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DESCRIPTION Fluocinolone Acetonide Ointment USP, 0.025% is intended for topical administration. The active component is the corticosteroid fluocinolone acetonide, which has the chemical name pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-. It has the following chemical structure: Fluocinolone Acetonide Ointment USP, 0.025% contains 0.25 mg/g of fluocinolone acetonide USP in a white petrolatum USP vehicle. Structure

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 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 metabolites are also excreted into the bile.

PRECAUTIONS General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS – Pediatric Use ) . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than that for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions, especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test ACTH stimulation test Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Pregnancy Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids.

ory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS – Pediatric Use ) . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.

Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than that for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions, especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.

Pregnancy Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.

Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: Burning Hypertrichosis Maceration of the skin Itching Acneiform eruptions Secondary infection Irritation Hypopigmentation Skin atrophy Dryness Perioral dermatitis Striae Folliculitis Allergic contact dermatitis Miliaria To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda/gov/medwatch.

<table styleCode="Noautorules" width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td valign="top"><paragraph>Burning</paragraph></td><td valign="top"><paragraph>Hypertrichosis</paragraph></td><td valign="top"><paragraph>Maceration of the skin</paragraph></td></tr><tr><td valign="top"><paragraph>Itching</paragraph></td><td valign="top"><paragraph>Acneiform eruptions</paragraph></td><td valign="top"><paragraph>Secondary infection</paragraph></td></tr><tr><td valign="top"><paragraph>Irritation</paragraph></td><td valign="top"><paragraph>Hypopigmentation</paragraph></td><td valign="top"><paragraph>Skin atrophy</paragraph></td></tr><tr><td valign="top"><paragraph>Dryness</paragraph></td><td valign="top"><paragraph>Perioral dermatitis</paragraph></td><td valign="top"><paragraph>Striae</paragraph></td></tr><tr><td valign="top"><paragraph>Folliculitis</paragraph></td><td valign="top"><paragraph>Allergic contact dermatitis</paragraph></td><td valign="top"><paragraph>Miliaria</paragraph></td></tr></tbody></table>

DOSAGE AND ADMINISTRATION Fluocinolone Acetonide Ointment is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressing may be used for the management of psoriasis or recalcitrant conditions. Some plastic films may be flammable and due care should be exercised in their use. Similarly, caution should be employed when such films are used on children or left in their proximity, to avoid the possibility of accidental suffocation. If an infection develops, the use of the occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.

1 INDICATIONS AND USAGE Fluocinolone acetonide oil is indicated for the topical treatment of chronic eczematous external otitis in adults and pediatric patients 2 years of age and older. Fluocinolone acetonide oil is a corticosteroid indicated for the topical treatment of chronic eczematous external otitis in adults and pediatric patients 2 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Fluocinolone acetonide oil is for otic administration only. Not for oral, ophthalmic, or intravaginal use. Apply fluocinolone acetonide oil into the affected ear using the supplied ear dropper. To apply, tilt head to one side so that the ear is facing up. Then gently pull the ear lobe backward and upward and apply 5 drops of fluocinolone acetonide oil into the ear. Keep head tilted for about a minute to allow fluocinolone acetonide oil to penetrate lower into the ear canal. Gently pat excess material dripping out of the ear using a clean cotton ball. Follow these instructions twice each day for 7 to 14 days. Discontinue fluocinolone acetonide oil when control of disease is achieved within 2 weeks, or contact the healthcare provider if no improvement is seen within 2 weeks. Do not use on the face, axillae, or groin unless directed by the healthcare provider. Do not apply to intertriginous areas due to the increased risk of local adverse reactions [ see Adverse Reactions (6) and Use in Specific Populations (8.4) ]. • Fluocinolone acetonide oil is not for oral, ophthalmic, or intravaginal use. ( 2 ) • Apply 5 drops of fluocinolone acetonide oil into the affected ear twice daily for 7 to 14 days. ( 2 ) • Do not use on face or intertriginous areas. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Ear drops, containing fluocinolone acetonide supplied in bottles containing 20 mL (dropper included). Ear drops, containing fluocinolone acetonide, supplied in bottles containing 20 mL. ( 3 )

5 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 )] .

ids. 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: • Endocrine System Adverse Reactions [see Warnings and Precautions (5.1 ), Use in Specific Populations (8.4)] • Local Adverse Reactions [see Warnings and Precautions (5.2 )] • Ophthalmic Adverse Reactions [ see Warnings and Precautions (5.3) ] The most commonly reported adverse reactions (≥ 1%) were headache (3%), URI (2%), cough (2%), eczematous otitis (1%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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. In trials that enrolled 154 subjects (adults and pediatric subjects 2 years and older) with chronic eczematous external otitis who were treated with five drops per ear of fluocinolone acetonide oil twice daily for a maximum 14 days of treatment, the following adverse reactions were reported: Table 1: Adverse Reactions in ≥1% of Fluocinolone Acetonide Oil - Treated Adult and Pediatric Subjects 2 Years of Age and Older with Chronic Eczematous External Otitis, N=154 Adverse Reaction n (%) Headache 4 (3) URI 3 (2) Cough 3 (2) Eczematous otitis 2 (1) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of products containing topical corticosteroids. Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Endocrine Disorders: HPA axis suppression and Cushing’s syndrome [see Use in Specific Populations (8.4) ] Eye Disorders : glaucoma and cataracts [see Warnings and Precautions (5.3) ] Nervous System Disorders: intracranial hypertension including bulging fontanelles, headaches, and bilateral papilledema [see Use in Specific Populations (8.4) ]

<table width="100%"><caption/><tbody><tr><td><content styleCode="bold"> Adverse Reaction</content></td><td><content styleCode="bold">n (%)</content></td></tr><tr><td> Headache</td><td> 4 (3)</td></tr><tr><td> URI</td><td> 3 (2)</td></tr><tr><td> Cough</td><td> 3 (2)</td></tr><tr><td> Eczematous otitis</td><td> 2 (1)</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from case reports, case series, and observational studies on fluocinolone acetonide use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Observational studies suggest maternal use of high to super-high potency topical steroids may be associated with an increased risk of low birthweight infants. Advise pregnant women to use fluocinolone acetonide oil on the smallest area of skin and for the shortest duration possible. Corticosteroids can cause fetal malformations in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids cause fetal malformations after dermal application in laboratory animals. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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. 8.2 Lactation Risk Summary There is no information regarding the presence of fluocinolone acetonide in breast milk or its effects on the breastfed infant or on milk production. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluocinolone acetonide oil and any potential adverse effects on the breastfed infant from fluocinolone acetonide oil or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of fluocinolone acetonide oil for the topical treatment of chronic eczematous external otitis have been established in pediatric patients aged 2 years and older. Safety and effectiveness of fluocinolone acetonide oil in pediatric patients with chronic eczematous external otitis below the age of 2 years have not been established. Systemic Adverse Reactions in Pediatric Patients HPA Axis suppression, Cushing’s syndrome, and intracranial hypertension 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. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk for systemic adverse reactions than are adults when treated with topical corticosteroids [see Warnings and Precautions (5.1) ]. Evaluation in Peanut-Sensitive Pediatric Patients A clinical trial was conducted to assess the safety of the formulation of fluocinolone acetonide oil, which contains refined peanut oil, in patients with known peanut allergies. The trial enrolled 13 pediatric subjects with atopic dermatitis, 6 to 17 years of age. Fluocinolone acetonide oil is not approved for the treatment of atopic dermatitis. Of the 13 subjects, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls).

ith known peanut allergies. The trial enrolled 13 pediatric subjects with atopic dermatitis, 6 to 17 years of age. Fluocinolone acetonide oil is not approved for the treatment of atopic dermatitis. Of the 13 subjects, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). The trial evaluated the subjects’ responses to both prick test and patch test utilizing refined peanut oil, the formulation of fluocinolone acetonide oil and histamine/saline controls. Subjects were also treated with the formulation of fluocinolone acetonide oil twice daily for 7 days. Prick test and patch test results for all 13 subjects were negative to the formulation of fluocinolone acetonide oil and the refined peanut oil. One of the 9 peanut-sensitive subjects experienced an exacerbation of atopic dermatitis after 5 days of use on the formulation of fluocinolone acetonide oil. Evaluation in Pediatric Patients 2 to 6 years old Use of the formulation of fluocinolone acetonide oil in pediatric patients 2 to 6 years old is supported by open-label safety trials conducted in 33 pediatric subjects (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis. Baseline body surface area involvement was 50% to 75% in 15 subjects and greater than 75% in 18 subjects. Subjects were treated with the formulation of fluocinolone acetonide oil twice daily for 4 weeks. Morning pre-stimulation cortisol and post-ACTH stimulation cortisol levels were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal: cortisol > 7µg/dL) but all had normal responses to 0.25 mg of ACTH stimulation (cortisol > 18 µg/dL) [see Clinical Pharmacology (12.2) ].

8.1 Pregnancy Risk Summary Available data from case reports, case series, and observational studies on fluocinolone acetonide use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Observational studies suggest maternal use of high to super-high potency topical steroids may be associated with an increased risk of low birthweight infants. Advise pregnant women to use fluocinolone acetonide oil on the smallest area of skin and for the shortest duration possible. Corticosteroids can cause fetal malformations in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids cause fetal malformations after dermal application in laboratory animals. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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.

8.4 Pediatric Use The safety and effectiveness of fluocinolone acetonide oil for the topical treatment of chronic eczematous external otitis have been established in pediatric patients aged 2 years and older. Safety and effectiveness of fluocinolone acetonide oil in pediatric patients with chronic eczematous external otitis below the age of 2 years have not been established. Systemic Adverse Reactions in Pediatric Patients HPA Axis suppression, Cushing’s syndrome, and intracranial hypertension 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. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk for systemic adverse reactions than are adults when treated with topical corticosteroids [see Warnings and Precautions (5.1) ]. Evaluation in Peanut-Sensitive Pediatric Patients A clinical trial was conducted to assess the safety of the formulation of fluocinolone acetonide oil, which contains refined peanut oil, in patients with known peanut allergies. The trial enrolled 13 pediatric subjects with atopic dermatitis, 6 to 17 years of age. Fluocinolone acetonide oil is not approved for the treatment of atopic dermatitis. Of the 13 subjects, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). The trial evaluated the subjects’ responses to both prick test and patch test utilizing refined peanut oil, the formulation of fluocinolone acetonide oil and histamine/saline controls. Subjects were also treated with the formulation of fluocinolone acetonide oil twice daily for 7 days. Prick test and patch test results for all 13 subjects were negative to the formulation of fluocinolone acetonide oil and the refined peanut oil. One of the 9 peanut-sensitive subjects experienced an exacerbation of atopic dermatitis after 5 days of use on the formulation of fluocinolone acetonide oil. Evaluation in Pediatric Patients 2 to 6 years old Use of the formulation of fluocinolone acetonide oil in pediatric patients 2 to 6 years old is supported by open-label safety trials conducted in 33 pediatric subjects (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis. Baseline body surface area involvement was 50% to 75% in 15 subjects and greater than 75% in 18 subjects. Subjects were treated with the formulation of fluocinolone acetonide oil twice daily for 4 weeks. Morning pre-stimulation cortisol and post-ACTH stimulation cortisol levels were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal: cortisol > 7µg/dL) but all had normal responses to 0.25 mg of ACTH stimulation (cortisol > 18 µg/dL) [see Clinical Pharmacology (12.2) ].

