OZURDEX

1 INDICATIONS AND USAGE OZURDEX is a corticosteroid indicated for: The treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) ( 1.1 ) The treatment of non-infectious uveitis affecting the posterior segment of the eye ( 1.2 ) The treatment of diabetic macular edema ( 1.3 ) 1.1 Retinal Vein Occlusion OZURDEX ® (dexamethasone intravitreal implant) is indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). 1.2 Posterior Segment Uveitis OZURDEX is indicated for the treatment of non-infectious uveitis affecting the posterior segment of the eye. 1.3 Diabetic Macular Edema OZURDEX is indicated for the treatment of diabetic macular edema.

2 DOSAGE AND ADMINISTRATION For ophthalmic intravitreal injection. ( 2.1 ) The intravitreal injection procedure should be carried out under controlled aseptic conditions. ( 2.2 ) Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. ( 2.2 ) 2.1 General Dosing Information For ophthalmic intravitreal injection. 2.2 Administration The intravitreal injection procedure should be carried out under controlled aseptic conditions which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide applied to the periocular skin, eyelid and ocular surface are recommended to be given prior to the injection. Remove the foil pouch from the carton and examine for damage. Then, open the foil pouch over a sterile field and gently drop the applicator on a sterile tray. Perform a detailed visual inspection of the applicator, including ensuring that the actuator button has not been depressed, and the safety tab is in place. Carefully remove the plastic safety cap taking care to avoid contacting the needle tip. Inspect the needle tip for damage prior to use; the implant retention plug may be visible in the bevel and should not be removed. Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not twist or flex the tab. The long axis of the applicator should be held parallel to the limbus, and the sclera should be engaged at an oblique angle with the bevel of the needle up (away from the sclera) to create a shelved scleral path. The tip of the needle is advanced within the sclera for about 1 mm (parallel to the limbus), then re-directed toward the center of the eye and advanced until penetration of the sclera is completed and the vitreous cavity is entered. The needle should not be advanced past the point where the sleeve touches the conjunctiva. Slowly depress the actuator button until an audible and/or palpable click is noted. Before withdrawing the applicator from the eye, make sure that the actuator button is fully depressed and has locked flush with the applicator surface. Remove the needle in the same direction as used to enter the vitreous. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay. Each applicator can only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new applicator must be used, and the sterile field, syringe, gloves, drapes, and eyelid speculum should be changed before OZURDEX is administered to the other eye.

4 CONTRAINDICATIONS Ocular or periocular infections ( 4.1 ) Glaucoma ( 4.2 ) Torn or ruptured posterior lens capsule ( 4.3 ) Hypersensitivity ( 4.4 ) 4.1 Ocular or Periocular Infections OZURDEX (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. 4.2 Glaucoma OZURDEX is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8. 4.3 Torn or Ruptured Posterior Lens Capsule OZURDEX is contraindicated in patients whose posterior lens capsule is torn or ruptured because of the risk of migration into the anterior chamber. Laser posterior capsulotomy in pseudophakic patients is not a contraindication for OZURDEX use. 4. 4 Hypersensitivity OZURDEX is contraindicated in patients with known hypersensitivity to any components of this product [see Adverse Reactions ( 6 )] .

5 WARNINGS AND PRECAUTIONS Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. ( 5.1 ) Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. ( 5.2 ) 5.1 Intravitreal Injection-related Effects Intravitreal injections, including those with OZURDEX, have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection [see Patient Counseling Information ( 17 )] . 5.2 Steroid-related Effects Use of corticosteroids including OZURDEX may produce posterior subcapsular cataracts, increased intraocular pressure, and glaucoma. Use of corticosteroids may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses [see Adverse Reactions ( 6.1 )] . Corticosteroids are not recommended to be used in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection.

