction studies have been conducted with fluocinolone 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility acetonide. Corticosteroids are generally teratogenic in laboratory animals when Long-term animal studies have not been performed on RETISERT to evaluate the administered systemically at relatively low dosage levels. Fluocinolone acetonide when carcinogenic potential or the effect on fertility of fluocinolone acetonide. 9028009 administered subcutaneously at a dose of 0.13 mg/kg/day (approximately 10,000 times REF-RET-0173

6 November/December 2020 | Insert to Retina Today November/December 2020 | Insert to Retina Today 7

Untitled-5 6 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 6-7 11/6/20 10:09 AM Following implantation of RETISERT, nearly all patients will experience an immediate and the daily clinical dose of RETISERT), during days 6 to 18 of pregnancy in the rabbit, Fluocinolone acetonide was not genotoxic in vitro in the Ames test, the mouse temporary decrease in visual acuity in the implanted eye which lasts for approximately induced abortion at the end of the third and at the beginning of the fourth gestational lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay. one to four weeks post-operatively. week. When administered subcutaneously to rats and rabbits during gestation at a 14 CLINICAL STUDIES maternal toxic dose of 50 mcg/kg/day (approximately 4,000 times the clinical dose 5.3 Increase in Intraocular Pressure In two randomized, double-masked, multicenter controlled clinical trials, 224 patients of RETISERT), fluocinolone acetonide caused abortions and malformations in a few Prolonged use of corticosteroids may result in elevated IOP and/or glaucoma with with chronic (a one year or greater history) non-infectious uveitis affecting the posterior surviving fetuses. damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should segment of one or both eyes were randomized to receive a 0.59 mg RETISERT. The be used with caution in the presence of glaucoma. Patients must be monitored for There are no adequate and well-controlled studies in pregnant women. RETISERT primary efficacy endpoint in both trials was the rate of recurrence of uveitis affecting elevated IOP. should be used during pregnancy only if the potential benefit justifies the potential risk the posterior segment of the study eye in the 34 week pre-implantation period to the fetus. compared to the rate of recurrence in the 34 week post-implantation period. Uveitis Based on clinical trials with RETISERT, within 3-years post-implantation, approximately recurrence rates at 1, 2, and 3 year post-implantation were also compared to the 34 77% of patients will require IOP lowering medications to control intraocular pressure 8.3 Nursing Mothers week pre-implantation period. and 37% of patients will require filtering procedures to control intraocular pressure [see It is not known whether ocular administration of corticosteroids could result in sufficient Adverse Reactions (6.1)]. systemic absorption to produce detectable quantities in human milk. Systemic Detailed results are shown in Table 1 below: steroids appear in human milk and could suppress growth, interfere with endogenous 5.4 Separation of Implant Components Table 1: Uveitis Recurrence Rates corticosteroid production, or cause other untoward effects. Caution should be exercised In vitro stability studies show that the strength of the adhesive bond between the when RETISERT is implanted in a nursing woman. STUDY 1 STUDY 2 silicone cup reservoir and the suture tab is reduced with prolonged hydration, indicating N=108 N=116 a potential for the separation of these components. The suture tab composition is a 8.4 Pediatric Use TIME POINT silicone elastomer reinforced with a polyester mesh. Physicians should periodically Safety and effectiveness in pediatric patients below the age of 12 years have not Uveitis Recurrence Rates1,2 monitor the integrity of the implant by visual inspection. been established. N (%) 5.5 Other Corticosteroid Induced Adverse Reactions 8.5 Geriatric Use 34 Weeks Pre-implantation 58 (53.7) 46 (39.7) RETISERT should be used with caution in patients with a history of a viral, bacterial, No overall differences in safety and effectiveness have been observed between elderly 34 Weeks Post-implantation 2 (1.8) 15 (12.9) mycobacterial or fungal infection of the cornea and conjunctiva including epithelial and younger patients. 1 Year Post-implantation 4 (3.7) 15 (12.9) herpes simplex keratitis (dendritic keratitis), vaccinia and varicella. Use of ocular steroids 11 DESCRIPTION 2 Years Post-implantation 11 (10.2) 16 (13.8) may prolong the course and may exacerbate the severity of many viral infections of RETISERT® (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant designed the eye (including herpes simplex). Employment of a corticosteroid medication in the 3 Years Post-implantation 22 (20.4) 20 (17.2) to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal treatment of patients with a history of herpes simplex requires great caution. 3 initial rate of 0.6 mcg/day, decreasing over the first month to a steady state between 3 Years Post-implantation 33 (30.6) 28 (24.1) Prolonged use of corticosteroids may suppress the host response and thus increase 0.3-0.4 mcg/day over approximately 30 months. The drug substance is the synthetic 1 the hazard of secondary ocular infections (bacterial, fungal, and viral). In acute purulent corticosteroid fluocinolone acetonide, represented by the following structural formula: Recurrence of uveitis for all post-implantation time points was compared to the conditions of the eye, steroids may mask infection or enhance existing infection. Fungal 34 weeks pre-implantation time point. 2 2 and viral infections of the cornea are particularly prone to develop coincidentally with p-value <0.01 from McNemar’s χ test. 3 long-term application of steroids. The possibility of fungal invasion should be considered Results presented include imputed recurrences. Recurrences were imputed when a in any persistent corneal ulceration where steroid treatment has been used. subject was not seen within 10 weeks of their final scheduled visit. Since resistance to infections is known to be reduced by corticosteroids, simultaneous 16 HOW SUPPLIED/STORAGE AND HANDLING bilateral implantation should not be carried out, in order to limit the potential for bilateral The implant consists of a tablet encased in a silicone elastomer cup containing a post-operative infection. release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The silicone elastomer cup assembly is attached to a silicone elastomer suture Ocular administration of corticosteroids has also been associated with delayed wound tab with silicone adhesive. Each RETISERT is approximately 3 mm x 2 mm x 5 mm. healing and perforation of the globe where there is thinning of the sclera. Each implant is stored in a clear polycarbonate case within a foil pouch within a Tyvek The use of steroids after cataract surgery may delay healing and increase the incidence peelable overwrap. Each packaged implant is provided in a carton which includes the of bleb formation. package insert.

6 November/December 2020 | Insert to Retina Today November/December 2020 | Insert to Retina Today 7

Untitled-5 7 12/4/20 2:23 PM BAUS6856_Retisert_2020_CaseStudy-3_P7.indd 6-7 11/6/20 10:09 AM ™ RETISERT ® PATIENT CASE STUDY SERIES

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