11 DESCRIPTION Fluocinolone Acetonide Oil (Ear Drops) contains fluocinolone acetonide [(6α, 11β, 16α)-6,9-difluoro-11,21-dihydroxy-16, 17[(1-methylethylidene)bis(oxy)]- pregna-1,4-diene3,20-dione, cyclic 16,17 acetal with acetone], a synthetic corticosteroid for topical dermatologic use. Chemically, fluocinolone acetonide is C 24 H 30 F 2 O 6 . It has the following structural formula: Fluocinolone acetonide has a molecular weight of 452.50. It is a white crystalline powder that is odorless, stable in light, and melts at 270°C with decomposition; soluble in alcohol, acetone and methanol; slightly soluble in chloroform; insoluble in water. Each gram of fluocinolone acetonide oil contains approximately 0.11 mg of fluocinolone acetonide in a blend of oils, which contains isopropyl alcohol, isopropyl myristate, light mineral oil, oleth-2 and refined peanut oil. Fluocinolone acetonide oil is formulated with 48% refined peanut oil. The bulk refined peanut oil, used in fluocinolone acetonide oil is heated between 232°C - 246°C (450°F - 475°F) for at least 15 minutes, which should provide for adequate decomposition of allergenic proteins. Fluocinolone -structure.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action in eczematous external otitis is unknown. 12.2 Pharmacodynamics Vasoconstrictor Assay Fluocinolone acetonide oil is in the low to medium range of potency as compared with other topical corticosteroids in vasoconstrictor studies. However, similar blanching scores do not necessarily imply therapeutic equivalence. Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression HPA axis suppression was evaluated in 33 pediatric subjects 2 to 12 years old (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis. Subjects were treated with the formulation of fluocinolone acetonide oil twice daily for 4 weeks. Baseline body surface area involvement was 50% to 75% in 15 subjects and greater than 75% in 18 subjects. Morning pre-stimulation cortisol and post- ACTH stimulation cortisol levels were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal cortisol >7 µg/dL) but all had normal responses to 0.25 mg of ACTH stimulation (cortisol >18 µg/dL) [see Warnings and Precautions ( 5.1 )] . 12.3 Pharmacokinetics Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the product formulation and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may increase percutaneous absorption. The use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids may be necessary due to the fact that circulating levels are often below the level of detection. Once absorbed through the skin, topical corticosteroids are metabolized, primarily in the liver, and are then excreted by the kidneys. Some corticosteroids and their metabolites are also excreted in the bile.

12.1 Mechanism of Action Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action in eczematous external otitis is unknown.

12.2 Pharmacodynamics Vasoconstrictor Assay Fluocinolone acetonide oil is in the low to medium range of potency as compared with other topical corticosteroids in vasoconstrictor studies. However, similar blanching scores do not necessarily imply therapeutic equivalence. Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression HPA axis suppression was evaluated in 33 pediatric subjects 2 to 12 years old (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis. Subjects were treated with the formulation of fluocinolone acetonide oil twice daily for 4 weeks. Baseline body surface area involvement was 50% to 75% in 15 subjects and greater than 75% in 18 subjects. Morning pre-stimulation cortisol and post- ACTH stimulation cortisol levels were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal cortisol >7 µg/dL) but all had normal responses to 0.25 mg of ACTH stimulation (cortisol >18 µg/dL) [see Warnings and Precautions ( 5.1 )] .

12.3 Pharmacokinetics Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the product formulation and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may increase percutaneous absorption. The use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids may be necessary due to the fact that circulating levels are often below the level of detection. Once absorbed through the skin, topical corticosteroids are metabolized, primarily in the liver, and are then excreted by the kidneys. Some corticosteroids and their metabolites are also excreted in the bile.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility No carcinogenicity, genotoxicity, or fertility studies were conducted with fluocinolone acetonide oil. However, some corticosteroids are genotoxic in various genotoxicity tests (i.e., the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay).

13.1 Carcinogenesis, mutagenesis, impairment of fertility No carcinogenicity, genotoxicity, or fertility studies were conducted with fluocinolone acetonide oil. However, some corticosteroids are genotoxic in various genotoxicity tests (i.e., the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay).

14 CLINICAL STUDIES In two vehicle-controlled trials (Trial 1 and Trial 2), 154 subjects (adults and pediatric subjects 2 years of age and older) with chronic eczematous external otitis were treated with 5 drops per ear of fluocinolone acetonide oil twice daily for 7 days. Efficacy was assessed on Day 7 by clearance of the signs and symptoms of eczematous external otitis, and the results are presented in the following table: Table 2: Efficacy Results at Day 7 in Subjects with Chronic Eczematous External Otitis in Trial 1 and 2* Fluocinolone acetonide oil Vehicle Study 1 30% (14/47) 7% (3/46) Study 2 32% (9/28) 3% (1/30) *Erythema, scaling, pruritus, erosion/oozing/crusting and debris

<table width="70%"><caption/><tbody><tr><td/><td><content styleCode="bold">Fluocinolone acetonide oil</content></td><td><content styleCode="bold">Vehicle</content></td></tr><tr><td> Study 1</td><td>30% (14/47)</td><td> 7% (3/46)</td></tr><tr><td> Study 2</td><td> 32% (9/28)</td><td> 3% (1/30)</td></tr></tbody></table>

16 HOW SUPPLIED / STORAGE AND HANDLING Fluocinolone Acetonide Oil (Ear Drops) is supplied in bottles containing 20 mL, (dropper included) (NDC # 64980-329-20). Storage: Keep tightly closed. Store at 20°-25°C (68°-77°F); excursions permitted to 15°- 30°C (59°-86°F) [ see USP Controlled Room Temperature ]. Discard fluocinolone acetonide oil (Ear Drops) 2 months after initial use.

17 PATIENT COUNSELING INFORMATION Administration Instructions Advise patients that fluocinolone acetonide oil is for otic administration only and not for oral, ophthalmic, or intravaginal use [ see Dosage and Administration( 2 ) ]. Advise patients to avoid use of fluocinolone acetonide oil on the face, axillae, or groin unless directed by their healthcare provider [ see Dosage and Administration ( 2 )] . Advise patients to discontinue therapy when control of disease is achieved. Instruct patients to contact their healthcare provider if no improvement is seen within 2 weeks [see Dosage and Administration ( 2 )] . Endocrine System Adverse Reactions Instruct patients not to use other corticosteroid-containing products while using fluocinolone acetonide oil without first consulting their healthcare provider [see Warnings and Precautions ( 5.1 )] . Ophthalmic Adverse Reactions Advise patients to avoid contact with the eyes and in case of contact, wash eyes liberally with water. Instruct patients to tell their healthcare provider if they develop any visual symptoms [ see Warnings and Precautions ( 5.3 ) ]. Pregnancy and Lactation Advise patients to use fluocinolone acetonide oil on the smallest area of skin and for the shortest duration possible while pregnant or breastfeeding. Advise patients that are breastfeeding not to apply fluocinolone acetonide oil directly to the nipple and areola to avoid direct infant exposure [ See Use in Specific Populations (8.1 and 8.2) ]. Manufactured by: Lyne Laboratories, Inc. Brockton, MA 02301 Manufactured for: Rising Pharma Holdings, Inc. East Brunswick, NJ 08816 Revised : 02/2026 PIR32920-03

DESCRIPTION Fluocinolone Acetonide Cream USP, 0.01% and 0.025% are intended for topical administration. The active component is the corticosteroid fluocinolone acetonide, which has the chemical name pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-. It has the following chemical structure: Fluocinolone Acetonide Cream USP, 0.01% contains 0.1 mg/g of fluocinolone acetonide USP and Fluocinolone Acetonide Cream USP, 0.025% contains 0.25 mg/g of fluocinolone acetonide USP in a water-washable aqueous base of butylated hydroxytoluene, cetyl alcohol, citric acid, edetate disodium, methylparaben and propylparaben (preservatives), mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, simethicone, stearyl alcohol, water (purified) and white wax. Structure

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 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 metabolites are also excreted into the bile.

PRECAUTIONS General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS – Pediatric Use) . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than that for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions, especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test ACTH stimulation test Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Pregnancy Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids.

General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS – Pediatric Use) . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.

DOSAGE AND ADMINISTRATION Fluocinolone Acetonide Cream is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressing may be used for the management of psoriasis or recalcitrant conditions. Some plastic films may be flammable and due care should be exercised in their use. Similarly, caution should be employed when such films are used on children or left in their proximity, to avoid the possibility of accidental suffocation. If an infection develops, the use of the occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.

HOW SUPPLIED Fluocinolone Acetonide Cream USP, 0.01% is supplied in 15 g Tube – NDC 62559-288-15 60 g Tube – NDC 62559-288-60 Fluocinolone Acetonide Cream USP, 0.025% is supplied in 15 g Tube – NDC 62559-289-15 60 g Tube – NDC 62559-289-60

DESCRIPTION Fluocinolone acetonide topical oil, 0.01% (scalp oil) contains fluocinolone acetonide {(6α, 11β, 16α)-6,9-difluoro-11,21-dihydroxy-16,17[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione, cyclic 16,17 acetal with acetone}, a synthetic corticosteroid for topical dermatologic use. This formulation is also marketed as fluocinolone acetonide topical oil, 0.01% (body oil) for use as body oil for atopic dermatitis in adults and for moderate to severe atopic dermatitis in pediatric patients 2 years and older, and as fluocinolone acetonide oil, 0.01% (ear drops) for chronic eczematous external otitis. Chemically, fluocinolone acetonide is C 24 H 30 F 2 O 6 . It has the following structural formula: Fluocinolone acetonide has a molecular weight of 452.50. It is a white crystalline powder that is odorless, stable in light, and melts at 270°C with decomposition; soluble in alcohol, acetone and methanol; slightly soluble in chloroform; insoluble in water. Each gram of fluocinolone acetonide topical oil, 0.01% (scalp oil) contains approximately 0.11 mg of fluocinolone acetonide in a blend of oils, which contain isopropyl alcohol, isopropyl myristate, light mineral oil, oleth-2 and refined peanut oil NF. Each packaged product contains 2 shower caps. The shower cap is made of low density polyethylene material with rubber elastic.

