Medical Policy



Subject: Intravitreal Corticosteroid Implants
Document #: DRUG.00032 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses the following intravitreal corticosteroid implants:

An intravitreal corticosteroid implant is a drug delivery system, surgically implanted in the vitreous of the eye, for sustained release of a corticosteroid.

Position Statement

I. Fluocinolone acetonide intravitreal implant (Iluvien)

Medically Necessary:

Fluocinolone acetonide intravitreal implant (Iluvien) is considered medically necessary for the treatment of diabetic macular edema.

Investigational and Not Medically Necessary:

All other uses of fluocinolone acetonide intravitreal implant (Iluvien) are considered investigational and not medically necessary.

II. Fluocinolone acetonide intravitreal implant (Retisert)

Medically Necessary:

Fluocinolone acetonide intravitreal implant (Retisert) is considered medically necessary to treat chronic (duration of 1 year or more) non-infectious uveitis affecting the posterior segment of the eye.

Investigational and Not Medically Necessary:

All other uses of fluocinolone acetonide intravitreal implant (Retisert) are considered investigational and not medically necessary, including, but not limited to, the treatment of diabetic macular edema.

III. Dexamethasone intravitreal implant (Ozurdex)

Medically Necessary:

Dexamethasone intravitreal implant (Ozurdex) is considered medically necessary for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO); or

Dexamethasone intravitreal implant (Ozurdex) is considered medically necessary for the treatment of chronic (duration of 1 year or more) non-infectious uveitis affecting the posterior segment of the eye; or

Dexamethasone intravitreal implant (Ozurdex) is considered medically necessary for the treatment of diabetic macular edema.

Investigational and Not Medically Necessary:

All other uses of dexamethasone intravitreal implant (Ozurdex) are considered investigational and not medically necessary.

NOTE: Please refer to Rationale section below for contraindications of Iluvien, Retisert and Ozurdex.

Rationale

Fluocinolone acetonide intravitreal implant (Iluvien)

In September 2014, the U.S. Food and Drug Administration (FDA) approved Iluvien (fluocinolone acetonide implant) to treat diabetic macular edema in individuals who received previous treatment with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. The safety and efficacy of Iluvien was studied in two multi-center, randomized, sham-controlled, masked trials, the FAME (Fluocinolone Acetonide for Diabetic Macular Edema) A and B studies (Campochiaro, 2011; Campochiaro, 2012) in which individuals with diabetic macular edema were randomized to one of two Iluvien insert groups (low-dose insert [n=375], or high-dose insert [n=393]) or a sham group (n=185). The primary efficacy endpoint in both trials was the proportion of persons in whom vision had improved by 15 letters or more from baseline after 24 months. In each of the insert groups, 28% of subjects achieved this goal vs. 16% in the sham group. Mean change from baseline best corrected visual acuity (BCVA) was also significantly higher in the insert groups compared to sham. There was a drop in visual acuity between months 9 and 18 in the insertion group due to the development of cataracts which later improved with surgery.

Warnings and precautions (Iluvien product information, 2014):

Contraindications for Iluvien placement (Iluvien product information, 2014) are:

Additionally, pivotal trials are underway to evaluate the effect of Iluvien in the treatment of noninfectious posterior uveitis, although no data is available at this time (Cabrera, 2014).

Fluocinolone acetonide intravitreal implant (Retisert)

On April 11, 2005, the U.S. Food and Drug Administration (FDA) approved Retisert (fluocinolone acetonide implant) as an orphan drug for the single indication of chronic non-infectious uveitis affecting the posterior segment of the eye. FDA approval of Retisert was based in part on the results of two randomized double-masked multicenter clinical trials including 224 individuals with chronic (persisting for at least 1 year) non-infectious uveitis affecting the posterior segment of one or both eyes. 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 period post implantation compared to the rate of recurrence in the 34-week period pre implantation. The rates of recurrence ranged from approximately 7% to 14% for the 34-week period post implantation as compared to approximately 40-54% for the 34-week period pre implantation. Current evidence supporting the safety and efficacy of the fluocinolone acetonide intravitreal implant for this indication includes the results of several multicenter, randomized, controlled clinical trials (Callanan, 2008; Pavesio, 2010).

