Dexamethasone Intravitreal Implant
Dexamethasone Intravitreal Implant 0.7 mg (OzurdexTM, Allergan®) is a biodegradable corticosteroid intravitreal implant that has been approved by the FDA for treatment of diabetic macular edema (DME), macular edema following a branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO), and posterior segment non-infectious uveitis. It was initially approved in June 2009 for post-CRVO or post-BRVO macular edema. Approval for posterior uveitis was in September 2010, followed by approval for DME in individuals with a pseudophakic or phakic lens in June 2014 with a subsequent revision in September 2014 to DME in the general population.
Ozurdex has been shown to be effective in eyes that have undergone vitrectomy. Typically, intravitreal injections clear too quickly from vitrectomized eyes.
Macular edema occurs following a retinal vein occlusion due to the blockage of blood flow, leading to a buildup of fluid. Retinal vein occlusion can lead to increased retinal capillary pressure, increased vascular permeability, and retinal neovascularization.
Diabetic Macular Edema results from microvascular injury due to elevated glucose levels. The damage to the retinal blood vessels leads to fluid leakage and swelling within the retina.
Uveitis describes a group of ocular inflammatory conditions. Posterior uveitis describes inflammation of the retina or choroid.
Mechanism of Action
Dexamethasone is a corticosteroid, which is a class of anti-inflammatory medications. Because of their anti-inflammatory effects, corticosteroids are a mainstay treatment for macular edema and uveitis.
Corticosteroids inhibit phospholipase A2 which leads to the blockage of the arachidonic acid pathway. Blockage of this pathway leads to decreased synthesis of thromboxanes, leukotrienes, and prostaglandins which are inflammatory mediators. Tight junctions between cells in the retinal capillaries are stabilized as a result, which decreases fluid buildup in the retina and permeability of the vessels.
Intravitreal injections can increase the chances of endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Corticosteroids can increase the risk for cataracts, increase intraocular pressure, glaucoma or infection. The implant could migrate from the posterior chamber to the anterior chamber in the case of a torn posterior lens capsule.
Carcinogenesis/Mutagenesis/Impairment of Fertility
There are limited studies on the carcinogenic effect or effect on fertility of Ozurdex. However, studies have shown that dexamethasone does not have a mutagenic effect on in vitro bacterial or mammalian cells or in vivo mouse cells.
There is limited data and studies on the use of Ozurdex in pregnant women. Animal studies with topical ocular use of dexamethasone showed cleft palate, embryo fetal death, and malformations of the intestines and kidneys. Therefore, caution should be exercised when administering Ozurdex to a pregnant woman.
Systemic use of dexamethasone can lead to corticosteroid secretion in human breast milk. This can affect the infant through growth suppression or interference with endogenous corticosteroid production. However, systemic absorption of intravitreal dexamethasone is low and is therefore not as likely to be secreted in human milk in large amounts. Caution should be exercised.
There is no data regarding the safety and efficacy in pediatric patients.
Contraindications and Adverse Reactions
Patients should not be given Ozurdex if they have an ocular or periocular infection or suspicion of one, advanced glaucoma, a non-intact posterior lens capsule, or hypersensitivity to Ozurdex or any of its contents. Ocular or periocular infections include corneal or conjunctival viral infections, such as herpes simplex keratitis, vaccinia, varicella, mycobacteria, and fungus.
Adverse Reactions include:
- Increased Intraocular Pressure
- Conjunctival hemorrhage
- Eye pain
- Conjunctival hyperemia
- Ocular hypertension
- Vitreous detachment
While uncommon, there has been a report of a fractured implant. It is possible that the implant broke during injection . However, the implant was still functional and stable despite the fracture.
Administration, Dosing, and Preparation
Ozurdex is an intravitreal implant that contains 0.7 mg dexamethasone7. It uses the Novadur® drug delivery system, which contains a poly D,L sustained lactide-co-glycolide (PLGA) polymer matrix that degrades to lactic acid and glycolic acid7. This degradation allows for an extended and slow release of the dexamethasone7. The implant can deliver dexamethasone for up to six months, with a peak effectiveness between 60 and 90 days.
The intravitreal injection should be done under aseptic conditions1. Use of anesthetic and antibiotic medications are recommended prior to injection1. The implant is delivered into the vitreous cavity via a 22-gauge needle. The applicator should be held parallel to the limbus. A shelved scleral path should be created through scleral engagement at an oblique angle with bevel of the needle up. Scleral engagement should be 4 mm away from the limbus and once the needle tip is 1 mm into the sclera, the needle should be repositioned to advance to the center of the eye. The actuator button should be pushed down until a click is heard, and the needle and applicator can then be removed from the eye. It is important to ensure that the actuator button is fully depressed before withdrawal.
Each applicator should only be used once for a single eye. If both eyes need Ozurdex treatment, two applicators and aseptic procedures should be done.
Following BRVO or CRVO In order to evaluate the use of Ozurdex in patients with macular edema following BRVO or CRVO, two identical, multicenter, masked, randomized, 6-month, sham-controlled clinical trials were done. In the two trials which both included patients vision loss from macular edema due to BRVO and patients vision loss from macular edema due to CRVO, there were a total of 1267 patients. The patients were randomized into three cohorts in a 1:1:1 distribution: one group of 427 with a 0.7 mg Dexamethasone implant, one group of 414 with a 0.35 mg Dexamethasone implant, and a sham group of 426.
