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A fluocinolone acetonide intravitreal implant (e.g., Retisert™) may be considered medically necessary for the treatment of chronic noninfectious posterior uveitis, in one or both eyes, in patients who are intolerant of, refractory to, or not a candidate for systemic corticosteroids.
A fluocinolone acetonide intravitreal implant (e.g., Retisert™) is considered experimental, investigational and unproven for all other indications.
A dexamethasone intravitreal implant (e.g., Ozurdex®) may be considered medically necessary for the treatment of macular edema with any one of the following:
A dexamethasone intravitreal implant (e.g., Ozurdex®) is considered experimental, investigational and unproven for the treatment of all other indications.
An intravitreal implant is a drug delivery system, surgically implanted in the vitreous of the eye, for sustained release of a drug to the posterior eye segment. A fluocinolone acetonide intravitreal implant (Retisert®; Bausch and Lomb, Rochester, N.Y.) is commercially available for the treatment of noninfectious posterior uveitis. Intravitreal implants are being investigated for a variety of inflammatory eye conditions.
Uveitis encompasses a variety of conditions, of either infectious or noninfectious etiologies, that are characterized by inflammation of any part of the uveal tract of the eye (iris, ciliary body, choroid). Infectious etiologies include syphilis, toxoplasmosis, cytomegalovirus retinitis, and candidiasis. Noninfectious etiologies include sarcoidosis, Behcet’s disease, and “white dot” syndromes, such as multifocal choroiditis or “birdshot” chorioretinopathy. Uveitis may also be idiopathic, have a sudden or insidious onset, a duration that is limited (less than three months) or persistent, and a course that may be acute, recurrent, or chronic.
The classification scheme recommended by the Uveitis Study Group and the Standardization of Uveitis Nomenclature (SUN) Working Group is based on anatomic location. Patients with anterior uveitis typically develop symptoms such as light sensitivity, pain, tearing, and redness of the sclera. In posterior uveitis, which comprises approximately 5% to 38% of all uveitis cases in the U.S., the primary site of inflammation is the choroid or retina (or both). Patients with intermediate or posterior uveitis typically experience minimal pain, decreased visual acuity, and the presence of floaters (bits of vitreous debris or cells that cast shadows on the retina). Chronic inflammation associated with posterior segment uveitis can lead to cataracts and glaucoma and to structural damage to the eye, resulting in severe and permanent vision loss.
The goal of therapy is to reduce the inflammatory process in the eye while minimizing the adverse effects of the therapeutic regimen. Noninfectious uveitis typically responds well to corticosteroid treatment, with selection of the route of administration (topical, systemic, periocular, or intraocular injection) based on the cause, location, and severity of the disease. Each therapeutic approach has its own drawbacks. For example, topical corticosteroids require frequent (e.g., hourly) administration and may not adequately penetrate the posterior segment of the eye due to their poor ability to penetrate ocular tissues. Long-term systemic therapies can be associated with substantial adverse effects such as hypertension and osteoporosis. Repeated (every 4-6 weeks) intraocular corticosteroid injections may result in pain, intraocular infection, globe perforation, fibrosis of the extraocular muscles, reactions to the delivery vehicle, increased intraocular pressure, and cataract development. With any route of administration, cataracts are a frequent complication of long-term corticosteroid therapy.
Immunosuppressive therapy (e.g., antimetabolites, alkylating agents, T-cell inhibitors, and tumor necrosis factor [TNF]-inhibitors) may also be utilized to control severe uveitis. Immunosuppressive therapy is typically reserved for patients who require chronic high-dose systemic steroids to control their disease. While effective, immunosuppressants may have serious and potentially life-threatening adverse effects, including renal and hepatic failure and bone marrow suppression.
Intravitreal implants are being developed to deliver a constant concentration of drug over a prolonged period of time. A fluocinolone acetonide intravitreal implant (Retisert®) is being evaluated for the treatment of noninfectious posterior uveitis and other conditions of the eye. The Retisert® sterile implant consists of a tablet containing 0.59 mg fluocinolone acetonide, a synthetic corticosteroid that is less soluble in aqueous solution than dexamethasone. The tablet is encased in a silicone elastomer cup with a release orifice and membrane; the entire elastomer cup assembly is attached to a suture tab. Following implantation (via pars plana incision and suturing) in the vitreous, the implant releases the active drug at a rate of 0.3–0.4 mcg/day over a period of approximately 30 months. Although the continuous local release of steroid may reduce or eliminate the need for intravitreal injections and/or long-term systemic therapy, surgical implantation of the device carries its own risks, and the implant could potentially increase ocular toxicity due to increased corticosteroid concentrations in the eye over a longer duration.
