Fluocinolone Acetonide
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Overview
Fluocinolone acetonide (IluvienTM, Alimera®) is a corticosteroid intravitreal implant that was approved for treatment of diabetic macular edema by the FDA in September 2014 (Food and Drug Administration, USA).[1]
Diabetic Macular Edema (DME) is a leading cause of blindness and a potential complication of diabetes. It results from microvascular damage due hyperglycemia, elevated cholesterol, oxygen free radicals, and advanced glycemic end products. The microvascular damage leads to a decrease in the structural integrity of the blood-retinal barrier, leading to retinal leakage and swelling.[2]
Patient Selection
Iluvien is indicated for patients with diabetic macular edema (DME) who have previously been on a course of corticosteroids. In addition, the patients should not have had a rise in intraocular pressure when taking the corticosteroids.[3]
Mechanism of Action
Fluocinolone acetonide is a corticosteroid. Corticosteroids can decrease edema through affecting intracellular signaling and through stabilizing the structural integrity of the cells.[4]
Corticosteroids inhibit the action of the enzyme phospholipase A2. Inhibition of phospholipase A2 prevents the release of arachidonic acid, which is the precursor to inflammatory mediators such as prostaglandins and leukotrienes. Through blocking the production of these mediators, intracellular signaling that promotes fluid leakage and cellular swelling is decreased, reducing edema.[4]
Corticosteroids also reduce edema through decreasing the paracellular movement of water and solutes by increasing the structure of the tight junctions between cells. Through their effects on adenosine signaling, they can decrease the permeability of the blood-retinal barrier.[4]
Warnings/Precautions
General
Intravitreal Injections increase the risk for endophthalmitis or increased intraocular pressure. Corticosteroids increase the chance for development of a cataract. In addition, they increase the risk for reactivation of ocular herpes simplex. The implant may migrate, particularly in patients with an absent or torn posterior capsule, as this allows access to the anterior chamber.[3]
Carcinogenesis/Mutagenesis/Impairment of Fertility
There are limited studies on the carcinogenic effect or effect on fertility.[3]
Pregnancy
There is limited data regarding the safety of Iluvien in pregnant women. Systemic absorption is minimal but corticosteroids can be teratogenic systemically. Therefore, caution should be exercised when administering Iluvien to pregnant women.[3]
Nursing Mothers
Systemic absorption of fluocinolone acetonide intravitreal injections is minimal. However, systemic corticosteroids do get secreted into human breast milk, affecting the production of corticosteroids and development of the infant. Therefore, while use of Iluvien is not contraindicated in nursing mothers, caution should be exercised.[3]
Pediatric Use
There is no data regarding the safety and efficacy in pediatric patients.[3]
Contraindications and Adverse Reactions
Patients should not be given Iluvien if they have an ocular or periocular infection, glaucoma with a cup to disc ratio greater than 0.8, and hypersensitivity to Iluvien or any of its contents.[3]
The most common adverse reactions reported during the clinical trials were formation of cataracts and elevated intraocular pressure. Other reported adverse effects were eye pain, conjunctival hemorrhage, posterior capsular opacification, eye irritation, vitreous detachment, and myodesopsia.[2]
Administration, Dosing, and Preparation
Iluvien is an intravitreal implant that contains 0.19 mg fluocinolone acetonide. The implant initially releases fluocinolone acetonide at a rate of 0.25 µg/day and it lasts for 36 months.[3]
The intravitreal injection should be done using aseptic procedures. Ideally, the implant should be placed inferior to the optic disc and posterior to the equator of the eye. The injection should enter the conjunctiva and sclera 4 mm inferotemporal from the limbus. Ideally, the conjunctiva should be slightly displaced upon injection so that the needle entry points in the conjunctiva and sclera do not align once released. Care should be taken to ensure that minimal air is injected along with the implant. After the injection, inspection using an indirect ophthalmoscope should be done to ensure the correct placement of the implant.[3]
Clinical Trials
FAME
FAME clinical trials are two Phase III parallel, prospective, randomized, sham injection-controlled, double-masked multicenter trials of 953 patients with diabetic macular edema who had previously been treated with at least 1 laser treatment. The patients were randomized into three cohorts in a 1:2:2 distribution: 185 patients in the sham injection cohort, 375 patients in the low dose (0.2 µg/day) insert cohort, and 393 patients in the high dose (0.5 µg/day) insert cohort. At 24 months, both the percentage of patients in the low and high dose groups that had an improvement in Early Treatment Diabetic Retinopathy Trial (ETDRS) letter score of 15 or more was significantly greater than the percentage of patients in the sham group. 28.7% of patients in the low dose group and 28.6% of patients in the high dose group had an improvement from baseline ETDRS letter score of 15 or more compared to 16.2% in the sham group. Over the course of 24 months, both the low and high dose groups had significant improvement in foveal thickness compared to the sham group.[5]
An additional study that evaluated results at 36 months found continued visual benefits[6]. Post hoc analysis of the data at 36 months demonstrated that the sustained intraocular release of fluocinolone acetonide slows proliferative diabetic retinopathy development and diabetic retinopathy progression[7]. This was determined through a masked reading of fundus photography and fluorescein angiography to determine Diabetic Retinopathy Severity Score grade and retinal perfusion status[7].