CLINICAL PHARMACOLOGY Like other topical corticosteroids, fluocinolone acetonide has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 . Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Occlusion of topical corticosteroids can enhance penetration. Topical corticosteroids can be absorbed from normal intact skin. Also, inflammation and/or other disease processes in the skin can increase percutaneous absorption. Fluocinolone acetonide topical oil, 0.01% is in the low to medium range of potency as compared with other topical corticosteroids.

CLINICAL STUDIES In a vehicle-controlled study for the treatment of psoriasis of the scalp in adults, after 21 days of treatment, 60% of patients on active treatment and 21% of patients on the drug vehicle had excellent to cleared clinical response. Open-label safety studies on 33 children (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis, and baseline body surface area involvement greater than 75% in 18 patients, and 50% to 75% in 15 patients, were treated with fluocinolone acetonide topical oil, 0.01% twice daily for 4 weeks. Morning pre-stimulation cortisol level and post-Cortrosyn stimulation cortisol level were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre- stimulation cortisol levels (3.2 to 6.6 ug/dL; normal: cortisol > 7 ug/dL) but all had normal responses to 0.25 mg of Cortrosyn stimulation (cortisol > 18 ug/dL). A clinical study was conducted to assess the safety of fluocinolone acetonide topical oil, 0.01%, which contains refined peanut oil, on subjects with known peanut allergies. The study enrolled 13 patients with atopic dermatitis, 6 to 17 years of age. Of the 13 patients, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). The study evaluated the responses to both prick test and patch test utilizing refined peanut oil NF, fluocinolone acetonide topical oil, 0.01% and histamine/saline controls, on the 13 individuals. These subjects were also treated with fluocinolone acetonide topical oil, 0.01% twice daily for 7 days. Prick test and patch test results for all 13 patients were negative to fluocinolone acetonide topical oil, 0.01% and the refined peanut oil. One of the 9 peanut-sensitive patients experienced an exacerbation of atopic dermatitis after 5 days of fluocinolone acetonide topical oil, 0.01% use. Importantly, the bulk peanut oil NF, used in fluocinolone acetonide topical oil, 0.01% is heated at 475° F for at least 15 minutes, which should provide for adequate decomposition of allergenic proteins.

CONTRAINDICATIONS Fluocinolone acetonide topical oil, 0.01% is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. This product contains refined peanut oil NF (see PRECAUTIONS section).

PRECAUTIONS General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary- adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Infrequently, signs and symptoms of glucocorticoid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. (see PRECAUTIONS-Pediatric use ) Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than noting a clinical exacerbation, which may occur with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic testing. One peanut sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with fluocinolone acetonide topical oil, 0.01% (see CLINICAL STUDIES section). If wheal and flare type reactions (which may be limited to pruritus) or other manifestations of hypersensitivity develop, fluocinolone acetonide topical oil, 0.01% should be discontinued immediately and appropriate therapy instituted. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of fluocinolone acetonide topical oil, 0.01% should be discontinued until the infection has been adequately controlled. Fluocinolone acetonide topical oil, 0.01% is formulated with 48% refined peanut oil NF. Physicians should use caution in prescribing fluocinolone acetonide topical oil, 0.01% for peanut sensitive individuals. Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. In case of contact, wash eyes liberally with water. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. Patients should promptly report to their physician any worsening of their skin condition. 4. Parents of pediatric patients should be advised not to use fluocinolone acetonide topical oil, 0.01% in the treatment of diaper dermatitis. Fluocinolone acetonide topical oil, 0.01% should not be applied to the diaper area as diapers or plastic pants may constitute occlusive dressing. 5. This medication should not be used on the face, underarm, or groin unless directed by the physician. 6. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician.

diapers or plastic pants may constitute occlusive dressing. 5. This medication should not be used on the face, underarm, or groin unless directed by the physician. 6. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician. Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH stimulation test A.M. plasma cortisol test Urinary free cortisol test Carcinogenesis, mutagenesis, and impairment of fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of fluocinolone acetonide topical oil, 0.01%. Studies have not been performed to evaluate the mutagenic potential of fluocinolone acetonide, the active ingredient in fluocinolone acetonide topical oil, 0.01%. Some corticosteroids have been found to be genotoxic in various genotoxicity tests (i.e. the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay). Pregnancy: Teratogenic effects: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from fluocinolone acetonide topical oil, 0.01%. Therefore, fluocinolone acetonide topical oil, 0.01% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when fluocinolone acetonide topical oil, 0.01% is administered to a nursing woman. Pediatric Use: Fluocinolone acetonide topical oil, 0.01% may be used twice daily for up to 4 weeks in pediatric patients 2 years and older with moderate to severe atopic dermatitis. Fluocinolone acetonide topical oil, 0.01% should not be applied to the diaper area. Application to intertriginous areas should be avoided due to the increased possibility of local adverse events such as striae, atrophy, and telangiectasia, which may be irreversible. The smallest amount of drug needed to cover the affected areas should be applied. Long term safety in the pediatric population has not been established. Fluocinolone acetonide topical oil, 0.01% is not recommended for use on the face (see ADVERSE REACTIONS section). Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. (see PRECAUTIONS ). HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios.

teroids in infants and children. (see PRECAUTIONS ). HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Fluocinolone acetonide topical oil, 0.01% is formulated with 48% refined peanut oil NF. Physicians should use caution in prescribing fluocinolone acetonide topical oil, 0.01% for peanut sensitive individuals.

ADVERSE REACTIONS The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. One peanut sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with fluocinolone acetonide topical oil, 0.01%. A post marketing (open-label) safety study was conducted in 58 children to evaluate the local safety of fluocinolone acetonide topical oil, 0.01% when applied twice daily for 4 weeks to the face in children (2 to 12 years) with moderate to severe atopic dermatitis (see Table of Incidence of Adverse Events ). Incidence of Adverse Events (%) N=58 Adverse Event (AE) * # of patients (%) Day 14 Day 28 † D ay 56 ‡ * The number of individual adverse events reported does not necessarily reflect the number of individual subjects, since one subject could have multiple reporting of an adverse event. † End of Treat ment ‡ Four Weeks Post Treatment Any AE 15 (25.9) 6 (10.3) 7 (12.1) 7 (12.1) Telangiectasia 5 (8.6) 3 (5.2) 4 (6.9) 2 (3.5) Erythema 3 (5.2) 3 (5.2) Itching 3 (5.2) 3 (5.2) Irritation 3 (5.2) 3 (5.2) Burning 3 (5.2) 3 (5.2) Hypopigmentation 2 (3.5) 2 (3.5) Shiny skin 1 (1.7) 1 (1.7) Secondary atopic dermatitis 1 (1.7) 1 (1.7) Papules and pustules 1 (1.7) 1 (1.7) Keratosis pilaris 1 (1.7) 1 (1.7) Folliculitis 1 (1.7) 1 (1.7) Facial herpes simplex 1 (1.7) 1 (1.7) Acneiform eruption 1 (1.7) 1 (1.7) Ear infection 1 (1.7) 1 (1.7) To report SUSPECTED ADVERSE REACTIONS, contact Quagen Pharmaceuticals LLC at 1-888-344-9603 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table cellspacing="0" cellpadding="0" border="0"><caption>Incidence of Adverse Events (%) N=58 </caption><thead><tr><th styleCode="Lrule Rrule Toprule" colspan="1"><content styleCode="bold">Adverse <content ID="event">Event</content> (AE)<linkHtml href="#number">*</linkHtml></content></th><th styleCode="Lrule Rrule Toprule" colspan="1"><content styleCode="bold"># of patients (%) </content></th><th styleCode="Lrule Rrule Toprule" colspan="1"><content styleCode="bold">Day 14 </content></th><th styleCode="Lrule Rrule Toprule" colspan="1"><content styleCode="bold"><content ID="day">Day</content> 28<linkHtml href="#treat">&#x2020;</linkHtml></content></th><th styleCode="Lrule Rrule Toprule" colspan="1"><content styleCode="bold"> D<content ID="ay">ay</content> 56<linkHtml href="#weeks">&#x2021;</linkHtml></content></th></tr></thead><tfoot><tr><td colspan="5"><content styleCode="bold"><linkHtml href="#event">*</linkHtml> The <content ID="number">number</content> of individual adverse events reported does not necessarily reflect the number of individual subjects, since one subject could have multiple reporting of an adverse event.

</th></tr></thead><tfoot><tr><td colspan="5"><content styleCode="bold"><linkHtml href="#event">*</linkHtml> The <content ID="number">number</content> of individual adverse events reported does not necessarily reflect the number of individual subjects, since one subject could have multiple reporting of an adverse event. <linkHtml href="#day">&#x2020;</linkHtml> End of <content ID="treat">Treat</content>ment <linkHtml href="#ay">&#x2021;</linkHtml> Four <content ID="weeks">Weeks</content> Post Treatment</content></td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Any AE</td><td styleCode="Rrule" valign="middle"> 15 (25.9)</td><td styleCode="Rrule" valign="middle"> 6 (10.3)</td><td styleCode="Rrule" valign="middle"> 7 (12.1)</td><td styleCode="Rrule" valign="middle"> 7 (12.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Telangiectasia</td><td styleCode="Rrule" valign="middle"> 5 (8.6)</td><td styleCode="Rrule" valign="middle"> 3 (5.2)</td><td styleCode="Rrule" valign="middle"> 4 (6.9)</td><td styleCode="Rrule" valign="middle"> 2 (3.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Erythema</td><td styleCode="Rrule" valign="middle"> 3 (5.2)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 3 (5.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Itching </td><td styleCode="Rrule" valign="middle"> 3 (5.2)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 3 (5.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Irritation</td><td styleCode="Rrule" valign="middle"> 3 (5.2)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 3 (5.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Burning</td><td styleCode="Rrule" valign="middle"> 3 (5.2)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 3 (5.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Hypopigmentation</td><td styleCode="Rrule" valign="middle"> 2 (3.5)</td><td styleCode="Rrule" valign="middle"> 2 (3.5)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Shiny skin</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Secondary atopic dermatitis</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Papules and pustules</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Keratosis pilaris</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Folliculitis</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styl

ode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Folliculitis</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styl eCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Facial herpes simplex</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Acneiform eruption</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/></tr><tr><td styleCode="Lrule Rrule" valign="middle"> Ear infection</td><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/><td styleCode="Rrule" valign="middle"> 1 (1.7)</td><td styleCode="Rrule" valign="middle"/></tr></tbody></table>

DOSAGE AND ADMINISTRATION Fluocinolone acetonide topical oil, 0.01% for scalp psoriasis in adults (scalp oil): For the treatment of scalp psoriasis, wet or dampen hair and scalp thoroughly. Apply a thin film of fluocinolone acetonide topical oil, 0.01% on the scalp, massage well and cover scalp with the supplied shower cap. Leave on overnight or for a minimum of 4 hours before washing off. Wash hair with regular shampoo and rinse thoroughly.

