Chapter 31
Sustained-Release Drug Delivery Implants
Intraocular sustained-release drug delivery implants are classified into (1) free-floating, (2) non-refillable scleral-fixated, and (3) refillable scleral-fixated implants.
Free floating devices include Ozurdex® (Allergan Inc./AbbVie, Irvine, CA, USA), Illuvien® (Alimera Sciences Inc., Alpharetta, CA, USA), and Yutiq™ (EyePoint Pharmaceuticals, Inc. MA, USA). These are further categorized as biodegradable (Ozurdex®) and non-biodegradable (Illuvien® and Yutiq™).
Ozurdex® (dexamethasone 700 µg/implant) has been approved for use in diabetic macular oedema (DMO)[1] and macular oedema secondary to retinal vein occlusion (RVO)[2] and non-infectious posterior uveitis.[3] The implant is pre-loaded in a 22-gauge applicator which is injected via a shelved scleral tunnel technique to minimise vitreous prolapse. Biodegradable implants demonstrate efficacy for 3-6 months and follow an exponential decrease in their drug concentration.
Illuvien® (fluocinolone acetonide 0.19 mg/insert) was approved by the Food and Drug Administration (FDA) in 2014 for DMO based on the FAME study.[4] It demonstrates efficacy for 2-3 years and follows a linear decrease in the drug concentration providing 0.25 µg of fluocinolone acetonide daily over 36 months.
Yutiq™ (fluocinolone acetonide 0.18 mg/insert) has been approved by the FDA for non-infectious posterior uveitis.[5] It provides 0.25 µg of fluocinolone acetonide daily over 36 months. Both Illuvien® and Yutiq™ are injected via a pre-loaded device through a 25-gauge needle placed perpendicular to the sclera through the pars plana.
With all intraocular steroid implants, patients should be reviewed within 1 week and again at 12 weeks to monitor treatment effect and detect any clinically significant IOP rise.
All free-floating implants are contraindicated in patients with a torn or ruptured posterior lens capsule due to the risk of anterior segment migration. Other contraindications include active ocular or periocular infection and advanced glaucoma.
Boyer DS, Yoon YH, Belfort R, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014; 121(10):1904-14.
Haller JA, Bandello F, Belfort R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117(6):1134-1146.
Lowder C, Belfort R, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129(5):545-53.
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.e2.
Jaffe GJ, Pavesio CE, Study Investigators. Effect of a fluocinolone acetonide insert on recurrence rates in noninfectious intermediate, posterior, or panuveitis: three-year results. Ophthalmology. 2020;127(10):1395-1404.
Retisert® (Bausch & Lomb, Rochester, NY, USA) is a non-biodegradable, non-refillable scleral-fixated device containing 0.59 mg of fluocinolone acetonide which lasts for 2-3 years. Although this device remains in the vitreous cavity without degrading, 0.6 µg of fluocinolone acetonide is released daily over the first month following by 0.3 µg /day over the following 30-36 months. Retisert® was approved by the FDA in 2005 for non-infectious posterior uveitis based on the MUST trial.[6] Retisert® surgery requires the insertion of a 25-gauge infusion line, especially in a vitrectomised eye or when an old Retisert needs to be removed. A localised conjunctival peritomy in the inferotemporal or inferonasal quadrant is then performed. A double-armed 8-0 Prolene suture is passed through the anchoring strut of the implant and tied over with a single knot. At 4.0 mm posterior to the limbus, a 20-gauge MVR blade is used to enter the sclera at a site known to be free from peripheral traction, detachment or snow banking, and where the overlying conjunctiva is healthy. The incision is enlarged and prolapsed vitreous is excised. Bridging uveal tissue should be cut to avoid suprachoroidal placement, the use of diathermy or laser here will limit haemorrhage. The strut is then held with a needle holder and inserted into the eye with the drug tablet facing the front of the eye, taking care not to damage the membrane covering. Each needle on the double-armed 8-0 Prolene is passed through each lip of the scleral incision securing the strut deep in the wound. The ends of the 8-0 Prolene are left long. These are flattened against the sclera by adjacent interrupted 9-0 Prolene sutures placed on either side of the 8-0 Prolene anchoring suture. The knots of these 9-0 Prolene sutures are rotated and the wound should be inspected to ensure that no part of the implant strut is visible. Binocular indirect ophthalmoscopy (BIO) is then performed to visualise the correct position of the implant prior to closure of the conjunctiva. The infusion can be removed after ensuring there is an adequate seal to maintain intraocular pressure.
Vitrasert® (Bausch & Lomb, Rochester, NY, USA), another non-biodegradable implant, releases ganciclovir for the sustained treatment of cytomegalovirus (CMV) retinitis. This implant contains 4.5 mg of ganciclovir and is surgically fixed to the pars plana. It delivers ganciclovir at 1 µg /hour into the vitreous for 6-8 months. Further treatment requires replacement of the implant or implanting an additional one.[7,8] The Vitrasert® implant is no longer routinely used in clinical practice. The implant procedure for Vitrasert® is similar to Retisert® described above.