Retrospective analysis of visual acuity in the low-dose cohort demonstrated that 85.7% of the patients had an improved or stable best corrected visual acuity (BCVA) over 36 months. Improved BCVA was defined as ≥5 letter improvement and stable was defined as <4 letter improvement or worsening.[8]
PALADIN
PALADIN is a phase 4 open label single group assignment study of 95 patients, who received Iluvien (Fluocinolone Acetonide Intravitreal Implant 0.19 mg). In this study, there were a total of 115 study eyes. The goal of the study was to evaluate the intraocular pressure to observe any effect that the Iluvien implant may have. Patients were followed for 36 months prior to the implant and for 24 months following the implant. The study found that mean intraocular pressure remained stable through the pre-implant and post-implant time periods. Prior to the implant, 2 procedures were done to lower intraocular pressure. Post implant, 6 procedures were done to lower intraocular pressure.[9]
NEW DAY
NEW DAY is a randomized, double masked, controlled, parallel-group, multi-center study of 300 patients with Diabetic Macular Edema who have never been treated or have not been treated in greater than 12 months. If the patient has been treated previously, they will be excluded if they have received greater than 4 intravitreal injections. The patients will be grouped into two cohorts: those who will receive the Iluvien 0.19 mg intravitreal implant followed by additional aflibercept (2 mg/0.05 mL) as needed and those who will receive intravitreal aflibercept injections (5 doses of 2 mg every 4 weeks) followed by additional aflibercept (2 mg/0.05 mL) as needed. This study will evaluate the mean total number of supplemental aflibercept injections needed as the primary measure. Other measures to be evaluated include best corrected visual acuity and center subfield thickness. This study is estimated to be completed in June 2024.[10]
References
- ↑ Billing and Coding: FDA approves Iluvien for Diabetic Macular Edema. CMS.gov. https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleId=54750#:~:text=On%20September%2026%2C%202014%2C%20The,clinically%20significant%20rise%20in%20intraocular. Accessed June 25, 2023
- ↑ 2.0 2.1 Habib, MS. ILUVIEN technology in the treatment of center-involving diabetic macular edema: a review of the literature. Ther Deliv. 2018;9(4). doi:10.4155/tde-2018-0006
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Highlights of Prescribing Information: IluvienTM (Fluocinolone acetonide intravitreal implant 0.19 mg) for intravitreal injection. AccessDataFDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/201923s000lbl.pdf. Accessed June 25, 2023.
- ↑ 4.0 4.1 4.2 Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of corticosteroids for diabetic macular edema. Investig Ophthalmol Vis Sci. 2018;59(1):1-12. doi:10.1167/iovs.17-22259
- ↑ Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635. doi:10.1016/j.ophtha.2010.12.028
- ↑ Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125-2132. doi:10.1016/j.ophtha.2012.04.030
- ↑ 7.0 7.1 Wykoff CC, Chakravarth U, Campochiaro PA, et al. Long-term effects of intravitreal 0.19 mg fluocinolone acetonide implant on progression and regression of diabetic retinopathy. Ophthalmology. 2017;124(4):440-449. doi:10.1016/j.ophtha.2016.11.034
- ↑ John VJ. Early versus long-term changes in visual acuity (VA) with continuous 0.2 µg/day fluocinolone acetonide (FAc) microdosing. Investig Ophthalmol Vis Sci. 2017;58(8):915.
- ↑ Mansour SE, Kiernan DF, Roth DB. Two-year interim safety results of the 0.2 µg/day fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema: the observational PALADIN study. Br J Ophthalmol. 2021;105(3):414-419. doi:10.1136/bjophthalmol-2020-315984
- ↑ A study of intravitreal ILUVIEN implant as Baseline Therapy in Patients with Early Diabetic Macular Edema (DME) (NEW DAY). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04469595?cond=Diabetic%20Macular%20Edema&intr=Iluvien%200.19%20MG%20Drug%20Implant&rank=1. Accessed June 25, 2023.