HOW SUPPLIED Fluocinolone acetonide topical oil, 0.01% (scalp oil) is supplied in bottles containing 4 fluid ounces. It is labeled as fluocinolone acetonide topical oil, 0.01% (scalp oil) (NDC # 71335-2883-1). Fluocinolone acetonide topical oil, 0.01% (scalp oil) is supplied with 2 shower caps. Keep tightly closed. Store at 25°C (68° to 77°F); excursions permitted to 15°–30°C (59°–86° F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

for initiation of therapy in inflammatory dermatoses. Rx Only Manufactured for: MEDIMETRIKS PHARMACEUTICALS, INC. 383 Route 46 West, Fairfield, NJ 07004-2402 USA www.medimetriks.com Manufactured by: Ferndale Laboratories, Inc., Ferndale, MI 48220 IP027-R3 Rev. 10/2022

DESCRIPTION SYNALAR ® (fluocinolone acetonide) Cream 0.025% is intended for topical administration. The active component is the corticosteroid fluocinolone acetonide, which has the chemical name pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-. It has the following chemical structure: SYNALAR ® Cream contains fluocinolone acetonide 0.25 mg/g in a water-washable aqueous base of butylated hydroxytoluene, cetyl alcohol, citric acid, edetate disodium, methylparaben and propylparaben (preservatives), mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, simethicone, stearyl alcohol, water (purified) and white beeswax. Chemical Structure

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 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 metabolites are also excreted into the bile.

PRECAUTIONS General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS—Pediatric Use ) . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. Patients should be advised not to use this medication for any disorder other than that for which it was prescribed. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. Patients should report any signs of local adverse reactions, especially under occlusive dressing. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test ACTH stimulation test Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Pregnancy Category C Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids.

ory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroidinduced hypothalmic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS—Pediatric Use ) . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short-term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.

Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. Patients should be advised not to use this medication for any disorder other than that for which it was prescribed. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. Patients should report any signs of local adverse reactions, especially under occlusive dressing. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.

Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroidinduced hypothalmic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: Burning Hypertrichosis Maceration of the skin Itching Acneiform eruptions Secondary infection Irritation Hypopigmentation Skin atrophy Dryness Perioral dermatitis Striae Folliculitis Allergic contact dermatitis Miliaria

<table width="100%" styleCode="Noautorules"><col width="20%" align="left" valign="top"/><col width="40%" align="left" valign="top"/><col width="40%" align="left" valign="top"/><tbody><tr><td>Burning </td><td>Hypertrichosis </td><td>Maceration of the skin </td></tr><tr><td>Itching </td><td>Acneiform eruptions </td><td>Secondary infection </td></tr><tr><td>Irritation </td><td>Hypopigmentation </td><td>Skin atrophy </td></tr><tr><td>Dryness </td><td>Perioral dermatitis </td><td>Striae </td></tr><tr><td>Folliculitis </td><td>Allergic contact dermatitis </td><td>Miliaria </td></tr></tbody></table>

DOSAGE AND ADMINISTRATION SYNALAR ® Cream is generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. In hairy sites, the hair should be parted to allow direct contact with the lesion. Occlusive dressing may be used for the management of psoriasis or recalcitrant conditions. Some plastic films may be flammable and due care should be exercised in their use. Similarly, caution should be employed when such films are used on children or left in their proximity, to avoid the possibility of accidental suffocation. If an infection develops, the use of the occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.

HOW SUPPLIED SYNALAR ® (fluocinolone acetonide) Cream 0.025% is supplied in 120 g Tube – NDC 43538-900-12 STORAGE Store at room temperature 15-25°C (59-77°F); avoid freezing and excessive heat above 40°C (104°F). To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks Pharmaceuticals, Inc. at 1-973-882-7512 or FDA at 1-800-FDA-1088 or www.fda/gov/medwatch.

STORAGE Store at room temperature 15-25°C (59-77°F); avoid freezing and excessive heat above 40°C (104°F). To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks Pharmaceuticals, Inc. at 1-973-882-7512 or FDA at 1-800-FDA-1088 or www.fda/gov/medwatch.

1 INDICATIONS AND USAGE RETISERT ® is indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. RETISERT is a corticosteroid indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. (1)

2 DOSAGE AND ADMINISTRATION RETISERT is surgically implanted into the posterior segment of the affected eye through a pars plana incision. (2.1) RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of 0.6 mcg/day, decreasing over the first month to a steady state between 0.3-0.4 mcg/day over approximately 30 months. (2.1) Aseptic technique should be maintained at all times prior to and during the surgical implantation procedure. (2.2) 2.1 Dosing Information RETISERT is implanted into the posterior segment of the affected eye through a pars plana incision. The implant contains one tablet of 0.59 mg of fluocinolone acetonide. RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of 0.6 mcg/day, decreasing over the first month to a steady state between 0.3-0.4 mcg/day over approximately 30 months. Following depletion of fluocinolone acetonide as evidenced by recurrence of uveitis, RETISERT may be replaced. 2.2 Handling of Implant Caution should be exercised in handling RETISERT in order to avoid damage to the implant, which may result in an increased rate of drug release from the implant. Thus, RETISERT should be handled only by the suture tab. Care should be taken during implantation and explantation to avoid sheer forces on the implant that could disengage the silicone cup reservoir (which contains a fluocinolone acetonide tablet) from the suture tab. Aseptic technique should be maintained at all times prior to and during the surgical implantation procedure. RETISERT should not be resterilized by any method.

4 CONTRAINDICATIONS Surgical placement of RETISERT is contraindicated in active viral, bacterial, mycobacterial and fungal infections of ocular structures. (4.1) 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures Surgical placement of RETISERT is contraindicated in active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in active bacterial, mycobacterial or fungal infections of the eye.

5 WARNINGS AND PRECAUTIONS Cataract formation: Nearly all phakic patients are expected to develop cataracts and require cataract surgery. (5.1) Endophthalmitis: Late onset endophthalmitis has been observed. (5.2) Increase in intraocular pressure: Use of corticosteroids may result in elevated IOP and/or glaucoma. (5.3) IOP lowering medications were required in > 75% of patients; filtering surgeries were required in > 35% of patients. (6.1) Separation of implant components: Physicians should periodically monitor the integrity of the implant by visual inspection. (5.4) 5.1 Cataract Formation Use of corticosteroids may result in posterior subcapsular cataract formation. Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. 5.2 Endophthalmitis and Surgical Complications Late onset endophthalmitis has been observed. These events are often related to the integrity of the surgical wound site. Careful attention to assure tight closure of the scleral wound and the integrity of the overlying conjunctiva at the wound site is important. Potential complications accompanying intraocular surgery to place RETISERT into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. Following implantation of RETISERT, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively. 5.3 Increase in Intraocular Pressure Prolonged use of corticosteroids may result in elevated IOP and/or glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. Patients must be monitored for elevated IOP. Based on clinical trials with RETISERT, within 3-years post-implantation, approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure [see Adverse Reactions ( 6.1 )] . 5.4 Separation of Implant Components In vitro stability studies show that the strength of the adhesive bond between the silicone cup reservoir and the suture tab is reduced with prolonged hydration, indicating a potential for the separation of these components. The suture tab composition is a silicone elastomer reinforced with a polyester mesh. Physicians should periodically monitor the integrity of the implant by visual inspection. 5.5 Other Corticosteroid Induced Adverse Reactions RETISERT should be used with caution in patients with a history of a viral, bacterial, mycobacterial or fungal infection of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia and varicella. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections (bacterial, fungal, and viral).

the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections (bacterial, fungal, and viral). In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term application of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used. Since resistance to infections is known to be reduced by corticosteroids, simultaneous bilateral implantation should not be carried out, in order to limit the potential for bilateral post-operative infection. Ocular administration of corticosteroids has also been associated with delayed wound healing and perforation of the globe where there is thinning of the sclera. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

