First approved pharmacotherapy for macular edema following BRVO and CRVO

 A biodegradable dexamethasone implant Drug incorporated into polymer matrix Sustained medication release Polymer matrix gradually breaks down into inert compounds Extruded form is implanted with an applicator – the NOVADUR™ implant  Self-sealing wound

Rod shaped tiny implant 0.45 mm in diameter and 6 mm in length Contains 0.7mg of Dexamethasone (preservative free) Novadur is a proprietary and innovative drug delivery system (DDS). Dexamethasone embedded in an inactive biodegradable PLGA matrix. (60/40 drug/polymer)

Applicator and Applicator and NOVADUR™ implant

Surface Release

Diffusion

Bulk Erosion

Biodegradable Implant Gradually Transforms Into Water and Carbon Dioxide Lactic Acid Glycolic Acid Water and Carbon Dioxide

After 3 Weeks Before Implantation

 Implanted with 22-gauge applicator Through the pars plana  Wound is self-sealing No sutures required  Implant does not need to be sutured into place

Retinal vein occlusion (RVO) 1 Inflammation: a key component in the pathogenesis of retinal disease 1,2 Wet age-related macular degeneration (wet AMD) 2 Diabetic retinopathy (DR)/ diabetic macular edema (DME) 1 Inflammation Neovascularisation Vascular leakage Retinal disease Uveitis 1 1. Johnson MW. Am J Ophthalmol 2009;147:11–21; 2. Nowak JZ. Pharmacol Rep 2006;58:353–63.

Macular Edema  Vasodilation  Leukostasis   Diapedesis  Permeability  Inflammatory proteins Primary Inflammatory Disease  Uveitis Inflammatory Mediator  IL-1, 6, 8  TNF-Alpha Healthy Retinal Microvessel VEGF Vascular Disease  Diabetes  CRVO/ BRVO

 Corticosteroids inhibit the inflammatory response to a variety of inciting agents.  They inhibit the edema formation, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, deposition of collagen, and scar formation associated with inflammation  They inhibit the edema formation, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, deposition of collagen, and scar formation associated with inflammation. They stabilize endothelial cells tight junctions, inhibit the synthesis of VEGF, prostaglandins & other key cytokines.  They stabilize endothelial cells tight junctions, inhibit the synthesis of VEGF, prostaglandins & other key cytokines.

 Arachidonic acid is released from membrane phospholipids by phospholipase A 2.  It is postulated that lipocortins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.  Corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins.

Arachidonic acid Corticosteroids Phospholipase A 2. Prostaglandins Leukotrienes lipocortins

Macular Edema Healthy Retinal Microvessel VEGF  Vasodilation  Leukostasis  Diapedesis  Permeability  Inflammatory proteins Vascular Disease  Diabetes  CRVO/ BRVO Primary Inflammatory Disease  Uveitis Inflammatory Mediator  IL-1  TNF-Alpha Corticosteroids

Table 59-2 Goodman & Gilman 9th Edition *approximated from the literatureCorticosteroid Relative Potencies Cortisone0.8 Cortisol1 Prednisone4 Methylprednisolone5 Triamcinolone5 Fluorination at 9  position increases corticosteroid receptor binding Betamethasone25 Dexamethasone25 Fluocinolone acetonide 25* 25*

 Desired characteristics of an implantable intravitreal drug delivery system Controlled, sustained drug release Simple insertion procedure Biodegradable implant (does not need to be removed) Long-term safety