ILUVIEN

ILUVIEN is a sterile non-bioerodable intravitreal implant containing 0.19 mg (190 mcg) fluocinolone acetonide in a 36-month sustained-release drug delivery system. ILUVIEN is designed to release fluocinolone acetonide at an initial rate of 0.25 mcg/day. ILUVIEN is preloaded into a single-use applicator to facilitate injection of the implant directly into the vitreous. The drug substance is a synthetic corticosteroid, fluocinolone acetonide. The chemical name for fluocinolone acetonide is (6α,11β, 16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis-(oxy)]-pregna-1,4-diene-3,20-dione. Its chemical structure is: MW 452.50; molecular formula C 24 H 30 F 2 0 6 Fluocinolone acetonide is a white or almost white, microcrystalline powder, practically insoluble in water, soluble in methanol, ethanol, chloroform and acetone, and sparingly soluble in ether. Each ILUVIEN consists of a light brown 3.5mm x 0.37mm implant containing 0.19 mg of the active ingredient fluocinolone acetonide and the following inactive ingredients: polyimide tube, polyvinyl alcohol, silicone adhesive and water for injection. iluvien-figure-3

ILUVIEN is a corticosteroid indicated for: the treatment of diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. (1.1) the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. (1.2) 1.1 Diabetic Macular Edema ILUVIEN ® is indicated for the treatment of diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. 1.2 Chronic Non-Infectious Uveitis Affecting the Posterior Segment ILUVIEN ® is indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.

For ophthalmic intravitreal injection. (2.1) The intravitreal injection procedure should be carried out under 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. The initial prescription and renewal of the medication order of ILUVIEN should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy, and, where appropriate, fluorescein staining. 2.2 Administration The intravitreal injection procedure should be carried out under aseptic conditions, which include use of sterile gloves, a sterile drape, a sterile caliper, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection. The injection procedure for ILUVIEN is as follows: The exterior of the tray should not be considered sterile. An assistant (non-sterile) should remove the tray from the carton and examine the tray and lid for damage. If damaged, do not use unit. If acceptable, the assistant should peel the lid from the tray without touching the interior surface. Visually check through the viewing window of the preloaded applicator to ensure that there is a drug implant inside. Remove the applicator from the tray with sterile gloved hands touching only the sterile interior tray surface and applicator. Prior to injection, the applicator tip must be kept above the horizontal plane to ensure that the implant is properly positioned within the applicator. To reduce the amount of air administered with the implant, the administration procedure requires two steps. Before inserting the needle into the eye, remove the protective cap then gently push the applicator button down and slide it to the first stop (at the curved black marks alongside the button track). At the first stop, release the button and it should move to the UP position. If the button does not rise to the UP position, do not proceed with this unit. Optimal placement of the implant is inferior to the optic disc and posterior to the equator of the eye. Measure 4 millimeters inferotemporal from the limbus with the aid of calipers for point of entry into the sclera. Inspect the tip of the needle to ensure it is not bent. Gently displace the conjunctiva so that after withdrawing the needle, the conjunctival and scleral needle entry sites will not align. Care should be taken to avoid contact between the needle and the lid margin or lashes. Insert the needle through the conjunctiva and sclera. To release the implant, while the button is in the UP position, advance the button by sliding it forward to the end of the button track and remove the needle. Note: Ensure that the button reaches the end of the track before removing the needle. Remove the lid speculum and perform indirect ophthalmoscopy to verify placement of the implant, adequate central retinal artery perfusion and absence of any other complications. Following the injection, patients should be monitored for change 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 without delay any symptoms suggestive of endophthalmitis.

Ocular or Periocular Infections (4.1) Glaucoma (4.2) Hypersensitivity (4.3) 4.1 Ocular or Periocular Infections ILUVIEN is contraindicated in patients with active or suspected ocular or periocular infections including most viral disease of the cornea and conjunctiva including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections and fungal diseases. 4.2 Glaucoma ILUVIEN is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8. 4.3 Hypersensitivity ILUVIEN is contraindicated in patients with known hypersensitivity to any components of this product.