6 ADVERSE REACTIONS Ocular adverse events included procedural complications, and eye pain (> 50%). Thirty-five to forty percent of patients reported ocular/conjunctival hyperemia, reduced visual acuity, and conjunctival hemorrhage. (6.1) The most common non-ocular event reported was headache (33%). (6.2) To report SUSPECTED ADVERSE REACTIONS, contactBausch & Lomb Incorporated at 1-800-553-5340or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience - Ocular Events The available safety data includes exposure to RETISERT in patients with chronic non-infectious uveitis affecting the posterior segment in two multicenter controlled clinical trials. Patients were randomized to dosage regimens of 0.59 mg or 2.1 mg implants. The most frequently reported ocular adverse events were cataract, increased intraocular pressure, procedural complication, and eye pain. These events occurred in approximately 50 - 90% of patients. Cataract includes aggravated cataract, and posterior capsular opacification. Procedural complications includes post-op complication, post-op wound complication, post-op wound site erythema, and wound dehiscense. Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. IOP lowering medications to lower intraocular pressure were required in approximately 77% of patients; filtering surgeries were required to control intraocular pressure in 37% of patients. Ocular adverse events occurring in approximately 10 - 40% of patients in decreasing order of incidence were ocular/conjunctival hyperemia, reduced visual acuity, glaucoma, conjunctival hemorrhage, blurred vision, abnormal sensation in the eye, eye irritation, maculopathy, vitreous floaters, hypotony, pruritus, ptosis, increased tearing, vitreous hemorrhage, dry eye, eyelid edema, macular edema and visual disturbance. Ocular adverse events occurring in approximately 5 - 9% of patients in decreasing order of incidence were eye discharge, photophobia, blepharitis, corneal edema, iris adhesions, choroidal detachment, diplopia, eye swelling, retinal detachment, photopsia, retinal hemorrhage and hyphema. 6.2 Clinical Trials Experience - Non-Ocular Events The most frequently reported non-ocular adverse event was headache (33%). Other non-ocular adverse events occurring in approximately 5-20% of patients in decreasing order of incidence were nasopharyngitis, arthralgia, sinusitis, dizziness, pyrexia, upper respiratory tract infection, influenza, vomiting, nausea, cough, back pain, limb pain, and rash.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Adequate and well-controlled studies with RETISERT have not been conducted in pregnant women to inform drug-associated risk. Animal reproduction studies have not been conducted with RETISERT. It is not known whether RETISERT can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. RETISERT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. 8.2 Lactation Risk Summary There are no data on the presence of RETISERT in human milk, the effects on the breastfed infant, or the effects on milk production. Systemically administered corticosteroids are present in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Clinical or nonclinical lactation studies have not been conducted with RETISERT. It is not known whether intravitreal treatment with RETISERT could result in sufficient systemic absorption to produce detectable quantities of fluocinolone acetonide in human milk, or affect breastfed infants or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RETISERT and any potential adverse effects on the breastfed child from RETISERT or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 years have not been established. 8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients.

8.1 Pregnancy Risk Summary Adequate and well-controlled studies with RETISERT have not been conducted in pregnant women to inform drug-associated risk. Animal reproduction studies have not been conducted with RETISERT. It is not known whether RETISERT can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. RETISERT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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.

11 DESCRIPTION RETISERT ® (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant designed to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal initial rate of 0.6 mcg/day, decreasing over the first month to a steady state between 0.3-0.4 mcg/day over approximately 30 months. The drug substance is the synthetic corticosteroid fluocinolone acetonide, represented by the following structural formula: C 24 H 30 F 2 O 6 Mol. Wt. 452.50 Chemical Name: Pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy-16,17-[(1-methyl-ethylidene)bis(oxy)],(6α,11β ,16α)-. Fluocinolone acetonide is a white crystalline powder, insoluble in water, and soluble in methanol. It has a melting point of 265-266ºC. Each RETISERT consists of a tablet containing 0.59 mg of the active ingredient, Fluocinolone Acetonide, USP, and the following inactives: magnesium stearate, microcrystalline cellulose, and polyvinyl alcohol. chemical structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 . Corticosteroids are capable of producing a rise in intraocular pressure. 12.3 Pharmacokinetics In a subset of patients who received the intravitreal implant, and had blood samples taken at various times (weeks 1, 4 and 34) after implantation, plasma levels of fluocinolone acetonide were below the limit of detection (0.2 ng/mL) at all times. Aqueous and vitreous humor samples were assayed for fluocinolone acetonide in a further subset of patients. While detectable concentrations of fluocinolone acetonide were seen throughout the observation interval (up to 34 months), the concentrations were highly variable, ranging from below the limit of detection (0.2 ng/mL) to 589 ng/mL.

12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 . Corticosteroids are capable of producing a rise in intraocular pressure.

12.3 Pharmacokinetics In a subset of patients who received the intravitreal implant, and had blood samples taken at various times (weeks 1, 4 and 34) after implantation, plasma levels of fluocinolone acetonide were below the limit of detection (0.2 ng/mL) at all times. Aqueous and vitreous humor samples were assayed for fluocinolone acetonide in a further subset of patients. While detectable concentrations of fluocinolone acetonide were seen throughout the observation interval (up to 34 months), the concentrations were highly variable, ranging from below the limit of detection (0.2 ng/mL) to 589 ng/mL.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to determine the carcinogenic potential or the effect on fertility of RETISERT. Fluocinolone acetonide was not genotoxic in vitro in the Ames test (S. typhimurium and E. coli), the mouse lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to determine the carcinogenic potential or the effect on fertility of RETISERT. Fluocinolone acetonide was not genotoxic in vitro in the Ames test (S. typhimurium and E. coli), the mouse lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay.

14 CLINICAL STUDIES In two randomized, double-masked, multicenter controlled clinical trials, 224 patients with chronic (a one year or greater history) non-infectious uveitis affecting the posterior segment of one or both eyes were randomized to receive a 0.59 mg RETISERT. The primary efficacy endpoint in both trials was the rate of recurrence of uveitis affecting the posterior segment of the study eye in the 34 week pre-implantation period compared to the rate of recurrence in the 34 week post-implantation period. Uveitis recurrence rates at 1, 2, and 3 year post-implantation were also compared to the 34 week pre-implantation period. Detailed results are shown in Table 1 below: Table 1: Uveitis Recurrence Rates TIME POINT STUDY 1 STUDY 2 N=108 N=116 Uveitis Recurrence Rates 1,2 N (%) 34 Weeks Pre- implantation 58 (53.7) 46 (39.7) 34 Weeks Post- implantation 2 (1.8) 15 (12.9) 1 Year Post-implantation 4 (3.7) 15 (12.9) 2 Years Post-implantation 11 (10.2) 16 (13.8) 3 Years Post-implantation 22 (20.4) 20 (17.2) 3 Years 3 Post- implantation 33 (30.6) 28 (24.1) 1 Recurrence of uveitis for all post-implantation time points was compared to the 34 weeks pre-implantation time point. 2 p-value <0.01 from McNemar’s χ 2 test. 3 Results presented include imputed recurrences. Recurrences were imputed when a subject was not seen within 10 weeks of their final scheduled visit. In assessing the effect of RETISERT on the corneal endothelial cell density in eyes that have been implanted for a minimum of 1 year, the results indicate that eyes containing the RETISERT implant for an average of 3.54 years had a lower mean corneal endothelial cell density (mean paired difference of -435 cells/mm 2 ) compared with non-implanted eyes (p<0.01).

<table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">TIME POINT</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">STUDY 1</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">STUDY 2</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>N=108</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>N=116</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"><paragraph>Uveitis Recurrence Rates ^1,2 N (%) </paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34 Weeks Pre- implantation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>58 (53.7)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>46 (39.7)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>34 Weeks Post- implantation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 (1.8)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15 (12.9)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 Year Post-implantation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4 (3.7)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15 (12.9)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 Years Post-implantation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11 (10.2)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16 (13.8)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 Years Post-implantation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>22 (20.4)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20 (17.2)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3 Years ³Post- implantation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>33 (30.6)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>28 (24.1)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING The implant consists of a tablet encased in a silicone elastomer cup containing a release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The silicone elastomer cup assembly is attached to a silicone elastomer suture tab with silicone adhesive. Each RETISERT is approximately 3 mm x 2 mm x 5 mm. Each implant is stored in a clear polycarbonate case within a foil pouch within a Tyvek peelable overwrap. Each packaged implant is provided in a carton which includes the package insert. NDC 24208-416-01 0.59 mg 1 count Storage: Store in the original container at 15°C to 25°C (59°F to 77°F). Protect from freezing.

17 PATIENT COUNSELING INFORMATION Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of RETISERT. As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. Following implantation of RETISERT, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively. Based on clinical trials with RETISERT, within 3 years post-implantation, approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure [see Adverse Reactions ( 6.1 )] . Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. Manufactured for: Bausch & Lomb Americas Inc Bridgewater, NJ 08807 USA Manufactured by: Bausch + Lomb Ireland Limited Waterford, Ireland RETISERT is a trademark of Bausch & Lomb Incorporated or its affiliates. © 2025 Bausch & Lomb Incorporated or its affiliates 9028012

1 INDICATIONS AND USAGE 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.

2 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.

on, 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.

3 DOSAGE FORMS AND STRENGTHS ILUVIEN is a non-bioerodable intravitreal implant in a drug delivery system containing 0.19 mg fluocinolone acetonide, designed to release fluocinolone acetonide at an initial rate of 0.25 mcg/day and lasting 36 months. Intravitreal implant containing 0.19 mg fluocinolone acetonide in a drug delivery system. (3)

4 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.

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) Intraocular Pressure (IOP) Increase : Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity, and fields of vision. (5.2) Cataracts : Use of corticosteroids may result in posterior subcapsular cataract formation. (5.3) Delayed Healing : The use of corticosteroids after cataract surgery may delay healing and increase the incidence of bleb formation. (5.4) Corneal and Scleral Melting : In those diseases causing thinning of the cornea or sclera, ophthalmic corticosteroids may lead to perforation of the globe. (5.5) Bacterial Infections : Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. (5.6) Viral Infections : Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). (5.7) Fungal Infections : Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. (5.8) Implant Migration : The implant may migrate into the anterior chamber if the posterior lens capsule is not intact. (5.9) 5.1 Intravitreal Injection-related Effects Intravitreal injections, including those with ILUVIEN, have been associated with endophthalmitis, eye inflammation, increased or decreased intraocular pressure, and choroidal or retinal detachments. For patients with non-infectious uveitis affecting the posterior segment, hypotony has been observed within 24 hours of injection and has resolved within 2 weeks. Patients should be monitored following the intravitreal injection [see Patient Counseling Information (17) ] . Patients may experience temporary blurred vision after injection of the implant. 5.2 Intraocular Pressure (IOP) Increase Prolonged use of corticosteroids may result in the development of glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be routinely monitored during the course of the treatment. 5.3 Cataracts The use of corticosteroids may result in posterior subcapsular cataract formation. 5.4 Delayed Corneal Wound Healing The use of corticosteroids after cataract surgery may delay healing and increase the incidence of bleb formation. 5.5 Corneal and Scleral Melting Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of ophthalmic corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation of the globe. 5.6 Bacterial Infections Prolonged use of corticosteroids may suppress the host immune response and thus increase the hazard of secondary ocular infections.

wn to cause corneal and scleral thinning. Use of ophthalmic corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation of the globe. 5.6 Bacterial Infections Prolonged use of corticosteroids may suppress the host immune response and thus increase the hazard of secondary ocular infections. Acute purulent or parasitic infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication. If signs and symptoms fail to improve after 2 days, the patient should be reevaluated. 5.7 Viral Infections Use of ocular corticosteroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended. 5.8 Fungal Infections Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid application. Fungus invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. 5.9 Risk of Implant Migration Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.

