An intravitreal corticosteroid implant is a drug delivery system, surgically implanted in the vitreous of the eye, for sustained release of a corticosteroid. This document addresses the following intravitreal corticosteroid implants used to various conditions of the eye: 

• Dexamethasone intravitreal implant (Ozurdex^®_, Allergan Inc., Irvine, CA)
• Fluocinolone acetonide intravitreal implant (Retisert™, Bausch & Lomb Inc., Rochester, NY)

I. Fluocinolone acetonide intravitreal implant (Retisert)

Medically Necessary: 

Fluocinolone acetonide intravitreal implant is considered medically necessary to treat chronic (duration of one 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 are considered investigational and not medically necessary, including, but not limited to, the treatment of diabetic macular edema.

II. Dexamethasone intravitreal implant (Ozurdex)

Medically Necessary: 

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

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

Investigational and Not Medically Necessary: 

All other uses of dexamethasone intravitreal implant are considered investigational and not medical necessary.

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 one 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 three-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 group (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 three years, the rate of eye drop use increased 78% for all-dose groups, compared to 36% for non-implanted eyes (p <0.01). Similarly, 40% of all-dose subjects required IOP-lowering surgery, compared to 2% of non-implanted 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. One hundred forty 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< or =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.

Contraindications for the surgical placement of Retisert 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 (Retisert product information, 2009).

Research is also being conducted on evaluating the safety and efficacy of fluocinolone acetonide intravitreal implant therapy in individuals with diabetic macular edema. In a meta-analysis, Grover and colleagues (2008) indicated there may be beneficial effect obtained from the use of fluocinolone acetonide for the treatment of diabetic macular edema, but their conclusion was limited by the heterogeneity of the reported trial results and the use of unpublished data. At this time there is a lack of sufficient evidence in the peer-reviewed medical literature to support the use of fluocinolone acetonide intravitreal implant for diabetic macular edema or any other off-label indication.

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 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, six month sham-controlled clinical trials. Haller and colleagues (2010) reported on the 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 best corrected visual acuity (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.

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 eight of the trial. The percentage of eyes with a vitreous haze score of 0 at week eight 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 six months. In addition, it was noted that the 0.7 mg DEX implant demonstrated greater efficacy than the 0.35 implant, with similar safety.

Ozurdex is contraindicated in individuals with advanced glaucoma and in those with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases (Ozurdex Product Information, 2010).

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. Causes of uveitis can include autoimmune disorders, 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 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 two to four 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 six 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.

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.

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

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
When services may be Medically Necessary when criteria are met:

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

Dexamethasone implant
When services may be Medically Necessary when criteria are met:

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, for all other diagnoses, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. 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.
2. 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.
3. 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.
4. Lowder C, Belfort R Jr, Lightman S, et al; for the Ozurdex HURON Study Group. Dexamethasone Intravitreal Implant for Noninfectious Intermediate or Posterior Uveitis. Arch Ophthalmol. 2011 Jan 10. [Epub ahead of print].
5. 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.
6. Taylor SR, Isa H, Joshi L, Lightman S. New developments in corticosteroid therapy for uveitis. Ophthalmologica. 2010; 224 Suppl 1:46-53. Epub 2010 Aug 18.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2010^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2010.
2. Dexamethasone. In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated December 14, 2010. Available at: http://www.thomsonhc.com. Accessed on January 10, 2011.
3. Fluocinolone Acetonide. In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated February 5, 2010. Available at: http://www.thomsonhc.com. Accessed on January 10, 2011.
4. Grover D, Li TJ, Chong CCW. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2008; (1):CD005656.
5. Ozurdex^® [Product Information], Irvine, CA. Allergan, Inc.; September 2010, Available at: http://www.allergan.com/assets/pdf/ozurdex_pi.pdf. Accessed on January 10, 2011.
6. Retisert^™ [Product Information], Rochester, NY. Bausch and Lomb, Inc.; March 2009. Available at: http://www.bausch.com/en_US/downloads/ecp/pharma/general/retisert_pkginsert.pdf. Accessed on January 10, 2011.

1. American Academy of Ophthalmology. Available at: http://www.aao.org/. Accessed on  January 10, 2011.
2. National Library of Medicine. Medline Plus. Uvetis. Last updated on 07/28/2010. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001005.htm. Accessed on January 10, 2011.

Dexamethasone Intravitreal Implant
Fluocinolone Acetonide
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.