Callanan and colleagues (2008) reported the safety and efficacy results of a 3-year study designed to evaluate the fluocinolone acetonide implant in individuals with non-infectious posterior uveitis. This prospective, dose-masked, dose-randomized, historically controlled, multicenter trial was completed in September 2005. A total of 278 individuals were randomized to receive the implant in one eye while the other eye was not implanted and left as a control. One hundred and ten subjects received the 0.59 mg dose (low dose) implant and 168 received the 2.1 mg dose (high dose) implant. The fluocinolone acetonide implant reduced the rate of recurrence from 62% in the year preceding implantation to 20% and 41% post implantation in the study eyes receiving the low and high dose implant, respectively. The authors also reported that 23% and 18% of high and low dose eyes improved their visual acuity significantly when compared to the respective nonimplanted eyes (p<0.01). In contrast to these findings, there was no significant difference found for the proportion of eyes with deteriorating visual acuity. The percentage of eyes requiring adjunctive systemic medications decreased significantly, with nearly 80% reduction, regardless of dose or study visit. The number of individuals requiring periocular injections decreased by approximately 95% in the first year, and this trend continued through the rest of the study period (p<0.01). The proportion of subjects requiring topical corticosteroids decreased by 50% in the first year of the study (p<0.01), but subsequently increased to pre-implant levels during years 2-3. It should be noted that the proportion of subjects requiring intraocular injections and topical steroids increased throughout the study period for nonimplanted eyes. The proportion of individuals with a reduction in the area of cystoid macular edema (CME) declined significantly in the treated eyes. For low-dose subjects, the reduction was 73% at 3 years, compared to 28% reduction in nonimplanted eyes. For the high-dose group, reduction was reported as 45% at 3 years, compared to 22% in the nonimplanted eyes (p<0.01). Use of intraocular pressure (IOP) lowering eye drops and surgical interventions related to IOP significantly increased for implanted eyes compared to nonimplantated eyes. Over the course of 3 years, the rate of eye drop use increased 78% for all dose groups, compared to 36% for nonimplanted eyes (p<0.01). Similarly, 40% of all dose subjects required IOP-lowering surgery, compared to 2% of nonimplanted eyes (p<0.01). Overall, six implants were removed due to IOP-related complications. The authors reported significant increase in the incidence of cataracts in the implantation groups, with 67% of implanted eyes vs. 18% of nonimplanted eyes reporting increased cataract progression. Furthermore, 93% of implanted eyes underwent cataract surgery compared to 20% of nonimplanted eyes. Finally, the authors reported a significant number of adverse events (AEs), aside from increased IOP and cataracts. In the low- and high-dose eye groups, the most common AEs included eye pain (52% and 60% respectively), conjunctival hyperemia (31% and 38% respectively), conjunctival hemorrhage (29% and 34% respectively), and blurred vision (30% and 33% respectively). The investigators concluded the fluocinolone acetonide implant effectively reduced uveitis recurrences, improved or stabilized visual acuity in eyes with noninfectious posterior uveitis. In addition, Jaffe (2006) reported on a 34-week interim report describing this study which reported similar conclusions.

Pavesio and colleagues (2010) evaluated the safety and efficacy of fluocinolone acetonide implant compared with standard therapy in individuals with unilateral or bilateral noninfectious posterior uveitis in a randomized, open-label, controlled, phase 2b/3, multicenter superiority trial. The study was conducted from April 2002 through August 2005 at 37 centers across 10 countries. A total of 140 individuals received either a 0.59 mg fluocinolone acetonide intravitreal implant (n=66) or standard of care (SOC; n=74) with either systemic prednisolone or equivalent corticosteroid as monotherapy or, if deemed necessary by the investigator, combination therapy with an immunosuppressive agent and a lower dose of prednisolone or equivalent corticosteroid. The main outcome measure was time to first recurrence of uveitis. Eyes that received the fluocinolone acetonide intravitreal implant had delayed onset of observed recurrence of uveitis (p<0.01) and a lower rate of recurrence of uveitis (18.2% vs. 63.5%; p≤0.01) compared with the SOC study eyes. Adverse events commonly observed in the implanted eyes included cataracts requiring extraction (occurring in 87.8% of phakic implanted eyes) and increased IOP requiring IOP-lowering surgery (occurring in 21.2% of implanted eyes). There were no treatment-related nonocular adverse events observed in the implant group while such events occurred in 25.7% of subjects in the SOC group. The authors concluded that based on the results of this study, the fluocinolone acetonide intravitreal implant seemed to be more effective than SOC therapy in controlling the intraocular inflammation in those with posterior uveitis. It was also noted that although increased rates of cataract development and elevated IOP were observed with the fluocinolone acetonide implant, these events were well managed by conventional surgical or medical treatment.

In a follow-up of a randomized cohort, Tomkins-Netzer and colleagues (2015) evaluated the 2-year outcomes of uveitic macular edema of 148 eyes (117 subjects) enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial. A total of 134 eyes (108 subjects) completed a 2-year follow-up. Eyes were randomized to either systemic immunosuppression or intravitreal fluocinolone acetonide implant therapy. Randomization was stratified on the basis of the class of uveitis: intermediate uveitis and posterior or panuveitis. By year 2 of follow-up, 62% and 25% of eyes in the systemic and implant groups, respectively, received at least one supplemental regional corticosteroid injection. By year 2 follow-up, macular edema had improved in 71% of eyes and resolved in 60%. There were no differences between treatment groups in the percentage of eyes with macular edema improving and resolving. However, eyes randomized to implant had more improvement in macular thickness. Eyes with baseline fluorescein angiographic leakage were more likely to improve than those without. Overall, there was a mean 5-letter (1 line) improvement in BCVA at 2 years. Mean changes in BCVA from baseline at 2 years by macular edema response status were: resolution, +10 letters; improvement without resolution, +10 letters (P=0.92); little to no change, 6 letters (P=0.19); and worsening, -16 letters (worsening acuity; P=0.0003).

