Prescription Drugs

CLINICAL PHARMACOLOGY 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 A2 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 A2. Corticosteroids are capable of producing a rise in intraocular pressure. 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. 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 preimplantation period. Detailed results are shown in table 1 below: Table 1: Uveitis Recurrence Rates Time Point Study 1 N=108 Study 2 N=116 UVEITIS RECURRENCE RATES1,2 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 Years3 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 χ2 test. 3 Results presented include imputed recurrences. Recurrences were imputed when a subject was not seen within 10 weeks of their final scheduled visit.

CLINICAL PHARMACOLOGY 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 A2 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 A2. 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. Clinical Studies 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 3: Baseline BCVA (Letters) Study 1 Study 2 ILUVIEN (N=190) Sham (N=95) ILUVIEN (N=186) Sham (N=90) Mean (SD) 53 (13) 55 (11) 53 (12) 55 (11) Median (Range) 57 (19-75) 58 (25-69) 56 (20-70) 58 (21-68) Table 4: Visual Acuity outcomes at Month 24 (All randomized subjects with LOCF) Study Outcomes ILUVIEN Sham Estimated Difference (95% CI) 1a 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) 2b 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) aStudy 1: ILUVIEN, N=190; Sham, N=95 bStudy 2: ILUVIEN, N=186; Sham, N=90 Visual acuity outcomes by lens status (Phakic or Pseudophakic) at different visits are presented in Figure 2 and Figure 3. 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 2: Proportion of subjects with >=15 Letters Improvement from Baseline BCVA in the Study Eye Figure 3: 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 5. Table 5: Visual Acuity outcomes at Month 24 (Subgroup for pooled data with LOCF) Lens Status Outcomes ILUVIEN Sham Estimated Difference (95% CI) aPseudophakic 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) bPhakic 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) aPseudophakic : ILUVIEN, N=140; Sham, N=64 bPhakic: ILUVIEN, N=236; Sham, N=121

Find Lowest Prices on RETISERT® (fluocinolone acetonide) Intravitreal Implant 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 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. The drug substance is the synthetic corticosteroid fluocinolone acetonide, represented by the following structural formula: C24H30F2O6 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 265-266°C. Each RETISERT consists of a tablet containing 0.59 mg of the active ingredient, Fluocinolone Acetonide, USP, and the following inactives: microcrystalline cellulose, polyvinyl alcohol, and magnesium stearate.

Find Lowest Prices on ILUVIEN® (fluocinolone acetonide) Intravitreal Implant 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 μg/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-[(1methylethylidene)bis-(oxy)]-pregna-1,4-diene-3,20-dione. Its chemical structure is: MW 452.50; molecular formula C24H30F206 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.

INDICATIONS RETISERT is indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. DOSAGE AND ADMINISTRATION Dosing Information RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg 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 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. Following depletion of fluocinolone acetonide as evidenced by recurrence of uveitis, RETISERT may be replaced. 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. HOW SUPPLIED Dosage Forms And Strengths 0.59 mg fluocinolone acetonide intravitreal implant. 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 Storage: Store in the original container at 15° - 25°C (59° - 77°F). Protect from freezing. Revised May 2011. Marketed by: Bausch & Lomb Incorporated Rochester, NY 14609. Manufactured by: Bausch & Lomb Incorporated., Waterford, Ireland

INDICATIONS ILUVIEN® (fluocinolone acetonide intravitreal implant) 0.19 mg 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. DOSAGE AND ADMINISTRATION General Dosing Information For ophthalmic intravitreal injection. 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 elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report without delay any symptoms suggestive of endophthalmitis. HOW SUPPLIED Dosage Forms And Sterngths 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 μg/day and lasting 36 months. 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° -30° C (59° -86° F). Manufactured for: Alimera Sciences, Inc. 6120 Windward Parkway Alpharetta, GA 30005. Revised: Nov 2016.

PATIENT 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 Clinical Trials Experience - Ocular Events section). 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.

PATIENT 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. Intravitreal Injection-Related Effects 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. When To Seek Physician Advice 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 visual blurring after receiving an intravitreal injection. Advise patients not to drive or use machines until this has been resolved.

OVERDOSE No information provided. CONTRAINDICATIONS Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures Surgical placement of RETISERT (fluocinolone acetonide intravitreal implant) 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.

OVERDOSE No Information Provided CONTRAINDICATIONS 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. Glaucoma ILUVIEN is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8. Hypersensitivity ILUVIEN is contraindicated in patients with known hypersensitivity to any components of this product.

SIDE EFFECTS 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, macula 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. 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. DRUG INTERACTIONS No information provided.

SIDE EFFECTS 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. 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. ILUVIEN was studied in two multicenter, randomized, sham-controlled, 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 Patients and Non-ocular Adverse Reactions Reported by ≥5% of Patients Adverse Reactions ILUVIEN(N=375) n (%) Sham (N=185) n (%) Ocular Cataract1 192/2352 (82%) 61/1212 (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%) 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. 2235 of the 375 ILUVIEN subjects were phakic at baseline; 121 of 185 sham-controlled subjects were phakic at baseline. Increased Intraocular Pressure Table 2: Summary of Elevated IOP Related Adverse Reactions 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 during the Study Cataracts And Cataract Surgery 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. Postmarketing Experience The following reactions have been identified during post-marketing use of ILUVIEN in clinical practice. Because they are reported voluntarily estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to ILUVIEN, or a combination of these factors, include reports of drug administration error and reports of the drug being ineffective. DRUG INTERACTIONS No Information Provided

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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. 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. 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 Clinical Trials Experience - Ocular Events section). 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. 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). 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term animal studies have not been performed on RETISERT to evaluate the carcinogenic potential or the effect on fertility of fluocinolone acetonide. Fluocinolone acetonide was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay, or in vivo in the mouse bone marrow micronucleus assay. Use In Specific Populations Pregnancy Pregnancy Category C No adequate animal reproduction studies have been conducted with fluocinolone acetonide. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Fluocinolone acetonide when administered subcutaneously at a dose of 0.13 mg/kg/day (approximately 10,000 times the daily clinical dose of RETISERT), during days 6 to 18 of pregnancy in the rabbit, induced abortion at the end of the third and at the beginning of the fourth gestational week. When administered subcutaneously to rats and rabbits during gestation at a maternal toxic dose of 50 μg/kg/day (approximately 4,000 times the clinical dose of RETISERT), fluocinolone acetonide caused abortions and malformations in a few surviving fetuses. There are no adequate and well-controlled studies in pregnant women. RETISERT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when RETISERT is implanted in a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 years have not been established. Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Intravitreal Injection-Related Effects Intravitreal injections, including those with ILUVIEN, have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the intravitreal injection [see PATIENT INFORMATION]. Steroid-Related Effects Use of corticosteroids including ILUVIEN may produce posterior subcapsular cataracts, increased intraocular pressure and glaucoma. Use of corticosteroids may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids are not recommended to be used in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection. 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. Nonclinical Toxicology 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. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of ILUVIEN in pregnant women. 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. ILUVIEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Systemically administered corticosteroids are present in human milk and could suppress growth and interfere with endogenous corticosteroid production. The systemic concentration of fluocinolone acetonide following intravitreal treatment with ILUVIEN is low [see CLINICAL PHARMACOLOGY]. It is not known whether intravitreal treatment with ILUVIEN could result in sufficient systemic absorption to produce detectable quantities in human milk. Exercise caution when ILUVIEN is administered to a nursing woman. Pediatric Use Safety and effectiveness of ILUVIEN in pediatric patients have not been established. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.