6 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.

capsular, 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.

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.

<table width="650" styleCode="Noautorules" ID="table1"><caption>Table 1: Ocular Adverse Reactions Reported by &#x2265;1% of DME Patients and Non-ocular Adverse Reactions Reported by &#x2265;5% of DME Patients</caption><tfoot><tr><td colspan="5">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.</td></tr><tr><td colspan="5">² 235 of the 375 ILUVIEN subjects were phakic at baseline; 121 of 185 sham-controlled subjects were phakic at baseline.

diabetic in patients who were phakic at baseline. Among these patients, 80% of ILUVIEN subjects vs. 27% of sham-controlled subjects underwent cataract surgery.</td></tr><tr><td colspan="5">² 235 of the 375 ILUVIEN subjects were phakic at baseline; 121 of 185 sham-controlled subjects were phakic at baseline. </td></tr></tfoot><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Adverse Reactions</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">ILUVIEN (N=375) n (%)</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Sham (N=185) n (%)</content></td></tr><tr><td align="center" colspan="3" styleCode="Botrule Rrule Lrule bold">Ocular</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Cataract¹</td><td align="center" styleCode="Botrule Rrule Lrule">192/235² (82%)</td><td align="center" styleCode="Botrule Rrule Lrule">61/121² (50%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Myodesopsia</td><td align="center" styleCode="Botrule Rrule Lrule">80 (21%)</td><td align="center" styleCode="Botrule Rrule Lrule">17 (9%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Eye pain</td><td align="center" styleCode="Botrule Rrule Lrule">57 (15%)</td><td align="center" styleCode="Botrule Rrule Lrule">25 (14%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Conjunctival haemorrhage</td><td align="center" styleCode="Botrule Rrule Lrule">50 (13%)</td><td align="center" styleCode="Botrule Rrule Lrule">21 (11%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Posterior capsule opacification</td><td align="center" styleCode="Botrule Rrule Lrule">35 (9%)</td><td align="center" styleCode="Botrule Rrule Lrule">6 (3%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Eye irritation</td><td align="center" styleCode="Botrule Rrule Lrule">30 (8%)</td><td align="center" styleCode="Botrule Rrule Lrule">11 (6%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Vitreous detachment</td><td align="center" styleCode="Botrule Rrule Lrule">26 (7%)</td><td align="center" styleCode="Botrule Rrule Lrule">12 (7%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Conjunctivitis</td><td align="center" styleCode="Botrule Rrule Lrule">14 (4%)</td><td align="center" styleCode="Botrule Rrule Lrule">5 (3%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Corneal oedema</td><td align="center" styleCode="Botrule Rrule Lrule">13 (4%)</td><td align="center" styleCode="Botrule Rrule Lrule">3 (2%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Foreign body sensation in eyes</td><td align="center" styleCode="Botrule Rrule Lrule">12 (3%)</td><td align="center" styleCode="Botrule Rrule Lrule">4 (2%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Eye pruritus</td><td align="center" styleCode="Botrule Rrule Lrule">10 (3%)</td><td align="center" styleCode="Botrule Rrule Lrule">3 (2%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Ocular hyperaemia</td><td align="center" styleCode="Botrule Rrule Lrule">10 (3%)</td><td align="center" styleCode="Botrule Rrule Lrule">3 (2%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Optic atrophy</td><td align="center" styleCode="Botrule Rrule Lrule">9 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 (1%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Ocular discomfort</td><td align="center" styleCode="Botrule Rrule Lrule">8 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 (1%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Photop

ter" styleCode="Botrule Rrule Lrule">2 (1%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Ocular discomfort</td><td align="center" styleCode="Botrule Rrule Lrule">8 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 (1%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Photop hobia</td><td align="center" styleCode="Botrule Rrule Lrule">7 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 (1%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Retinal exudates</td><td align="center" styleCode="Botrule Rrule Lrule">7 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">0 (0%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Anterior chamber cell</td><td align="center" styleCode="Botrule Rrule Lrule">6 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 (1%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Eye discharge</td><td align="center" styleCode="Botrule Rrule Lrule">6 (2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 (1%)</td></tr><tr><td align="center" colspan="3" styleCode="Botrule Rrule Lrule bold">Non-ocular</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Anemia</td><td align="center" styleCode="Botrule Rrule Lrule">40 (11%)</td><td align="center" styleCode="Botrule Rrule Lrule">10 (5%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Headache</td><td align="center" styleCode="Botrule Rrule Lrule">33 (9%)</td><td align="center" styleCode="Botrule Rrule Lrule">11 (6%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Renal Failure</td><td align="center" styleCode="Botrule Rrule Lrule">32 (9%)</td><td align="center" styleCode="Botrule Rrule Lrule">10 (5%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Pneumonia</td><td align="center" styleCode="Botrule Rrule Lrule">28 (7%)</td><td align="center" styleCode="Botrule Rrule Lrule">8 (4%)</td></tr></tbody></table>

de="Botrule Rrule Lrule">32 (9%)</td><td align="center" styleCode="Botrule Rrule Lrule">10 (5%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Pneumonia</td><td align="center" styleCode="Botrule Rrule Lrule">28 (7%)</td><td align="center" styleCode="Botrule Rrule Lrule">8 (4%)</td></tr></tbody></table> <table width="700" styleCode="Noautorules" ID="table2"><caption>Table 2: Summary of Elevated IOP Related Adverse Reactions in DME Patients</caption><col width="10%"/><col width="5%"/><col width="5%"/><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Event</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">ILUVIEN (N=375) n (%)</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Sham (N=185) n (%)</content></td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">IOP elevation &#x2265; 10 mmHg from Baseline</td><td align="center" styleCode="Botrule Rrule Lrule">127 (34%)</td><td align="center" styleCode="Botrule Rrule Lrule">18 (10%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">IOP elevation &#x2265; 30 mmHg</td><td align="center" styleCode="Botrule Rrule Lrule">75 (20%)</td><td align="center" styleCode="Botrule Rrule Lrule">8 (4%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Any IOP-lowering medication</td><td align="center" styleCode="Botrule Rrule Lrule">144 (38%)</td><td align="center" styleCode="Botrule Rrule Lrule">26 (14%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Any surgical intervention for elevated intraocular pressure</td><td align="center" styleCode="Botrule Rrule Lrule">18 (5%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 (1%)</td></tr></tbody></table> <table width="650" styleCode="Noautorules" ID="table3"><caption>Table 3: Ocular Adverse Reactions Reported in &#x2265; 1% of Subject Eyes and Non-Ocular Adverse Reactions Reported in &#x2265; 2% of Patients with Non-Infectious Uveitis</caption><tfoot><tr><td colspan="3">¹ Includes cataract, cataract subcapsular and lenticular opacities in study eyes that were phakic at baseline.

Ocular Adverse Reactions Reported in &#x2265; 1% of Subject Eyes and Non-Ocular Adverse Reactions Reported in &#x2265; 2% of Patients with Non-Infectious Uveitis</caption><tfoot><tr><td colspan="3">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.</td></tr></tfoot><tbody><tr><td align="center" colspan="3" styleCode="Botrule Rrule Lrule Toprule bold">Ocular</td></tr><tr><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">ADVERSE REACTIONS</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%)</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule" valign="top"><content styleCode="bold">Sham Injection (N=94 Eyes) n (%) </content></td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Cataract¹</td><td align="center" styleCode="Botrule Rrule Lrule">63/113 (56%)</td><td align="center" styleCode="Botrule Rrule Lrule">13/56 (23%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Visual Acuity Reduced</td><td align="center" styleCode="Botrule Rrule Lrule">33 ( 15%)</td><td align="center" styleCode="Botrule Rrule Lrule">11 (12%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Macular Edema</td><td align="center" styleCode="Botrule Rrule Lrule">25 ( 11%)</td><td align="center" styleCode="Botrule Rrule Lrule">33 (35%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Uveitis</td><td align="center" styleCode="Botrule Rrule Lrule">22 ( 10%)</td><td align="center" styleCode="Botrule Rrule Lrule">33 ( 35%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Conjunctival Hemorrhage</td><td align="center" styleCode="Botrule Rrule Lrule">17 ( 8%)</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 5%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Eye Pain</td><td align="center" styleCode="Botrule Rrule Lrule">17 ( 8%)</td><td align="center" styleCode="Botrule Rrule Lrule">12 (13%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Hypotony Of Eye</td><td align="center" styleCode="Botrule Rrule Lrule">16 ( 7%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Anterior Chamber Inflammation</td><td align="center" styleCode="Botrule Rrule Lrule">12 ( 5%)</td><td align="center" styleCode="Botrule Rrule Lrule">6 ( 6%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Dry Eye</td><td align="center" styleCode="Botrule Rrule Lrule">10 ( 4%)</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 3%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Vitreous Opacities</td><td align="center" styleCode="Botrule Rrule Lrule">9 ( 4%)</td><td align="center" styleCode="Botrule Rrule Lrule">8 ( 9%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Conjunctivitis</td><td align="center" styleCode="Botrule Rrule Lrule">9 ( 4%)</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 5%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Posterior Capsule Opacification</td><td align="center" styleCode="Botrule Rrule Lrule">8 ( 4%)</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 3%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Ocular Hyperemia</td><td align="center" styleCode="Botrule Rrule Lrule">8 ( 4%)</td><td align="center" styleCode="Botrule Rrule Lrule">7 ( 7%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Vitreous Haze</td><td align="center" styleCode="Botrul

td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Ocular Hyperemia</td><td align="center" styleCode="Botrule Rrule Lrule">8 ( 4%)</td><td align="center" styleCode="Botrule Rrule Lrule">7 ( 7%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Vitreous Haze</td><td align="center" styleCode="Botrul e Rrule Lrule">7 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">4 ( 4%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Foreign Body Sensation In Eyes</td><td align="center" styleCode="Botrule Rrule Lrule">7 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 ( 2%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Vitritis</td><td align="center" styleCode="Botrule Rrule Lrule">6 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">8 ( 9%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Vitreous Floaters</td><td align="center" styleCode="Botrule Rrule Lrule">6 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 5%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Eye Pruritus</td><td align="center" styleCode="Botrule Rrule Lrule">6 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 5%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Conjunctival Hyperemia</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 ( 2%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Ocular Discomfort</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Macular Fibrosis</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 ( 2%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Glaucoma</td><td align="center" styleCode="Botrule Rrule Lrule">4 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Photopsia</td><td align="center" styleCode="Botrule Rrule Lrule">4 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 ( 2%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Vitreous Hemorrhage</td><td align="center" styleCode="Botrule Rrule Lrule">4 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">0</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Iridocyclitis</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">7 ( 7%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Eye Inflammation</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">2 ( 2%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Choroiditis</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Eye Irritation</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Visual Field Defect</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">0</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Lacrimation Increased</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">0</td></tr><tr><td align="center" colspan="3" styleCode="Botrule Rrule Lrule Toprule bold">Non-ocular</td></tr><tr><td align="center" styleCode="Toprule Botru