Warnings and precautions (Retisert product information, 2012):

Contraindications for Retisert placement (Retisert product information, 2012) are active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also active bacterial, mycobacterial or fungal infections of the eye.

Currently, the Retisert implant is not FDA approved for the treatment of diabetic macular edema. However, Iluvien, another brand of fluocinolone acetonide is now approved for this use. Although several randomized trials (Pearson, 2011; Campochiaro, 2011) suggest potential promise for the treatment of diabetic macular edema with fluocinolone acetonide intravitreal implant therapy, significant complications related to the use of this implant for diabetic macular edema have been reported. Associated complications include cataract formation, increased intraocular pressure (IOP), and surgery to lower IOP (Messenger, 2013). To date, there is a lack of sufficient evidence in the peer-reviewed medical literature to support the use of Retisert intravitreal implant for diabetic macular edema or any other off-label indication. Significant differences between Retisert and Iluvien include: different dosages of the drug being delivered to different areas of the eye. Retisert is a 0.59 mg sterile implant designed to release fluocinolone acetate to the posterior segment of the eye over approximately 30 months, while Iluvien is a 0.19 mg sterile implant in a 36-month drug delivery system injected directly into the vitreous.

Dexamethasone intravitreal implant (Ozurdex)

On June 17, 2009, the U.S. FDA approved Ozurdex (dexamethasone 0.7 mg intravitreal implant) for the treatment of macular edema after BRVO or CRVO. Subsequently, on September 24, 2010 the FDA also approved Ozurdex (dexamethasone 0.7 mg intravitreal implant) for the treatment of non-infectious ocular inflammation, or uveitis, affecting the posterior segment of the eye. The treatment of diabetic macular edema in persons who are pseudophakic or are phakic and scheduled for cataract surgery was added as an FDA approved indication in June 2014, and in September 2014 this indication was changed to diabetic macular edema without any additional qualifications. However, the 2014 prescribing information warns:

According to 2014 prescribing information, Ozurdex is contraindicated in individuals with the following conditions:

The safety and efficacy of dexamethasone intravitreal implant for the treatment of macular edema (ME) after BRVO or CRVO was studied in two identical, multicenter, masked, randomized, 6-month sham-controlled clinical trials. Haller and colleagues (2010) reported on the "Global Evaluation of implaNTable dExamethasone in retinal Vein occlusion with macular edema" (GENEVA) trials which evaluated a total of 1267 individuals at least 18 years of age with vision loss due to ME associated with either BRVO or CRVO. Participants were randomized to a single treatment with dexamethasone intravitreal implant (DEX implant) 0.7 mg (n=427), DEX implant 0.35 mg (n=414), or sham (n=426). The primary outcome measure for the combined data from the two studies was time to achieve a greater than or equal to 15-letter improvement in BCVA. Central retinal thickness, BCVA and safety were the secondary endpoints. After the single treatment, the time to achieve a greater than or equal to 15-letter improvement in BCVA was substantially less in both DEX implant groups compared to the sham group. The percentage of eyes with a greater than or equal to 15-letter loss in BCVA was substantially lower in the DEX implant 0.7 mg group compared with sham at all follow-up visits. Both DEX implant groups demonstrated an improvement in mean BCVA compared with sham at all follow-up visits. Improvements were seen in BCVA with DEX implant in participants with BRVO and in those with CRVO; however, response patterns differed. The IOP of DEX implant-treated eyes (both doses) peaked at day 60, but was not different from the sham by day 180. The authors concluded that the results of this study demonstrated that DEX implant can increase the chance of visual acuity improvement and reduce the risk of additional vision loss in eyes with BRVO or CRVO. Study results also demonstrated that if eyes with retinal vein occlusion remain untreated, a significant number will either experience further visual acuity loss or fail to improve. The implant appeared to be well tolerated with transient, manageable IOP increases noted in less than 16% of eyes.