Other implantable/injectable devices are being studied for a variety of eye conditions. Nonbiodegradable systems are thought to be preferable for treating chronic, long-term disease, while biodegradable products may be preferred for conditions that require short-term therapy. Intraocular corticosteroid therapies being studied include:
Ozurdex is a biodegradable intravitreal implant that delivers extended release dexamethasone to the vitreous cavity in the back of the eye, via Allergan’s NOVADUR delivery system. It is used to treat macular edema associated with RVO (retinal branch occlusion), thereby improving a patient’s visual acuity.
The fluocinolone acetonide implant has been studied in several multicenter, randomized, prospective, Phase III controlled clinical trials. Two of the studies were double-masked and compared two doses (0.59 mg versus 2.1 mg) of the fluocinolone acetonide implant in one eye compared to no treatment in the control eye. The 2010 study by Pavesio et al. was an open-label trial of the 0.59 mg implant versus standard of care.
In the first (Pivotal) Phase III trial, reported in 2006, 278 patients were randomly assigned in a 2:3 ratio to receive the 0.59 mg (n=110) or 2.1 mg (n=168) fluocinolone acetonide implant. Pooled results from both doses showed a reduction in recurrence rate in the implanted eye compared with an increase in recurrence in the non-implanted eye in the pre- and post-implant periods. Improvement of three or more lines in visual acuity was seen in significantly more implanted eyes compared with the non-implanted eyes. An increase in intraocular pressure was seen at week four with both doses, (approximately 6 mm Hg) compared with no significant change in intraocular pressure in the non-implanted eyes. Over the 34-week course of the study, increases of 10 mm Hg or more were seen in 59% of the implanted eyes compared with only 11% of the non-implanted eyes. Cataracts severe enough to require surgery were more commonly seen in implanted eyes versus non-implanted eyes (9.9% vs. 2.7%, respectively).
In the second Phase III trial, 239 patients were randomly assigned to receive fluocinolone acetonide 0.59 mg or 2.1 mg in a 1:1 ratio. A reduction in recurrence rate was seen in the implanted eye over the 34-week study, while an increase in recurrence rate was seen in the non-implanted eye. There was a greater improvement in visual acuity from baseline in the implanted eye compared with the non-implanted eye. A reduction in cystoid macular edema in the implanted eye compared with the non-implanted eye (69% vs. 23%, respectively) was also seen. The most commonly reported adverse events (50-90%) in the clinical trials included cataracts, increased intraocular pressure, post procedural complications associated with implant insertion, and ocular pain. Other ocular adverse events included decreased visual acuity, glaucoma, blurred vision, and abnormal sensation in the eye, eye irritation, and a change in tearing (either increased or decreased). Based on data available at this time, 60% of patients will experience an increase in intraocular pressure sufficient to require drug treatment within 34 weeks of implant; 32% of patients will require filtering procedures within two years of implant to control intraocular pressure, and nearly all phakic eyes will develop cataracts and require surgery within two years of receiving the implant. In addition, 31% of patients in these studies reported headache.
In 2010, Pavesio and colleagues published two-year results from a manufacturer-sponsored multicenter (10 European countries and 37 centers) randomized open-label controlled trial of the sustained release fluocinolone acetonide implant (0.59 mg) compared to standard of care. To be included in the study, subjects had to have a one-year or longer history of recurrent or recrudescent unilateral or asymmetric noninfectious posterior uveitis (NIPU) not associated with significant systemic activity of any underlying disease, with the last episode occurring within eight months of enrollment; systemic therapy for one month or longer; “quiet eyes” at the time of treatment, with either 0.2 mg/kg or more daily prednisolone, or the equivalent of 0.1 mg/kg or more daily prednisolone plus immunosuppressant at the time of randomization. At baseline, more subjects in the standard-of-care group were on tritherapy (8 vs. 4), indicating greater severity in the control group following randomization. Subjects in the implant group received the implant in one eye, followed by tapering of the steroids or other agents over a period of 12 weeks; this 12-week period was excluded from the analysis of implant efficacy to allow tapering of prestudy and postoperative anti-inflammatory therapy. The standard-of-care group received prednisolone or an equivalent corticosteroid (less than 15 mg/day for the average weight), or an immunosuppressive agent combined with a reduced dose of corticosteroid. After six months, if the disease was controlled, the treatment doses were tapered according to the standard guideline of each investigational site.
