Fluocinolone

INDICATIONS AND USAGE Fluocinolone Acetonide Topical Oil, 0.01% is a corticosteroid indicated for the • topical treatment of atopic dermatitis in adult patients ( 1.1 ) • topical treatment of moderate to severe atopic dermatitis in pediatric patients 3 months and older for up to 4 weeks ( 1.2 ) Limitations of Use: • Apply the least amount to cover affected areas. Discontinue when disease is controlled. ( 1.3 ) • Do not use in the diaper area. ( 1.3 ) • Do not use on the face, axillae, or groin. ( 1.3 , 6.2 , 8.4 ) 1.1 Adult Patients with Atopic Dermatitis Fluocinolone Acetonide Topical Oil, 0.01% is indicated for the topical treatment of atopic dermatitis in adult patients. 1.2 Pediatric Patients with Atopic Dermatitis Fluocinolone Acetonide Topical Oil, 0.01% is indicated for the topical treatment of moderate to severe atopic dermatitis in pediatric patients, 3 months and older for up to 4 weeks. Safety and effectiveness in pediatric patients younger than 3 months of age have not been established. 1.3 Limitations of Use Apply the least amount of Fluocinolone Acetonide Topical Oil, 0.01% needed to cover the affected areas. As with other corticosteroids, Fluocinolone Acetonide Topical Oil, 0.01% should be discontinued when control of disease is achieved. Contact the physician if no improvement is seen within 2 weeks. Fluocinolone Acetonide Topical Oil, 0.01% should not be applied to the diaper area; diapers or plastic pants may constitute occlusive use. Fluocinolone Acetonide Topical Oil, 0.01% should not be used on the face, axillae, or groin unless directed by the physician. Application to intertriginous areas should be avoided due to the increased risk of local adverse reactions. [see Adverse Reactions ( 6 ) and Use in Specific Populations ( 8.4 )] .

DOSAGE AND ADMINISTRATION 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.

WARNINGS AND PRECAUTIONS Endocrine System Adverse Reactions: o Topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, hyperglycemia, and glucosuria. (5.1) o Pediatric patients may be more susceptible to systemic toxicity from equivalent doses. (5.1,8.4) o Systemic absorption may require evaluation for HPA axis suppression. Potent corticosteroids use on large areas, prolonged use or occlusive use, altered skin barrier, liver failure, and young age may increase systemic absorption. Modify use should HPA axis suppression develop. ( 5.1 ). Local Adverse Reactions: Local adverse reactions may include atrophy, striae irritation, acneiform eruptions, hypopigmentation, and allergic contact dermatitis, and may be more likely with occlusive use or more potent corticosteroids. (5.2, 6.1) Ophthalmic Adverse Reactions: May increase the risks of glaucoma and posterior subcapsular cataract. Avoid contact of fluocinolone acetonide oil with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation. (5.3) 5.1 Endocrine System Adverse Reactions Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. Cushing’s syndrome, hyperglycemia, and glucosuria can result from systemic absorption of topical corticosteroids. HPA axis suppression and Cushing’s syndrome have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and subnormal response to ACTH stimulation. Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios [see Use in Specific Populations ( 8.4 )] . Conditions which increase systemic absorption include the use of more potent corticosteroids, use over large surface areas, use over prolonged periods, use of occlusive dressings, altered skin barrier, liver failure, and young age. Use of more than one corticosteroid-containing product at the same time may increase total systemic corticosteroid exposure. Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be periodically evaluated for HPA axis suppression. The ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, an attempt should be made to withdraw the drug to reduce the frequency of application, or to substitute a less potent corticosteroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. 5.2 Local Adverse Reactions Local adverse reactions may occur with use of topical corticosteroids, including fluocinolone acetonide oil, and may be more likely to occur with occlusive use, prolonged use, or use of higher potency corticosteroids. Some local adverse reactions may be irreversible. Reactions may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria [see Adverse Reactions ( 6.1 )] . 5.3 Ophthalmic Adverse Reactions Use of topical corticosteroids may increase the risks of glaucoma and posterior subcapsular cataract. Glaucoma and cataracts have been reported in postmarketing experience with the use of topical corticosteroid products. Avoid contact of fluocinolone acetonide oil with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation. 5.4 Allergic Contact Dermatitis Use of topical corticosteroids can cause allergic contact dermatitis. Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than a clinical exacerbation. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing. 5.5 Concomitant Skin Infections Use of topical corticosteroids may delay healing or worsen concomitant skin infections. Treat concomitant skin infections with an appropriate antimicrobial agent. If the infection persists unchanged, discontinue fluocinolone acetonide oil until the infection has been adequately treated. 5.6 Use in Peanut Sensitive Individuals Use caution in prescribing fluocinolone acetonide oil for peanut sensitive individuals [see Description (11)] . Should signs of hypersensitivity present (wheal and flare reactions, pruritus, or other manifestations), or should disease exacerbations occur, discontinue fluocinolone acetonide oil immediately and institute appropriate therapy.

CONTRAINDICATIONS 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.

ADVERSE REACTIONS 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.

CLINICAL PHARMACOLOGY: Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between the vasoconstrictor potency and therapeutic efficacy in man. Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION ). Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolities are also excreted into the bile.