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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:
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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® (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.
For ophthalmic intravitreal injection.
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:
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.
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.
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
Store at 15° -30° C (59° -86° F).
Manufactured for: Alimera Sciences, Inc. 6120 Windward Parkway Alpharetta, GA 30005. Revised: Nov 2016.
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, 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
| Adverse Reactions | ILUVIEN (N=375) n (%) |
Sham (N=185) n (%) |
| Ocular | ||
| Cataract1 | 192/2352 (82%) | 61/1212 (50%) |
| Myodesopsia | 80 (21%) | 17 (9%) |
| Ocular | ||
| 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. 2 235 of the 375 ILUVIEN subjects were phakic at baseline; 121 of 185 shamcontrolled subjects were phakic at baseline. |
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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
 |
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.
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
| Ocular | ||
| ADVERSE REACTIONS | Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%) |
Sham Injection (N=94 Eyes) n (%) |
| Cataract1 | 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%) |
| 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. | ||
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
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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.
No Information provided
Included as part of the PRECAUTIONS section.
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]. Patients may experience temporary blurred vision after injection of the implant.
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.
The use of corticosteroids may result in posterior subcapsular cataract formation.
The use of corticosteroids after cataract surgery may delay healing and increase the incidence of bleb formation.
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.
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.
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.
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.
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.
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.
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.
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].
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.
The safety and effectiveness of ILUVIEN have not been established in pediatric patients.
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
No Information Provided
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.
ILUVIEN is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8.
ILUVIEN is contraindicated in patients with known hypersensitivity to any components of this product.
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.
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.
Diabetic Macular Edema
The efficacy of ILUVIEN was assessed in two three year, randomized (2:1, active: sham), multicenter, double-masked, parallelgroups 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) | 53 (13) | 55 (11) | 53 (12) | 55 (11) |
| Median (Range) | 57 (19-75) | 58 (25-69) | 56 (20-70) | 58 (21-68) |
Table 6: 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 |
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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)
| 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 |
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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.
Table 8: Efficacy Results of Recurrence of Uveitis in Randomized Study Eyes
| Study 1 | Study 2 | |||
| FAc Implant N = 87 |
Sham N = 42 |
FAc Implant N = 101 |
Sham 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)
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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.
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.
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.