A total of 146 subjects were enrolled and randomly assigned to implants or standard of care; six subjects discontinued before treatment and were excluded from the intention-to-treat population. A total of 131 patients (90%) completed the two-year visit. Reasons for discontinuation before the two-year visit included adverse events (n=4), withdrawal of consent (n=1), and loss to follow-up (n=3). Subjects returned to the study site on weeks 1, 4, 8, 12, 18, 24, 30, and 34, then every three months from 1–3 years for safety and efficacy assessments. Assessments made at 34 weeks and yearly thereafter included physical examination, medical history, clinical laboratory tests, complete ophthalmic examination, visual field tests, and fluorescein angiography and bilateral fundus photography (masked assessments). In the event of a clinical recurrence, subjects were treated as appropriate, with corticosteroid injections as the preferred first-line therapy.
The primary efficacy outcome was time to first recurrence of uveitis (recurrent inflammation or inferred by use of adjunctive therapy at a level sufficient to reduce the potential for ocular inflammation). In a number of implant subjects, the tapering of anti-inflammatory therapy was insufficient. This led to early imputed or inferred failures, and in some subjects, uveitis medications were increased before the study eye experienced protocol-defined uveitis recurrence. Results were therefore presented as both true recurrences and as the combination of true plus inferred recurrences. When recurrences inferred for reasons not related to protocol-defined ocular inflammation were censored (11 subjects were removed from the at-risk population), Kaplan Meier analysis showed a significant decrease in the time to uveitis recurrence (6.3 months for 12 failures vs. 7.0 months for 44 failures). When all subjects were included in the analysis, the time to uveitis recurrence was not statistically different (p = 0.07).
Secondary efficacy outcomes included the percentage of subjects who had at least one recurrence, the number of recurrences per subject, the proportion of subjects with a visual acuity improvement greater than 15 letters from baseline, and in a subset of the subjects, if cystoid macula edema (CME) was present at baseline, the change in the size of the area of CME on fluorescein angiography. The proportion of subjects with a reduction in the area of CME greater than 1 mm2 was 87% in the implant group and 74% in the standard-of-care group. The proportion of subjects experiencing at least one recurrence was lower in the implant group when measured either by true plus inferred recurrence (35% vs. 65%, respectively) or by true recurrences of inflammation (18% vs. 64%, respectively). This indicates that patients in the implant group were more likely to be treated with an increase in medication in the absence of protocol-defined uveitis recurrence. Visual acuity in the standard-of-care group remained consistent over the course of the two-year study. Visual acuity in the implant group decreased after the surgery and again in the 15- to 18-month interval as a result of cataracts, then returned to baseline levels at 24-months, following extraction of the cataracts.
Ocular adverse events considered to be related to treatment were reported in 96% of subjects in the implant group compared with 40% of subjects in the standard-of-care group. Implanted eyes also had a greater number of serious ocular adverse events compared with standard-of-care eyes (91% vs. 24%, respectively). The most commonly reported adverse events in the implant group were cataract and elevated intraocular pressure or glaucoma. Of 66 implanted eyes, 49 (74%) were phakic at two years, compared to 57 (77%) of 74 eyes that received standard of care. Of the eyes that were phakic, 90% of implanted eyes and 23% of phakic standard of care eyes had a change in lens opacity of two grades or more; cataracts were extracted in 88% (43/49) of phakic implanted study eyes in comparison with 19% (11/57) of phakic standard-of-care eyes. Thus, development of cataracts of a severity requiring extraction occurred in 65% of the implanted eyes and 15% of eyes receiving standard of care. During the two-year follow-up, 55% of implanted eyes had an increase in intraocular pressure of 10 mm Hg or more from baseline compared with 11% of standard-of-care study eyes. Medication was required to control elevated intraocular pressure in 62% of implanted eyes compared with 20% of standard-of-care eyes, while intraocular-pressure-lowering surgery was performed in 21% of implanted eyes compared with 3% of standard-of-care eyes. The incidence of hypotony was significantly higher in implanted eyes (20% vs. 1%, respectively). By the two-year follow-up visit, eight eyes (12%) had been explanted: three because of hypotony, two because of elevated intraocular pressure, and one eye each because of scleral thinning; implant extrusion; and postoperative complications. A greater proportion of patients in the implant group had a decrease in visual acuity of three lines or more during the two-year follow-up, 79% in the implanted eyes versus 42% in the standard-of-care eyes. The decrease in visual acuity in implanted eyes was attributed to the implantation procedure at the one-day post-implantation visit (31% of implanted eyes) and cataract progression (47% of implanted eyes at 18 months). Visual acuity was similar in the two groups following cataract removal. Other serious ocular adverse events in implanted eyes included three cases of endophthalmitis (4.5%) compared with none (0%) for standard-of-care eyes. Rates of nonocular adverse events considered to be treatment-related were higher in the standard-of-care group (26% vs. 0%); three of the 19 adverse events in the standard-of-care group were considered to be serious (4% of the total standard-of-care group).