A scleral-fixated implant which releases ciliary neurotrophic factor (CNTF) (NT-501, Neurotech USA, Cumberland, Rhode Island, USA) has been used in phases 1-3 clinical trials for macular telangiectasia type.[2,9] This implant, which is surgically anchored to the sclera, contains genetically modified retinal pigment epithelial (RPE) cells. CNTF produced by the modified RPE cell line can diffuse into the vitreous cavity via a membrane which also serves as a barrier preventing an immunological reaction to these RPE cells. Whilst the procedure is similar to Retisert® implantation there are notable exceptions. The CNTF implant is transported in a warm culture medium and cannot be exposed to air for more than 2 minutes, nor can it come into contact with absorbent material. Thus, the scleral incision is made prior to opening the packaging and a device gripper is used to hold the implant via the anchor loop whilst a double-armed 9-0 Prolene anchoring suture is tied with two single throws. These 9-0 Prolene suture arms are tied to the sclerostomy edges at 90% depth (3-1-1) ensuring the loop is not visible and the implant is pointing away from the phakic lens. The long ends of the 9-0 Prolene anchoring sutures are flattened against sclera by adjacent 9-0 nylon sutures which also help to close the sclerostomy wound. Prior to closure of the peritomy, implant position is inspected with BIO to ensure there is no lens touch.
Altaweel MM, Holbrook JT, Jabs DA, et al. Randomized Comparison of Systemic Anti-inflammatory Therapy Versus Fluocinolone Acetonide Implant for Intermediate, Posterior and Panuveitis: The Multicenter Uveitis Steroid Treatment Trial. Ophthalmology 2011;118(10):1916-1926.
Martin DF, Ferris FL, Parks DJ, et al. Ganciclovir implant exchange: timing, surgical procedure, and complications. Arch Ophthalmol 1997;115:1389–1394.
Morley MG, Duker JS, Ashton P, Robinson MR. Replacing ganciclovir implants. Ophthalmology 1995;102:388–392.
Haller JA, Bandello F, Belfort R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117(6):1134-1146.
Chew EY, Clemons TE, Jaffe GJ, et al. Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in Patients with Macular Telangiectasia Type 2: A Randomized Clinical Trial. Ophthalmology 2019;126(4):540-549.
The Port Delivery System (PDS) is a refillable scleral-fixated implant. The PDS with 100mg/ml ranibizumab (Susvimo™, Genentech, USA) was approved by the FDA in October 2022 for the management of neovascular age-related macular degeneration (nAMD) in eyes with at least two prior anti-vascular endothelial growth factor (anti-VEGF) injections. Efficacy of the PDS in nAMD was demonstrated in the ARCHWAY study.[10]
Pre-operative assessment with fluorescein should be performed for patients considering the PDS. This must include a thorough anterior and dilated posterior segment examination to ensure the conjunctiva and sclera are not compromised. PDS implant surgery requires meticulous dissection and closure of the conjunctiva and Tenon’s capsule. After insertion of a 25-gauge infusion line, a 6x6 mm peritomy is created superotemporally. A 3.5 mm sclerostomy is performed, with haemostasis of the uveal bed using a 532 nm endolaser probe applied as a contiguous burn at 300 mW and 1000 ms duration. Once the pars plana is incised, a 10 second pause allows for the detection and treatment of any slow bleeding. The PDS, loaded on the insertion tool carrier, is inserted through the sclerostomy until the tool gripper tips abut the sclera. If the scleral incision is greater than 3.5mm implant dislocation and movement may occur. Tenon’s and the conjunctiva are closed carefully over the PDS, ensuring there is no tension which could promote exposure or extrusion of the device.[11,12
]
Refill-exchange can occur via the self-sealing silicone septum (1mm) using a 34G dual-bore needle connected to a 1ml syringe allowing for the simultaneous injection of 0.1ml ranibizumab, and removal of the spent solution in the PDS reservoir.[13] Ranibizumab is injected with five times the volume (0.1ml) of the reservoir (0.02ml) to ensure complete replacement of the spent solution. Prior to refilling, topical or subconjunctival anaesthesia (away from the implant) is given followed by povidone-iodine to the periocular skin, eyelid and ocular surface. A speculum should be inserted, and a 19-gauge filter needle is used to transfer ranibizumab from the nonsterile vial to the syringe which is then replaced by a refill needle. The plunger is advanced to the 0.1ml mark. Now the ranibizumab must be used within 15 minutes of adjusting the drug volume to avoid the drug drying in the needle and impeding flow during the refill process. No air bubbles can be present in the needle or syringe. The refill needle is aimed perpendicular to the septum for entry. A soft stop occurs when the refill needle contacts the patient’s conjunctiva. The syringe is injected over 5-10 seconds. A fluid-filled bleb during or after refill-exchange must prompt a check for a seidel positive leak.
The phase 2, multicenter, randomised, active treatment-controlled clinical trial of the ranibizumab-loaded PDS (LADDER) showed similar visual outcomes between monthly intravitreal injections and the PDS 100mg/ml.[14] The time to initial refill was 15 months in the 100mg/ml group. A phase 3 trial for nAMD (ARCHWAY10) has been completed whilst those for diabetic retinopathy (PAVILION, NCT04503551) and DMO (PAGODA, NCT04108156) are ongoing. There are ongoing trials for nAMD (VELODROME, NCT04657289; PORTAL, NCT03683251) comparing 36- to 24-weekly refill. A prospective real-world study is also underway (VOYAGER, NCT05476926).
Post-operatively clinicians must perform regular and careful examination of the conjunctiva, sclera and retina to check all parts of the implant are intact and there is no lens trauma, vitreous haemorrhage (VH), retinal tears or retinal detachment (RD). Signs of conjunctival erosion, fibrosis, and retraction should be noted given the risk of endophthalmitis. Particular attention should be placed on the PDS septum which must be perpendicular in an intact implant. If the septum is dislodged no refill-exchange procedures should be performed. Transillumination through the pupil can be used to visualise the septum. All patients should be advised to avoid eye rubbing.
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Westmead Eye Manual
This invaluable open-source textbook for eye care professionals summarises the steps ophthalmologists need to perform when examining a patient.