The most common adverse reactions reported are cataract development and increases in intraocular pressure. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alimera Sciences, Inc. at 1-844-445-8843 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions associated with ophthalmic steroids including ILUVIEN include cataract formation and subsequent cataract surgery, elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. Diabetic Macular Edema ILUVIEN was studied in two multicenter, randomized, sham-controlled, double-masked trials in which patients with diabetic macular edema (DME) were treated with either ILUVIEN (n=375) or sham (n=185). Table 1 summarizes safety data available when the last subject completed the last 36 month follow up visit for the two primary ILUVIEN trials. In these trials, subjects were eligible for retreatment no earlier than 12 months after study entry. Over the three year follow up period, approximately 75% of the ILUVIEN treated subjects received only one ILUVIEN implant. The most common ocular (study eye) and non-ocular adverse reactions are shown in Tables 1 and 2 : Table 1: Ocular Adverse Reactions Reported by ≥1% of DME Patients and Non-ocular Adverse Reactions Reported by ≥5% of DME Patients 1 Includes cataract, cataract nuclear, cataract subcapsular, cataract cortical and cataract diabetic in patients who were phakic at baseline. Among these patients, 80% of ILUVIEN subjects vs. 27% of sham-controlled subjects underwent cataract surgery. 2 235 of the 375 ILUVIEN subjects were phakic at baseline; 121 of 185 sham-controlled subjects were phakic at baseline. Adverse Reactions ILUVIEN (N=375) n (%) Sham (N=185) n (%) Ocular Cataract 1 192/235 2 (82%) 61/121 2 (50%) Myodesopsia 80 (21%) 17 (9%) Eye pain 57 (15%) 25 (14%) Conjunctival haemorrhage 50 (13%) 21 (11%) Posterior capsule opacification 35 (9%) 6 (3%) Eye irritation 30 (8%) 11 (6%) Vitreous detachment 26 (7%) 12 (7%) Conjunctivitis 14 (4%) 5 (3%) Corneal oedema 13 (4%) 3 (2%) Foreign body sensation in eyes 12 (3%) 4 (2%) Eye pruritus 10 (3%) 3 (2%) Ocular hyperaemia 10 (3%) 3 (2%) Optic atrophy 9 (2%) 2 (1%) Ocular discomfort 8 (2%) 1 (1%) Photophobia 7 (2%) 2 (1%) Retinal exudates 7 (2%) 0 (0%) Anterior chamber cell 6 (2%) 1 (1%) Eye discharge 6 (2%) 1 (1%) Non-ocular Anemia 40 (11%) 10 (5%) Headache 33 (9%) 11 (6%) Renal Failure 32 (9%) 10 (5%) Pneumonia 28 (7%) 8 (4%) Increased Intraocular Pressure (IOP) in DME Patients Table 2: Summary of Elevated IOP Related Adverse Reactions in DME Patients Event ILUVIEN (N=375) n (%) Sham (N=185) n (%) IOP elevation ≥ 10 mmHg from Baseline 127 (34%) 18 (10%) IOP elevation ≥ 30 mmHg 75 (20%) 8 (4%) Any IOP-lowering medication 144 (38%) 26 (14%) Any surgical intervention for elevated intraocular pressure 18 (5%) 1 (1%) Figure 1: Mean IOP in DME Patients Cataracts and Cataract Surgery in DME Patients In the DME studies at baseline, 235 of the 375 ILUVIEN subjects were phakic; 121 of 185 sham-controlled subjects were phakic. The incidence of cataract development in patients who had a phakic study eye was higher in the ILUVIEN group (82%) compared with Sham (50%). The median time of cataract being reported as an adverse event was approximately 12 months in the ILUVIEN group and 19 months in the Sham group. Among these patients, 80% of ILUVIEN subjects vs. 27% of sham-controlled subjects underwent cataract surgery, generally within the first 18 months (Median Month 15 for both ILUVIEN group and for Sham) of the studies. Chronic Non-Infectious