Haller and colleagues (2011) reported on a 6-month open-label extension of the GENEVA trials. A total of 1267 subjects who had clinically detectable macular edema associated with either CRVO or BRVO were enrolled. The mean visual acuity at baseline was approximately 54 letters (20/80) and the mean central retinal thickness was approximately 550 microns. About 75% of the subjects had macular edema for a duration of more than 3 months. Individuals were randomized to a single treatment with a 0.7 mg dexamethasone implant (n=427), 0.35 mg dexamethasone implant (n=414), or sham control (n=426). Individuals in both the implant and sham-control groups who completed the 6-month double-masked phase could receive a 0.7 mg dexamethasone implant if BCVA was less than 84 letters or retinal thickness was greater than 250 microns. At day 180, a total of 997 subjects received a dexamethasone implant, of which 341 received a second implant. Another 199 subjects entered into the open-label phase of the study for follow-up without receiving further treatment. The primary outcome at 12 months was safety, and results were analyzed according to the treatment received. Cataract progression over the 12 months occurred in 90 of 302 phakic eyes (29.8%) that received two implants in comparison with 31 of 296 eyes (10.5%) that received a single implant and 5 of 88 sham-treated phakic eyes (5.7%). Increases in IOP tended to be transient but increased to 35 mm Hg or more in about 15% of eyes at 60 days after implantation. A 15-letter or more improvement in BCVA was found in 30% of subjects at 60 days after the first implant and 32% of subjects at 60 days after the second dexamethasone implant. With the exception of cataract progression, the efficacy and safety of receiving two implants was similar to the efficacy and safety of one dexamethasone implant.

In 2013, Sadda and colleagues performed a post hoc analysis of pooled data from the GENEVA trials. Subjects with 6 or more week's duration of vision loss as a result of ME after BRVO or CRVO for whom angiographic data were available (n=329 eyes) were included in this study. Fluorescein angiography (FA) results were assessed by certified, masked graders using standardized protocols. The primary outcome measure in the parent studies was change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included FA measurements (to assess macular capillary leakage, neovascularization, and nonperfusion) and optical coherence tomography results (to assess central retinal thickness [CRT]). A total of 42% of eyes in the DEX implant group and 38% of eyes in the sham group had unreadable baseline assessments due to hemorrhage. Significantly fewer DEX implant-treated eyes (2%) than sham-treated eyes (9%) had unreadable assessments because of hemorrhage at day 180. The incidence of nonperfusion remained fairly steady from baseline to day 180 among eyes with gradable assessments. The proportion of eyes with active neovascularization increased from baseline to day 180 in the sham group, but stayed fairly constant in the DEX implant group (p=0.026 for DEX vs. sham). The mean area of overall nonperfusion and the mean area of macular capillary nonperfusion increased from baseline to day 180 in both treatment groups with no statistically significant difference between groups. There was a statistically significant positive correlation between changes in macular leakage and changes in CRT in both the DEX implant group (r=0.22; 95% confidence interval [CI], 0.03-0.40; p=0.023) and the sham group (r=0.29; 95% CI, 0.10-0.46; p=0.003). The authors concluded that clinical improvements observed with the DEX implant were accompanied by significant improvements in vascular parameters. Also suggested was that treatment with the DEX implant may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization.

The safety and efficacy of the dexamethasone intravitreal implant for the treatment of non-infectious uveitis affecting the posterior segment of the eye was studied in a single, multicenter, masked, randomized 26-week trial. Lowder and colleagues (2011) reported on the study which included 229 participants from 18 countries and 46 study sites randomized to receive a single treatment with a 0.35 mg DEX implant (n=76), 0.7 mg DEX implant (n=77) or a sham procedure (n=76). The mean duration of uveitis prior to the trial was 50.5 months in the 0.7 mg DEX, 43.9 months in the 0.35 mg DEX, and 61.2 months in the sham cohorts. A primary outcome measure was the percentage of eyes with a vitreous haze score of 0, which represents no inflammation, at week 8 of the trial. The percentage of eyes with a vitreous haze score of 0 at week 8 was 36% for the 0.35 mg DEX implant, 47% for the 0.7 mg DEX implant, and 12% for the sham. There were also significantly more eyes with improved visual acuity in the DEX implant groups than the sham group. The authors concluded that in this study a single dose of the DEX implant was well tolerated and produced significant improvements in intraocular inflammation and visual acuity that persisted for 6 months. In addition, it was noted that the 0.7 mg DEX implant demonstrated greater efficacy than the 0.35 implant, with similar safety.

Boyer and colleagues (2014), for the Ozurdex MEAD study group, evaluated the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg for the treatment of diabetic macular edema (DME) in two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols. A total of 1048 subjects with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 (Snellen equivalent), and central retinal thickness (CRT) of ≥ 300 µm by optical coherence tomography were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for subjects treated at month 36) at 40 or fewer scheduled visits. Individuals who met retreatment eligibility criteria could be retreated no more than every 6 months. The predefined primary efficacy endpoint was achievement of 15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP). The mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of subjects with a 15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg and DEX implant 0.35 mg than sham. Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 subjects (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required glaucoma incisional surgery. The authors concluded that the DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA with an acceptable safety profile.