"Botrule Rrule Lrule">Lacrimation Increased</td><td align="center" styleCode="Botrule Rrule Lrule">3 ( 1%)</td><td align="center" styleCode="Botrule Rrule Lrule">0</td></tr><tr><td align="center" colspan="3" styleCode="Botrule Rrule Lrule Toprule bold">Non-ocular</td></tr><tr><td align="center" styleCode="Toprule Botru le Rrule Lrule"><content styleCode="bold">ADVERSE REACTIONS</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Fluocinolone acetonide intravitreal implant (N=214 Patients) n (%)</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Sham Injection (N=94 Patients) n (%) </content> </td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Nasopharyngitis</td><td align="center" styleCode="Botrule Rrule Lrule">10 ( 5%)</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 5%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Hypertension</td><td align="center" styleCode="Botrule Rrule Lrule">6 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Arthralgia</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr></tbody></table>

de="Botrule Rrule Lrule">6 ( 3%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr><tr><td align="left" styleCode="Botrule Rrule Lrule">Arthralgia</td><td align="center" styleCode="Botrule Rrule Lrule">5 ( 2%)</td><td align="center" styleCode="Botrule Rrule Lrule">1 ( 1%)</td></tr></tbody></table> <table width="650" styleCode="Noautorules" ID="table4"><caption>Table 4: Summary of Elevated IOP Related Adverse Reactions in Patients with Non-Infectious Uveitis</caption><tbody><tr><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">ADVERSE REACTIONS</content></td><td align="center" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%)</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule Lrule"><content styleCode="bold">Sham (N=94 Eyes) n (%) </content></td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">IOP elevation &#x2265; 10 mmHg from Baseline</td><td valign="top" align="center" styleCode="Botrule Rrule Lrule">50 (22%)</td><td valign="top" align="center" styleCode="Botrule Rrule Lrule">11 (12%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">IOP elevation &gt; 30 mmHg</td><td align="center" styleCode="Botrule Rrule Lrule">28 (12%)</td><td align="center" styleCode="Botrule Rrule Lrule">3 (3%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Any IOP-lowering medication</td><td align="center" styleCode="Botrule Rrule Lrule">98 (43%)</td><td align="center" styleCode="Botrule Rrule Lrule">39 (41%)</td></tr><tr><td align="center" styleCode="Botrule Rrule Lrule">Any surgical intervention for elevated IOP</td><td valign="top" align="center" styleCode="Botrule Rrule Lrule">5 (2%)</td><td valign="top" align="center" styleCode="Botrule Rrule Lrule">2 (2%)</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ILUVIEN use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with fluocinolone acetonide. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. It is not known whether ILUVIEN can cause fetal harm when administered to a pregnant women or affect reproduction capacity. ILUVIEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States 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. 8.2 Lactation Risk Summary Systemically administered corticosteroids that are present in human milk can suppress growth and interfere with endogenous corticosteroid production. Clinical or nonclinical lactation studies have not been conducted with ILUVIEN. The systemic concentration of fluocinolone acetonide following intravitreal treatment with ILUVIEN is low [see Clinical Pharmacology (12.3) ]. It is not known whether intravitreal treatment with ILUVIEN could result in sufficient systemic absorption to produce detectable quantities in human milk, or affect breastfed infants or milk production. Exercise caution when ILUVIEN is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for ILUVIEN and any potential adverse effects on the breastfed infant from ILUVIEN or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ILUVIEN have not been established in pediatric patients. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ILUVIEN use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with fluocinolone acetonide. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. It is not known whether ILUVIEN can cause fetal harm when administered to a pregnant women or affect reproduction capacity. ILUVIEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States 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.

11 DESCRIPTION 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

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids inhibit inflammatory responses to a variety of inciting agents including multiple inflammatory cytokines. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. Corticosteroids are thought to act by inhibition of phospholipase A 2 via induction of inhibitory proteins collectively called lipocortins. It is postulated that these proteins control biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting release of the common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 . 12.3 Pharmacokinetics In a human pharmacokinetic study of ILUVIEN, fluocinolone acetonide concentrations in plasma were below the lower limit of quantitation of the assay (100 pg/mL) at all post-administration time points from Day 7 through Month 36 following intravitreal administration of a 0.2 mcg/day or 0.5 mcg/day fluocinolone acetonide insert.

12.1 Mechanism of Action Corticosteroids inhibit inflammatory responses to a variety of inciting agents including multiple inflammatory cytokines. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. Corticosteroids are thought to act by inhibition of phospholipase A 2 via induction of inhibitory proteins collectively called lipocortins. It is postulated that these proteins control biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting release of the common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 .

12.3 Pharmacokinetics In a human pharmacokinetic study of ILUVIEN, fluocinolone acetonide concentrations in plasma were below the lower limit of quantitation of the assay (100 pg/mL) at all post-administration time points from Day 7 through Month 36 following intravitreal administration of a 0.2 mcg/day or 0.5 mcg/day fluocinolone acetonide insert.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to determine the carcinogenic potential or the effect on fertility of ILUVIEN. Fluocinolone acetonide was not genotoxic in vitro in the Ames test (S. typhimurium and E. coli) and the mouse lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to determine the carcinogenic potential or the effect on fertility of ILUVIEN. Fluocinolone acetonide was not genotoxic in vitro in the Ames test (S. typhimurium and E. coli) and the mouse lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay.

14 CLINICAL STUDIES Diabetic Macular Edema The efficacy of ILUVIEN was assessed in two three year, randomized (2:1, active: sham), multicenter, double-masked, parallel-groups studies that enrolled patients with diabetic macular edema (DME) that had previously been treated with laser photocoagulation. The primary efficacy endpoint in both trials was the proportion of subjects in whom vision had improved by 15 letters or more from baseline after 24 months of follow-up. Table 5: Baseline BCVA (Letters) Study 1 Study 2 ILUVIEN (N=190) Sham (N=95) ILUVIEN (N=186) Sham (N=90) Mean (SD) Median (Range) 53 (13) 57 (19-75) 55 (11) 58 (25-69) 53 (12) 56 (20-70) 55 (11) 58 (21-68) Table 6: Visual Acuity Outcomes at Month 24 (All randomized subjects with LOCF) a Study 1: ILUVIEN , N=190; Sham, N=95 b Study 2: ILUVIEN , N=186; Sham, N=90 Study Outcomes ILUVIEN Sham Estimated Difference (95% CI) 1 a Gain of ≥15 letters in BCVA (n (%)) 51 (27%) 14 (15%) 12.1% (2.6%, 21.6%) Loss of ≥15 letters in BCVA (n (%)) 26 (14%) 5 (5%) 8.4% (1.8%, 15.1%) Mean change from baseline in BCVA (SD) 3.7 (18.7) 3.2 (13.1) 1.8 (-2.8, 6.3) 2 b Gain of ≥15 letters in BCVA (n (%)) 57 (31%) 16 (18%) 13.0% (2.7%, 23.4%) Loss of ≥15 letters in BCVA (n (%)) 22 (12%) 9 (10%) 1.8% (-5.9%, 9.6%) Mean change from baseline in BCVA (SD) 5.2 (18.0) 0.0 (15.6) 6.1 (1.4, 10.8) Visual acuity outcomes by lens status (Phakic or Pseudophakic) at different visits are presented in Figure 3 and Figure 4 . The occurrence of cataracts impacted visual acuity during the study. Patients who were pseudophakic at baseline achieved greater mean BCVA change from baseline at the Month 24 study visit. Figure 3: Proportion of Subjects with >=15 Letters Improvement from Baseline BCVA in the Study Eye Figure 4: Mean BCVA Change from Baseline The BCVA outcomes for the Pseudophakic and Phakic subgroups from Studies 1 and 2 at Month 24 are presented in Table 7 . Table 7: Visual Acuity outcomes at Month 24 (Subgroup for pooled data with LOCF) a Pseudophakic : ILUVIEN, N=140; Sham, N=64 b Phakic: ILUVIEN, N=236; Sham, N=121 Lens Status Outcomes ILUVIEN Sham Estimated Difference (95% CI) a Pseudophakic Gain of ≥15 letters in BCVA (n (%)) 39 (28%) 8 (13%) 15.4% (4.4%, 26.3%) Loss of ≥15 letters in BCVA (n (%)) 7 (5%) 7 (11%) -5.9% (-14.4%, 2.5%) Mean change from baseline in BCVA (SD) 7.1 (14.5) 1.5 (17.4) 5.6 (0.7, 10.6) b Phakic Gain of ≥15 letters in BCVA (n (%)) 69 (29%) 22 (18%) 11.1% (2.1%, 20.1%) Loss of ≥15 letters in BCVA (n (%)) 41 (17%) 7 (6%) 11.6% (5.2%, 18%) Mean change from baseline in BCVA (SD) 2.8 (20.1) 1.8 (12.6) 1 (-2.5 ,4.4) Chronic Non-Infectious Uveitis Affecting the Posterior Segment The efficacy of fluocinolone acetonide intravitreal implant was assessed in two randomized (2:1, fluocinolone acetonide intravitreal implant: sham-injection), multi-center, double-masked, parallel-groups studies (NCT #01694186 and #02746991) that enrolled patients with non-infectious uveitis affecting the posterior segment of the eye. The primary efficacy endpoint in both trials was the proportion of patients who experienced a recurrence of uveitis in the study eye within 6 months of follow-up; recurrence was also assessed at 12 months. Recurrence of uveitis was defined as either deterioration in visual acuity, vitreous haze attributable to non-infectious uveitis or the need for rescue medications.