Uveitis Affecting the Posterior Segment of the Eye Studies 1 and 2 were multicenter, randomized, sham injection-controlled, double-masked trials in which patients with non-infectious uveitis affecting the posterior segment of the eye were treated once with either fluocinolone acetonide intravitreal implant or sham injection, and then received standard care for the duration of the study. Study 3 was a multicenter, randomized, masked trial in which patients with non-infectious uveitis affecting the posterior segment of the eye were all treated once with fluocinolone acetonide intravitreal implant, administered by one of two different applicators, and then received standard care for the duration of the study. Table 3 summarizes data available from studies 1, 2 and 3 through 12 months for study eyes treated with fluocinolone acetonide intravitreal implant (n=226) or sham injection (n=94). The most common ocular (study eye) and non-ocular adverse reactions in patients with non-infectious uveitis are shown in Table 3 and Table 4 . Table 3: Ocular Adverse Reactions Reported in ≥ 1% of Subject Eyes and Non-Ocular Adverse Reactions Reported in ≥ 2% of Patients with Non-Infectious Uveitis 1 Includes cataract, cataract subcapsular and lenticular opacities in study eyes that were phakic at baseline. 113 of the 226 fluocinolone acetonide study eyes were phakic at baseline; 56 of 94 sham-controlled study eyes were phakic at baseline. Ocular ADVERSE REACTIONS Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%) Sham Injection (N=94 Eyes) n (%) Cataract 1 63/113 (56%) 13/56 (23%) Visual Acuity Reduced 33 ( 15%) 11 (12%) Macular Edema 25 ( 11%) 33 (35%) Uveitis 22 ( 10%) 33 ( 35%) Conjunctival Hemorrhage 17 ( 8%) 5 ( 5%) Eye Pain 17 ( 8%) 12 (13%) Hypotony Of Eye 16 ( 7%) 1 ( 1%) Anterior Chamber Inflammation 12 ( 5%) 6 ( 6%) Dry Eye 10 ( 4%) 3 ( 3%) Vitreous Opacities 9 ( 4%) 8 ( 9%) Conjunctivitis 9 ( 4%) 5 ( 5%) Posterior Capsule Opacification 8 ( 4%) 3 ( 3%) Ocular Hyperemia 8 ( 4%) 7 ( 7%) Vitreous Haze 7 ( 3%) 4 ( 4%) Foreign Body Sensation In Eyes 7 ( 3%) 2 ( 2%) Vitritis 6 ( 3%) 8 ( 9%) Vitreous Floaters 6 ( 3%) 5 ( 5%) Eye Pruritus 6 ( 3%) 5 ( 5%) Conjunctival Hyperemia 5 ( 2%) 2 ( 2%) Ocular Discomfort 5 ( 2%) 1 ( 1%) Macular Fibrosis 5 ( 2%) 2 ( 2%) Glaucoma 4 ( 2%) 1 ( 1%) Photopsia 4 ( 2%) 2 ( 2%) Vitreous Hemorrhage 4 ( 2%) 0 Iridocyclitis 3 ( 1%) 7 ( 7%) Eye Inflammation 3 ( 1%) 2 ( 2%) Choroiditis 3 ( 1%) 1 ( 1%) Eye Irritation 3 ( 1%) 1 ( 1%) Visual Field Defect 3 ( 1%) 0 Lacrimation Increased 3 ( 1%) 0 Non-ocular ADVERSE REACTIONS Fluocinolone acetonide intravitreal implant (N=214 Patients) n (%) Sham Injection (N=94 Patients) n (%) Nasopharyngitis 10 ( 5%) 5 ( 5%) Hypertension 6 ( 3%) 1 ( 1%) Arthralgia 5 ( 2%) 1 ( 1%) Table 4: Summary of Elevated IOP Related Adverse Reactions in Patients with Non-Infectious Uveitis ADVERSE REACTIONS Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%) Sham (N=94 Eyes) n (%) IOP elevation ≥ 10 mmHg from Baseline 50 (22%) 11 (12%) IOP elevation > 30 mmHg 28 (12%) 3 (3%) Any IOP-lowering medication 98 (43%) 39 (41%) Any surgical intervention for elevated IOP 5 (2%) 2 (2%) Figure 2: Mean IOP in Patients with Non-Infectious Uveitis iluvien-figure-1 iluvien-figure-2 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ILUVIEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. These reactions include reports of drug administration error and reports of the drug being ineffective.

Storage: Store at 15°C to 30°C (59°F to 86° F).