Multiple authors have further analyzed the MEAD study (Bower, 2014) and reported benefits of the DEX implant. In a 2014 post hoc data analysis, Kupperman and colleagues (2014) evaluated the onset and duration of improvement in best-corrected visual acuity (BCVA) in eyes treated with sustained-delivery 0.7 mg DEX implant for macular edema after branch or central retinal vein occlusion. Subjects received a single DEX implant (n=427) or sham procedure (n=426) in the study eye. The baseline mean BCVA was 20/80. At day 7, 10.3% of DEX implant treated eyes vs. 4.0% of sham treated eyes had at least a 15-letter improvement in the BCVA, and 27.2% of DEX implant-treated eyes vs. 10.6% of sham-treated eyes had at least a 10-letter improvement. The mean improvement at day 7 was 5.3 letters (branch retinal vein occlusion, 5.1; and central retinal vein occlusion, 5.8) with DEX implant and 1.6 letters (branch retinal vein occlusion, 2.3; and central retinal vein occlusion, 0.1) with sham. The mean time from initial observation of the 15-letter or greater BCVA gain to the last observation of 15-letter or greater BCVA gain was 70 days.

A subgroup analysis (Augustin, 2015) used pooled data from the MEAD study with identical protocols that evaluated the safety and efficacy of DEX implant for treatment of DME. Adults with diabetes mellitus and vision loss secondary to fovea-involved macular edema associated with diabetic retinopathy were enrolled. The subset analysis included individuals that had been previously treated with laser and/or medical therapy. Baseline characteristics of previously treated DEX 0.7 (n=247) and sham (n=261) adults were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham. A total of 21.5% of DEX 0.7 subjects vs. 11.1% of those in the sham group had at least a 15-letter BCVA gain from baseline at study end (P=0.002). Cataract-related adverse events occurred in 70.3% of baseline phakic subjects in the previously treated DEX 0.7 subgroup and vision gains were restored following cataract surgery. The authors concluded that this subgroup analysis has shown "beneficial effects of DEX implant 0.7 mg treatment on visual and anatomic outcomes in patients with previously treated DME."

Maturi and colleagues (2016) evaluated IOP increases in individuals with DME treated with DEX implant in the MEAD study. In the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively, ≥ 10 mmHg IOP increases from baseline occurred in 27.7%, 24.8%, and 3.7% of subjects. IOP-lowering medication was used by 41.5%, 37.6%, and 9.1% of subjects. Among the individuals treated with the DEX implant 0.7 mg with and without a ≥ 10 mmHg IOP increase, 21.9% (21 of 96) and 22.4% (57 of 255), respectively, achieved ≥ 15-letter best-corrected visual acuity gain at the end of the study. Mean average change in central retinal thickness from baseline was -127 μm and -106 μm, respectively. The authors concluded that the DEX implant demonstrated a clear benefit in improving outcomes in those who have increases in IOP, as well as in those without IOP increases.

Background/Overview

Fluocinolone acetonide intravitreal implant (Iluvien)

Diabetic macular edema is defined as retinal thickening within 2 disc diameters of the center of the macula, and results from retinal microvascular changes that compromise the blood-retinal barrier, causing leakage of plasma constituents into the surrounding retina and, consequently, retinal edema (Albert, 2000). Diabetes is a leading cause of new blindness in the United States, with clinically significant macular edema greatly contributing to this vision loss.

Iluvien is a small, nonbiodegradable cylindrical tube with a central drug-polymer matrix that releases 0.19 mg of fluocinolone acetonide into the vitreous cavity. It is inserted intravitreally via a 25-gauge needle in the same manner as in intravitreal injection and can be done in the office setting. It releases small doses of fluocinolone acetonide for at least 3 years.

Fluocinolone acetonide intravitreal implant (Retisert)

Uveitis is a broad term referring to a number of conditions that produce inflammation of the uvea, the vascular layer of the eye sandwiched between the sclera and the retina. Uveitis may affect any part of the uvea, including the anterior (iritis), intermediate (pars planitis), posterior (choroiditis), or the entire uvea (pan-uveitis). Uveitis may affect one or both eyes. Potential causes of uveitis are autoimmune disorders including sarcoidosis, infection, or exposure to toxins. However, the cause remains unknown in most individuals. 

Posterior uveitis primarily involves the choroid. If the adjacent retina is also affected it is called chorioretinitis. Posterior uveitis may follow a systemic infection or occur in association with an autoimmune disease. Symptoms may include redness of the eye, blurred vision, sensitivity to light, dark floating spots in the vision, and eye pain. The inflammation may lead to areas of scarring on the choroid and retina with corresponding areas of vision loss. For systemic infectious diseases, corticosteroids are often used along with antibiotic and anti-viral therapies. For autoimmune diseases, various forms of suppression of the immune system may be required. Chronic non-infectious uveitis may require long term corticosteroid therapy.