he proportion of patients who experienced a recurrence of uveitis in the study eye within 6 months of follow-up; recurrence was also assessed at 12 months. Recurrence of uveitis was defined as either deterioration in visual acuity, vitreous haze attributable to non-infectious uveitis or the need for rescue medications. Table 8: Efficacy Results of Recurrence of Uveitis in Randomized Study Eyes Study 1 Study 2 FAc Implant Sham FAc Implant Sham N = 87 N = 42 N = 101 N = 52 Eyes with recurrence within 6 months, n (%) 16 (18%) 33 (79%) 22 (22%) 28 (54%) Difference (95% CI) in recurrence rates 60% (41%, 73%) 32% (15%, 48%) P-value < 0.01 < 0.01 Eyes with recurrence within 12 months, n (%) 24 (28%) 36 (86%) 33 (33%) 31 (60%) Difference (95% CI) in recurrence rates 58% (40%, 70%) 27% (9%, 43%) Figure 5: Time to First Recurrence of Uveitis (ITT: All Randomized Patients) iluvien-figure-4 iluvien-figure-5 iluvien-figure-6

<table width="800" styleCode="Noautorules" ID="table5" cellpadding="2"><caption>Table 5: Baseline BCVA (Letters)</caption><tbody><tr><td align="center" styleCode="Lrule Toprule Rrule"/><td colspan="2" align="center" styleCode="Lrule Botrule Rrule Toprule"><content styleCode="bold">Study 1</content></td><td colspan="2" align="center" styleCode="Lrule Botrule Rrule Toprule"><content styleCode="bold">Study 2</content></td></tr><tr><td align="center" styleCode="Lrule Toprule Rrule Botrule"/><td align="center" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold">ILUVIEN (N=190)</content></td><td align="center" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold">Sham (N=95)</content></td><td align="center" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold">ILUVIEN (N=186)</content></td><td align="center" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold">Sham (N=90)</content></td></tr><tr><td styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold">Mean (SD) Median (Range)</content></td><td align="center" styleCode="Lrule Toprule Rrule Botrule">53 (13) 57 (19-75)</td><td align="center" styleCode="Lrule Toprule Rrule Botrule">55 (11) 58 (25-69)</td><td align="center" styleCode="Lrule Toprule Rrule Botrule">53 (12) 56 (20-70)</td><td align="center" styleCode="Lrule Toprule Rrule Botrule">55 (11) 58 (21-68)</td></tr></tbody></table>

"Lrule Toprule Rrule Botrule">53 (13) 57 (19-75)</td><td align="center" styleCode="Lrule Toprule Rrule Botrule">55 (11) 58 (25-69)</td><td align="center" styleCode="Lrule Toprule Rrule Botrule">53 (12) 56 (20-70)</td><td align="center" styleCode="Lrule Toprule Rrule Botrule">55 (11) 58 (21-68)</td></tr></tbody></table> <table width="800" styleCode="Noautorules" ID="table6" cellpadding="5"><caption>Table 6: Visual Acuity Outcomes at Month 24 (All randomized subjects with LOCF)</caption><col width="4%"/><col width="36%"/><col width="15%"/><col width="15%"/><col width="30%"/><tfoot><tr><td colspan="5"> ^aStudy 1: <content styleCode="bold">ILUVIEN</content>, N=190; Sham, N=95 ^bStudy 2: <content styleCode="bold">ILUVIEN</content>, N=186; Sham, N=90</td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Study </content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Outcomes</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> ILUVIEN</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Sham</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Estimated Difference (95% CI)</content></td></tr><tr><td valign="top" rowspan="3" styleCode="Lrule Toprule Rrule Botrule"> 1^a</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Gain of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 51 (27%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 14 (15%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 12.1% (2.6%, 21.6%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Loss of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 26 (14%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 5 (5%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 8.4% (1.8%, 15.1%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Mean change from baseline in BCVA (SD)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 3.7 (18.7)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 3.2 (13.1)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1.8 (-2.8, 6.3)</td></tr><tr><td valign="top" rowspan="3" styleCode="Lrule Toprule Rrule Botrule"> 2^b</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Gain of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 57 (31%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 16 (18%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 13.0% (2.7%, 23.4%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Loss of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 22 (12%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 9 (10%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1.8% (-5.9%, 9.6%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Mean change from baseline in BCVA (SD)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 5.2 (18.0)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 0.0 (15.6)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 6.1 (1.4, 10.8)</td></tr></tbody></table>

="Lrule Toprule Rrule Botrule"> Mean change from baseline in BCVA (SD)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 5.2 (18.0)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 0.0 (15.6)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 6.1 (1.4, 10.8)</td></tr></tbody></table> <table width="800" styleCode="Noautorules" ID="table7" cellpadding="5"><caption>Table 7: Visual Acuity outcomes at Month 24 (Subgroup for pooled data with LOCF)</caption><col width="12%"/><col width="35%"/><col width="15%"/><col width="15%"/><col width="23%"/><tfoot><tr><td colspan="5"> ^aPseudophakic : ILUVIEN, N=140; Sham, N=64 ^bPhakic: ILUVIEN, N=236; Sham, N=121</td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Lens Status</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Outcomes</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> ILUVIEN</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Sham</content></td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"><content styleCode="bold"> Estimated Difference (95% CI)</content></td></tr><tr><td valign="top" rowspan="3" styleCode="Lrule Toprule Rrule Botrule"> ^aPseudophakic</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Gain of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 39 (28%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 8 (13%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 15.4% (4.4%, 26.3%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Loss of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 7 (5%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 7 (11%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> -5.9% (-14.4%, 2.5%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Mean change from baseline in BCVA (SD)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 7.1 (14.5)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1.5 (17.4)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 5.6 (0.7, 10.6)</td></tr><tr><td valign="top" rowspan="3" styleCode="Lrule Toprule Rrule Botrule"> ^bPhakic</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Gain of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 69 (29%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 22 (18%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 11.1% (2.1%, 20.1%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Loss of &#x2265;15 letters in BCVA (n (%))</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 41 (17%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 7 (6%)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 11.6% (5.2%, 18%)</td></tr><tr><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> Mean change from baseline in BCVA (SD)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 2.8 (20.1)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1.8 (12.6)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1 (-2.5 ,4.4)</td></tr></tbody></table>

de="Lrule Toprule Rrule Botrule"> Mean change from baseline in BCVA (SD)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 2.8 (20.1)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1.8 (12.6)</td><td valign="top" styleCode="Lrule Toprule Rrule Botrule"> 1 (-2.5 ,4.4)</td></tr></tbody></table> <table width="830" styleCode="Noautorules" ID="table8" cellpadding="5"><caption>Table 8: Efficacy Results of Recurrence of Uveitis in Randomized Study Eyes</caption><col width="40%"/><col width="15%"/><col width="15%"/><col width="15%"/><col width="15%"/><tbody><tr><td align="center" valign="top" styleCode="Lrule Toprule bold"/><td align="center" valign="top" colspan="2" styleCode="Toprule bold">Study 1</td><td align="center" valign="top" colspan="2" styleCode="Toprule Rrule bold">Study 2</td></tr><tr><td align="center" valign="top" styleCode="Lrule bold"/><td align="center" valign="top" styleCode=" bold">FAc Implant</td><td align="center" valign="top" styleCode=" bold">Sham</td><td align="center" valign="top" styleCode=" bold">FAc Implant</td><td align="center" valign="top" styleCode="Rrule bold">Sham</td></tr><tr><td align="center" valign="top" styleCode="Lrule bold"/><td align="center" valign="top" styleCode="bold">N = 87</td><td align="center" valign="top" styleCode="bold">N = 42</td><td align="center" valign="top" styleCode="bold">N = 101</td><td align="center" valign="top" styleCode="Rrule bold">N = 52</td></tr><tr><td align="left" valign="top" styleCode="Lrule Toprule bold">Eyes with recurrence within 6 months, n (%)</td><td align="center" valign="top" styleCode="Toprule bold">16 (18%)</td><td align="center" valign="top" styleCode="Toprule bold">33 (79%)</td><td align="center" valign="top" styleCode="Toprule bold">22 (22%)</td><td align="center" valign="top" styleCode="Toprule Rrule bold">28 (54%)</td></tr><tr><td align="left" valign="top" styleCode="Lrule bold">Difference (95% CI) in recurrence rates</td><td align="center" colspan="2" valign="top" styleCode="bold">60% (41%, 73%)</td><td align="center" colspan="2" valign="top" styleCode="Rrule bold">32% (15%, 48%)</td></tr><tr><td align="left" valign="top" styleCode="Lrule ">P-value</td><td align="center" colspan="2" valign="top">&lt; 0.01</td><td align="center" colspan="2" valign="top" styleCode="Rrule">&lt; 0.01</td></tr><tr><td align="left" valign="top" styleCode="Lrule Toprule bold">Eyes with recurrence within 12 months, n (%)</td><td align="center" valign="top" styleCode="Toprule bold">24 (28%)</td><td align="center" valign="top" styleCode="Toprule bold">36 (86%)</td><td align="center" valign="top" styleCode="Toprule bold">33 (33%)</td><td align="center" valign="top" styleCode="Toprule Rrule bold">31 (60%)</td></tr><tr><td align="left" valign="top" styleCode="Lrule Botrule bold">Difference (95% CI) in recurrence rates</td><td align="center" colspan="2" valign="top" styleCode="Botrule bold">58% (40%, 70%)</td><td align="center" colspan="2" valign="top" styleCode="Rrule Botrule bold">27% (9%, 43%)</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING ILUVIEN® (fluocinolone acetonide intravitreal implant) 0.19 mg is supplied in a sterile, single-use preloaded applicator with a 25-gauge needle, packaged in a tray sealed with a lid inside a carton. NDC 68611-190-02 Storage: Store at 15°C to 30°C (59°F to 86° F).

17 PATIENT COUNSELING INFORMATION Steroid-related Effects Advise patients that a cataract may occur after treatment with ILUVIEN. If this occurs, advise patients that their vision will decrease, and they will need an operation to remove the cataract and restore their vision. Advise patients that they may develop increased intraocular pressure with ILUVIEN treatment, and the increased IOP may need to be managed with eye drops, or surgery. When to Seek Physician Advice Advise patients that in the days following intravitreal injection of ILUVIEN, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure. Advise patients that if the eye becomes red, sensitive to light, painful, or develops a change in vision, they should seek immediate care from an ophthalmologist. Driving and Using Machines Inform patients that they may experience temporary blurred vision after injection of the implant. Advise patients not to drive or use machines until this has been resolved. Manufactured for: Alimera Sciences, Inc. Baudette, MN 56623 Patented. alimera