6 ADVERSE REACTIONS In controlled studies, the most common adverse reactions reported by 20–70% of patients were cataract, increased intraocular pressure and conjunctival hemorrhage. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Figure 1: Mean IOP during the study 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse reactions associated with ophthalmic steroids including OZURDEX include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. Retinal Vein Occlusion and Posterior Segment Uveitis The following information is based on the combined clinical trial results from 3 initial, randomized, 6-month, sham-controlled studies (2 for retinal vein occlusion and 1 for posterior segment uveitis): Table 1: Adverse Reactions Reported by Greater than 2% of Patients MedDRA Term OZURDEX N=497 (%) Sham N=498 (%) Intraocular pressure increased 125 (25%) 10 (2%) Conjunctival hemorrhage 108 (22%) 79 (16%) Eye pain 40 (8%) 26 (5%) Conjunctival hyperemia 33 (7%) 27 (5%) Ocular hypertension 23 (5%) 3 (1%) Cataract 24 (5%) 10 (2%) Vitreous detachment 12 (2%) 8 (2%) Headache 19 (4%) 12 (2%) Increased IOP with OZURDEX peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX required surgical procedures for management of elevated IOP. Following a second injection of OZURDEX in cases where a second injection was indicated, the overall incidence of cataracts was higher after 1 year. In a 2 year observational study, among patients who received >2 injections, the most frequent adverse reaction was cataract 54% (n= 96 out of 178 phakic eyes at baseline). Other frequent adverse reactions from the 283 treated eyes, regardless of lens status at baseline, were increased IOP 24% (n = 68) and vitreous hemorrhage 6.0% (n = 17). Diabetic Macular Edema The following information is based on the combined clinical trial results from 2 randomized, 3-year, sham-controlled studies in patients with diabetic macular edema. Discontinuation rates due to the adverse reactions listed in Table 2 were 3% in the OZURDEX group and 1% in the Sham group. The most common ocular (study eye) and non-ocular adverse reactions are shown in Tables 2 and 3: Table 2: Ocular Adverse Reactions Reported by ≥ 1% of Patients and Non-ocular Adverse Reactions Reported by ≥ 5% of Patients MedDRA Term OZURDEX N=324 (%) Sham N=328 (%) Ocular Cataract 1 166/243 2 (68%) 49/230 (21%) Conjunctival hemorrhage 73 (23%) 44 (13%) Visual acuity reduced 28 (9%) 13 (4%) Conjunctivitis 19 (6%) 8 (2%) Vitreous floaters 16 (5%) 6 (2%) Conjunctival edema 15 (5%) 4 (1%) Dry eye 15 (5%) 7 (2%) Vitreous detachment 14 (4%) 8 (2%) Vitreous opacities 11 (3%) 3 (1%) Retinal aneurysm 10 (3%) 5 (2%) Foreign body sensation 7 (2%) 4 (1%) Corneal erosion 7 (2%) 3 (1%) Keratitis 6 (2%) 3 (1%) Anterior Chamber Inflammation 6 (2%) 0 (0%) Retinal tear 5 (2%) 2 (1%) Eyelid ptosis 5 (2%) 2 (1%) Non-ocular Hypertension 41 (13%) 21 (6%) Bronchitis 15 (5%) 8 (2%) 1 Includes cataract, cataract nuclear, cataract subcapsular, lenticular opacities in patients who were phakic at baseline. Among these patients, 61% of OZURDEX subjects vs. 8% of sham-controlled subjects underwent cataract surgery. 2 243 of the 324 OZURDEX subjects were phakic at baseline; 230 of 328 sham-controlled subjects were phakic at baseline. Increased Intraocular Pressure Table 3: Summary of Elevated Intraocular Pressure (IOP) Related Adverse Reactions IOP Treatment: N (%) OZURDEX N=324 Sham N=328 IOP elevation ≥10 mm Hg from Baseline at any visit 91 (28%) 13 (4%) ≥30 mm Hg IOP at any visit 50 (15%) 5 (2%) Any IOP lowering medication 136 (42%) 32 (10%) Any surgical intervention for elevated IOP * 4 (1.2%) 1 (0.3%) * OZURDEX: 1 surgical trabeculectomy for steroid-induced IOP increase, 1 surgical trabeculectomy for iris neovascularization, 1 laser iridotomy, 1 surgical iridectomy Sham: 1 laser iridotomy The increase in mean IOP was seen with each treatment cycle, and the mean IOP generally returned to baseline between treatment cycles (at the end of the 6 month period) shown below: Figure 1: Mean IOP during the study Cataracts and Cataract Surgery At baseline, 243 of the 324 OZURDEX subjects were phakic; 230 of 328 sham-controlled subjects were phakic. The incidence of cataract development in patients who had a phakic study eye was higher in the OZURDEX group (68%) compared with Sham (21%). The median time of cataract being reported as an adverse event was approximately 15 months in the OZURDEX group and 12 months in the Sham group. Among these patients, 61% of OZURDEX subjects vs. 8% of sham-controlled subjects underwent cataract surgery, generally between Month 18 and Month 39 (Median Month 21 for OZURDEX group and 20 for Sham) of the studies. 6.2 Postmarketing Experience The following reactions have been identified during post-approval use of OZURDEX in clinical practice. Because they are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to OZURDEX, or a combination of these factors, include: complication of device insertion resulting in ocular tissue injury including sclera, subconjunctiva, lens and retina (implant misplacement), device dislocation with or without corneal edema/corneal decompensation, endophthalmitis, hypotony of the eye (associated with vitreous leakage due to injection), and retinal detachment.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with OZURDEX in pregnant women. Topical ocular administration of dexamethasone in mice and rabbits during the period of organogenesis produced cleft palate and embryofetal death in mice, and malformations of the abdominal wall/intestines and kidneys in rabbits at doses 5 and 4 times higher than the recommended human ophthalmic dose (RHOD) of OZURDEX (0.7 milligrams dexamethasone), respectively. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Topical ocular administration of 0.15% dexamethasone (0.75 mg/kg/day) on gestational days 10 to 13 produced embryofetal lethality and a high incidence of cleft palate in mice. A dose of 0.75 mg/kg/day in the mouse is approximately 5 times an OZURDEX injection in humans (0.7 mg dexamethasone) on a mg/m 2 basis. In rabbits, topical ocular administration of 0.1% dexamethasone throughout organogenesis (0.20 mg/kg/day, on gestational day 6 followed by 0.13 mg/kg/day on gestational days 7-18) produced intestinal anomalies, intestinal aplasia, gastroschisis and hypoplastic kidneys. A dose of 0.13 mg/kg/day in the rabbit is approximately 4 times an OZURDEX injection in humans (0.7 mg dexamethasone) on a mg/m 2 basis. A no-observed-adverse-effect-level (NOAEL) was not identified in the mouse or rabbits studies.