The Retisert implant is an alternative to systemic corticosteroid therapy, providing high concentrations of steroid in close proximity to the involved choroids. The implant contains a 0.59 mg pellet of fluocinolone acetonide in a nonbiodegradable/polyvinyl acetate/silicone laminate and continuously delivers fluocinolone acetonide to the posterior segment of the eye for approximately 30 months. Under local anesthesia (retrobulbar or peribulbar block) in an operating room, Retisert is surgically implanted into the posterior segment of the involved eye. The implant is designed to release precise amounts of medication daily. Following depletion of the Retisert, the implant is removed and replaced with a new implant if therapy is to be continued. Periocular injections must be repeated every 2 to 4 months to maintain efficacy. Intravitreal delivery of the corticosteroid, fluocinolone acetonide, appears to target the involved area, increase efficacy and reduce systemic complications of corticosteroids.

Retisert  use has been associated with significant complications, which may include cataract formation, choroidal detachment, temporary decrease in visual acuity, endophthalmitis, increased intraocular pressure, retinal detachment, vitreous hemorrhage, and wound dehiscence. In clinical trials, approximately 60% of participants required medication to lower intraocular pressure, 40% required surgery to treat glaucoma, and 93% underwent cataract extraction. Corticosteroids should be used with caution in those with glaucoma, and individuals should be monitored for elevated IOP. 

Dexamethasone intravitreal implant (Ozurdex)

Retinal vein occlusion is a common vascular disorder of the retina and is one of the most common causes of vision loss after diabetic retinopathy. It is classified according to where the occlusion is located. Obstruction at a branch of the retinal vein is referred to as BRVO and obstruction of the retinal vein at the optic nerve is referred to as CRVO. BRVO is the most common form of retinal vein occlusion, whereas CRVO is less common.

The Ozurdex implant uses a solid polymer delivery system, in which biodegradable material is combined with dexamethasone to form a small rod-shaped implant which is injected in to the vitreous using a specially designed injector (Taylor, 2010). It can be inserted as an office based procedure, in contrast to Retisert. Dexamethasone is released over approximately 6 months, after which the implant dissolves, leaving no residue.

The most common adverse reactions to dexamethasone intravitreal implant reported in clinical studies have been increased intraocular pressure and conjunctival hemorrhage.

Definitions

Aphakia: The absence of the natural crystalline lens.

Diabetic macular edema: The leakage of fluid from retinal blood vessels which in turn causes the macula to swell; is common in diabetics.

Glaucoma: A disease characterized by destruction of the nerve fiber layer of the optic disc.

Intravitreal or intravitreous: In the vitreous, the clear, jelly-like substance that fills the posterior segment of the eye.

Phakic: An eye containing the natural lens.

Pseudophakic: An eye in which a natural lens is replaced with an artificial lens implant.

Vitreous body: A transparent jellylike substance that fills the posterior segment of the eye, delimited by the hyaloid membrane.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Fluocinolone acetonide implant [Retisert]
When services may be Medically Necessary when criteria are met:

CPT  
67027 Implantation of intravitreal drug delivery system (eg, ganciclovir implant), includes concomitant removal of vitreous [when specified as fluocinolone acetonide implant Retisert]
   
HCPCS  
J7311 Fluocinolone acetonide, intravitreal implant [Retisert]
   
ICD-10 Procedure For the following codes when specified as Retisert implantation:
08H033Z Insertion of infusion device into right eye, percutaneous approach
08H133Z Insertion of infusion device into left eye, percutaneous approach
   
ICD-10 Diagnosis  
H30.001-H30.049 Focal chorioretinal inflammation
H30.101-H30.149 Disseminated chorioretinal inflammation
H30.90-H30.93 Unspecified chorioretinal inflammation

When services are Investigational and Not Medically Necessary:
For procedure codes listed above for implantation of Retisert, when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Fluocinolone acetonide implant [Iluvien]
When services are Medically Necessary:

CPT  
67028 Intravitreal injection of a pharmacologic agent [when specified as fluocinolone acetonide implant Iluvien]
   
HCPCS  
J7313 Injection, fluocinolone acetonide intravitreal implant, 0.01 mg [Iluvien]
   