The percentage of eyes that had a ≥ 15 letter improvement in best-corrected visual acuity (BCVA) was significantly higher in both treatment groups compared to the sham group when evaluated at days 30 to 90. After one administration of the treatment, the time to achieve a ≥ 15 letter improvement in BCVA was less in both treatment groups. Improvement in mean BCVA was greater in both treatment groups, and the percentage of eyes with a ≥ 15 letter loss was significantly lower in the 0.7 group. Improvements were seen in patients with BRVO and patients with CRVO although the pattern differed. The results of these trials demonstrated efficacy of the dexamethasone intravitreal implant.
In order to evaluate the use of Ozurdex in patients with uveitis, a randomized, controlled trial of 229 patients with noninfectious intermediate or posterior uveitis was done. The patients were randomized into 3 cohorts in a 1:1:1 ratio: Dexamethasone Implant 0.7 mg, Dexamethasone Implant 0.35 mg, or sham procedure. The patients were followed for 26 weeks. The patients’ vision were evaluated using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). The questionnaire was done at baseline, week 8, week 16 and week 26. At 8 weeks, the 0.7 group showed significant improvements in near vision, distance vision, peripheral vision, vision-specific social functioning, and composite scare compared to sham. At 26 weeks, the 0.7 mg group showed significant improvements in distance vision, vision-specific role difficulties, vision-specific dependency, vision-specific social function, vision-specific mental health, and composite score compared to sham. The results of this trial demonstrated efficacy of the dexamethasone intravitreal implant.
Diabetic Macular Edema
In order to evaluate the use of Ozurdex in patients with diabetic macular edema (DME), two randomized, multicenter, masked, sham-controlled phase III clinical trials were done. In the two trials, a total of 1048 patients with DME were included. The patients all had a best-corrected visual acuity (BCVA) of 20/50 to 20/200 and a central retinal thickness (CRT) of ≥ 300 μm by optical coherence tomography (OCT). The patients were randomized into three cohorts in a 1:1:1 ratio: Dexamethasone Implant 0.7 mg, Dexamethasone Implant 0.35 mg, or sham procedure. The patients were followed for 36 months, and if they needed to be retreated, they could not be retreated within 6 months of the previous treatment. Patients were followed for 39 months if they were retreated at month 36.
Mean number of treatments were 4.1 for the 0.7 mg group, 4.4 for the 0.35 mg group, and 3.3 for the sham group. The percentage of patients with a ≥ 15 letter improvement in BCVA was 22.2% for the 0.7 mg group, 18.4% for the 0.35 mg group, and 12% for the sham group. Mean reduction in CRT was 111.6 μm in the 0.7 mg group, 107.9 μm in the 0.35 mg group, and 41.9 μm in the sham group. Both the BCVA and CRT improvement were statistically significant when comparing the sham groups and the treatment groups, demonstrating efficacy in treating DME.
- Highlights of Prescribing Information: OzurdexTM (Dexamethasone intravitreal implant 0.7 mg) for intravitreal injection. AccessDataFDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022315s009lbl.pdf. Accessed July 3, 2023.
- Drugs.com. Ozurdex FDA Approval History. Drugs.com. https://www.drugs.com/history/ozurdex.html. Accessed July 3, 2023.
- Haghjou N, Soheilian M, Abdekhodaie MJ. Sustained release intraocular drug delivery devices for treatment of uveitis. J Ophthalmic Vis Res. 2011;6(4):317-329. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306122/. Accessed July 3, 2023.
- Rhoades W, Dickson D, Nguyen QD, Do DV. Management of macular edema due to central retinal vein occlusion- The role of aflibercept. Taiwan J Ophthalmol. 2017;7(2):70-76. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602151/. Accessed July 3, 2023.
- Zur D, Igliki M, Loewenstein A. The role of steroids in the management of diabetic macular edema. Ophthalmic Res. 2019;62(4):231-236. https://karger.com/ore/article/62/4/231/266249/The-Role-of-Steroids-in-the-Management-of-Diabetic. Accessed July 3, 2023.
- Rishi P, Mathur G, Rishi E. Fractured Ozurdex implant in the vitreous cavity. Indian J Ophthalmol. 2012;60(4):337-338. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442483/. Accessed July 3, 2023.
- Kiss S. Sustained-release Corticosteroid Delivery Systems. Retina Today. https://retinatoday.com/articles/2010-may-june/sustained--release-corticosteroid-delivery-systems. Accessed July 3, 2023.
- Haller JA, Bandello F, Belfort Jr. R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Am J Ophthalmol. 2010;117(6):1134-1146. https://www.aaojournal.org/article/S0161-6420(10)00311-8/fulltext#articleInformation. Accessed July 3, 2023.
- Lightman S, Belfort Jr R, Naik R, et al. Vision-related functioning outcomes of dexamethasone intravitreal implant in noninfectious intermediate or posterior uveitis. Investig Ophthalmol Vis Sci. 2013;54:4864-4870. https://iovs.arvojournals.org/article.aspx?articleid=2128552. Accessed July 3, 2023.
- Boyer DS, Yoon YH, Belfort Jr R, et al. Three-year randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Am J Ophthalmol. 2014;121(10):1904-1914. https://www.aaojournal.org/article/S0161-6420(14)00378-9/fulltext. Accessed July 3, 2023.