ICD-10 Diagnosis  
E08.311-E08.3519 Diabetes mellitus due to underlying condition with diabetic retinopathy with macular edema [includes only codes E08.311 and ranges E08.3211-E08.3219, E08.3311-E08.3319, E08.3411-E08.3419, E08.3511-E08.3519]
E09.311-E09.3519 Drug or chemical induced diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E09.311 and ranges E09.3211-E09.3219, E09.3311-E09.3319, E09.3411-E09.3419, E09.3511-E09.3519]
E10.311-E10.3519 Type 1 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E10.311 and ranges E10.3211-E10.3219, E10.3311-E10.3319, E10.3411-E10.3419, E10.3511-E10.3519]
E11.311-E11.3519 Type 2 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E11.311 and ranges E11.3211-E11.3219, E11.3311-E11.3319, E11.3411-E11.3419, E11.3511-E11.3519]
E13.311-E13.3519 Other specified diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E13.311 and ranges E13.3211-E13.3219, E13.3311-E13.3319, E13.3411-E13.3419, E13.3511-E13.3519]

When services are Investigational and Not Medically Necessary:
For procedure codes listed above when specified as implantation of Iluvien for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Dexamethasone implant [Ozurdex]
When services are Medically Necessary:

CPT  
67028 Intravitreal injection of a pharmacologic agent [when specified as intravitreal injection of dexamethasone implant Ozurdex]
   
HCPCS  
J7312 Injection, dexamethasone intravitreal implant, 0.1 mg [Ozurdex]
   
ICD-10 Diagnosis  
E08.311-E08.3519 Diabetes mellitus due to underlying condition with diabetic retinopathy with macular edema [includes only codes E08.311 and ranges E08.3211-E08.3219, E08.3311-E08.3319, E08.3411-E08.3419, E08.3511-E08.3519]
E09.311-E09.3519 Drug or chemical induced diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E09.311 and ranges E09.3211-E09.3219, E09.3311-E09.3319, E09.3411-E09.3419, E09.3511-E09.3519]
E10.311-E10.3519 Type 1 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E10.311 and ranges E10.3211-E10.3219, E10.3311-E10.3319, E10.3411-E10.3419, E10.3511-E10.3519]
E11.311-E11.3519 Type 2 diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E11.311 and ranges E11.3211-E11.3219, E11.3311-E11.3319, E11.3411-E11.3419, E11.3511-E11.3519]
E13.311-E13.3519 Other specified diabetes mellitus with diabetic retinopathy with macular edema [includes only codes E13.311 and ranges E13.3211-E13.3219, E13.3311-E13.3319, E13.3411-E13.3419, E13.3511-E13.3519]
H34.8110 Central retinal vein occlusion, right eye, with macular edema
H34.8120 Central retinal vein occlusion, left eye, with macular edema
H34.8130 Central retinal vein occlusion, bilateral, with macular edema
H34.8190 Central retinal vein occlusion, unspecified eye, with macular edema
H34.8310 Tributary (branch) retinal vein occlusion, right eye, with macular edema
H34.8320 Tributary (branch) retinal vein occlusion, left eye, with macular edema
H34.8330 Tributary (branch) retinal vein occlusion, bilateral, with macular edema
H34.8390 Tributary (branch) retinal vein occlusion, unspecified eye, with macular edema

When services may be Medically Necessary when criteria are met:
For procedure codes listed above when specified as injection of Ozurdex implant, for the following diagnoses:

ICD-10 Diagnosis  
H30.001-H30.049 Focal chorioretinal inflammation
H30.101-H30.149 Disseminated chorioretinal inflammation
H30.90-H30.93 Unspecified chorioretinal inflammation

When services are Investigational and Not Medically Necessary:
For procedure codes listed above when specified as injection of Ozurdex implant when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Augustin AJ, Kuppermann BD, Lanzetta P, et al.; Ozurdex MEAD Study Group. Dexamethasone intravitreal implant in previously treated patients with diabetic macular edema: subgroup analysis of the MEAD study. BMC Ophthalmol. 2015; 15:150.
  2. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014; 121(10):1904-1914.
  3. Cabrera M, Yeh S, Albini TA. Sustained-release corticosteroid options. J Ophthalmol. 2014; 164692. doi: 10.1155/2014/164692. Epub 2014 Jul 23.
  4. Callanan DG, Jaffe GJ, Martin DF, et al. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008; 126(9):1191-1201.
  5. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012; 119(10):2125-2132.
  6. Campochiaro PA, Brown DM, Pearson A, et al. FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011; 118(4):626-635.
  7. Haller JA, Bandello F, Belfort R Jr, et al; Ozurdex Geneva Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010; 117(6):1134-1146.
  8. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011; 118(12):2453-2460.
  9. Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone Acetonide Uveitis Study Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006; 113(6):1020-1027.
  10. Kuppermann BD, Haller JA, Bandello F, et al. Onset and duration of visual acuity improvement after dexamethasone intravitreal implant in eyes with macular edema due to retinal vein occlusion. Retina. 2014; 34(9):1743-1749.
  11. Lowder C, Belfort R Jr, Lightman S, et al; Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011; 129(5):545-553.
  12. Maturi RK, Pollack A, Uy HS, et al; Ozurdex MEAD Study Group. Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year MEAD study. Retina. 2016; 36(6):1143-1152.
  13. Messenger WB, Beardsley RM, Flaxel CJ. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular edema. Drug Des Devel Ther. 2013; 7:425-434.
  14. Pavesio C, Zierhut M, Bairi K, et al. Fluocinolone Acetonide Study Group. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology. 2010; 117(3):567-575.
  15. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011; 118(8):1580-1587.
  16. Sadda S, Danis RP, Pappuru RR, et al. Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion. Ophthalmology. 2013; 120(7):1423-1431.
  17. Taylor SR, Isa H, Joshi L, Lightman S. New developments in corticosteroid therapy for uveitis. Ophthalmologica. 2010; 224 Suppl 1:46-53.
  18. Tomkins-Netzer O, Lightman S, Drye L, et al; Multicenter Uveitis Steroid Treatment Trial Research Group. Outcome of Treatment of Uveitic Macular Edema: The Multicenter Uveitis Steroid Treatment Trial 2-Year Results. Ophthalmology. 2015; 122(11):2351-2359.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Albert DM, Jakobiec FA. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia: WB Saunders Co; 2000.
  2. Dexamethasone. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated March 22, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 9, 2017.
  3. Fluocinolone Acetonide. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated March 7, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 9, 2017.
  4. Fluocinolone Acetonide Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio. Lexi-Comp., Inc. March 8, 2017. Accessed on March 9, 2017.
  5. Grover D, Li TJ, Chong CCW. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2008; (1):CD005656.
  6. Iluvien [Product Information], Alpharetta, GA. Alimera Sciences, Inc.; December 2014. Available at: http://www.alimerasciences.com/wp-content/uploads/2014/09/iluvien-prescribing-information.pdf. Accessed on March 9, 2017.
  7. Ozurdex [Product Information], Irvine, CA. Allergan, Inc.; September 2014. Available at: http://www.allergan.com/assets/pdf/ozurdex_pi.pdf. Accessed on March 9, 2017.
  8. Retisert [Product Information], Rochester, NY. Bausch and Lomb, Inc.; May 2012. Available at: http://www.bausch.com/Portals/107/-/m/BL/United%20States/USFiles/Package%20Inserts/Pharma/retisert-prescribing-information.pdf. Accessed on March 9, 2017.
Websites for Additional Information
  1. National Library of Medicine. Medline Plus. Uvetis. Last updated on August 2016. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001005.htm. Accessed on March 9, 2017.
Index

Dexamethasone Intravitreal Implant
Fluocinolone Acetonide
Iluvien
Intravitreal Corticosteroid Implant
Ozurdex
Retisert

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Rationale and References sections updated.
  10/01/2016 Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.
Revised 05/05/2016 MPTAC review. Rationale and Reference section updated. Numerical formatting edit made to position statement.
  01/01/2016 Updated Coding section with 01/01/2016 HCPCS changes, removed C9450 deleted 12/31/2015; also removed ICD-9 codes.
Reviewed 05/07/2015 MPTAC review. Note added in position statement section referring to Rationale section for contraindications of Iluvien, Retisert and Ozurdex. Rationale, Coding and Reference sections updated.
  04/01/2015 Updated Coding section with 04/01/2015 HCPCS changes.
Revised 11/13/2014 MPTAC review. Position statements added for fluocinolone acetonide intravitreal implant (Iluvien). Medically necessary statement added for dexamethasone intravitreal implant for the treatment of diabetic macular edema. Description, Rationale, Background, Coding and Reference Sections updated.
Reviewed 02/13/2014 MPTAC review. Rationale and Reference sections updated.
Reviewed 02/14/2013 MPTAC review. Rationale, Background, Definition, and Reference sections updated.
Reviewed 02/16/2012 MPTAC review. Rationale and Reference sections updated.
Revised 02/17/2011 MPTAC review. Investigational and not medically necessary statement for fluocinolone acetonide intravitreal implant (Retisert) clarified with the addition of "all" at the beginning of the sentence. Medically necessary and investigational and not medically necessary statements added for dexamethasone intravitreal implant (Ozurdex). Description, Title, Rationale, Background, Definitions, Coding, References, and Index updated.
Reviewed 08/19/2010 MPTAC review. Updated rationale, background and references.
Reviewed 08/27/2009 MPTAC review. No change to position statement. Updated rationale, references and websites.
Reviewed 08/28/2008 MPTAC review. Updated rationale, references and websites.
  02/21/2008 The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 08/23/2007 MPTAC review. References updated.
  01/01/2007 Updated Coding section with 01/01/2007 CPT/HCPCS changes.
Reviewed 09/14/2006 MPTAC review. Rationale and references updated. No change to position stance.
  04/12/2006 Updated coding.
New 09/22/2005 MPTAC initial document development.