Due to the increase in ocular adverse events requiring additional surgical procedures, 2-year results from a multicenter randomized controlled trial do not support an overall health benefit with the 0.59 mg fluocinolone acetonide intravitreal implant compared with the standard of care (systemic therapy) for all patients with recurrent noninfectious posterior uveitis. However, this procedure might be considered a reasonable alternative (medically necessary) when patients are intolerant or refractory to systemic or topical therapy. In addition, this therapy may be considered in patients for whom systemic steroid-related adverse effects are expected to be more frequent and/or severe than the ocular adverse effects.
Informed decision making is a key part of this process. Patients should be informed about the potential adverse effects of the fluocinolone acetonide intravitreal implant including cataracts, increased intraocular pressure or hypotony, endophthalmitis, and risk of need for additional surgical procedures. Because of the differing benefits and risks of treatment with intravitreal implants in comparison with systemic therapy, patients should make an informed choice between the treatments.
In two randomized, masked, parallel studies of Ozurdex in patients with macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO), dexamethasone-treated patients had significantly greater improvement in best-corrected visual acuity (BCVA) from baseline to 90 days (but not at 180 days) compared with sham-treated patients. Patients were randomized to receive an intravitreal dexamethasone implant of either 0.7 mg (n=427) or 0.35 mg (n=414), or a sham treatment (n=426; similar anesthesia and preparation of the eye followed by placement of a needleless applicator against the conjunctiva). Both studies were pivotal phase III trials evaluating use of a biodegradable dexamethasone implant. The primary endpoint of the first study was the proportion of patients achieving at least a 15-letter improvement in BCVA, and in the second study, it was the time to reach that level of improvement. As the two trials used identical study designs, the results were pooled for analyses. Sixty-six percent of patients had BRVO and 34% had CRVO, with 17% having duration of macular edema of less than 90 days. At baseline, mean visual acuity was approximately 54 letters (20/80) in all groups and mean central retinal thickness was approximately 550 micrometers. Dexamethasone-treated patients experienced greater improvement in BCVA at days 30, 60 and 90:
Differences at day 180 were not significant for either dexamethasone arm compared with the sham-treated arm. However, it was noted that a number of patients had their last follow up beyond 180 days. As the dexamethasone insert is engineered to deliver medication for only 180 days, a post-hoc analysis was conducted consisting of patients whose last evaluation was not delayed. In that analysis, patients in the dexamethasone 0.7 mg arm (n=208) did maintain significant improvement over patients in the sham-treated arm (n=229) at 180 days (26% versus 17% respectively, p=0.017). In both studies the time to clinical improvement in BCVA was significantly faster in dexamethasone-treated patients compared with sham (p less than 0.01). No significant differences were noted between the two dexamethasone doses in the proportion of patients achieving clinical response, time to achieve that level of improvement, nor in incidence of side effects. The most common adverse events in the dexamethasone 0.7 mg, 0.35 mg, and sham arms were eye pain (7.4%, 4.1%, 3.8%), ocular hypertension (4%, 3.9%, 0.7%), and anterior chamber cells (1.2%, 1.7%, 0%).
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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
Jaffe, G.J., Martin, D., et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology (2006) 113(6):1020-7.
Mohammad, D.A., Sweet, B.V., et al. Retisert: is the new advance in treatment of uveitis a good one? Ann Pharmacother (2007) 41(3):449-54.
Kuppermann, B.D., Blumenkranz, M.S. et al. Dexamethasone Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Archives of Ophthalmology (2007) 125(3):309-17.
Parodi, M.B., Bandello, F., et al. Branch retinal vein occlusion: classification and treatment. Ophthalmologica (2009) 223(5):298-305.
Callanan, D.G., Jaffe, G.J., et al. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmology (2008) 126(9):1191-201.
Bollinger, K.E., and S. D. Smith. Prevalence and management of elevated intraocular pressure after placement of an intravitreal sustained-release steroid implant. Curr Opin Ophthalmol (2009) 20(2):99-103.
Pavesio, C., Zierhut, M., et al. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology (2010) 117(3):567-75, 75 e1.
Haller JA, Bandello F, et al. Randomized, sham-controlled trial of dexamethasone intravitreal
implant in patients with macular edema due to retinal vein occlusion. Ophthalmology (2010 June) 117(6):1134-46.e3.
Intravitreal Implant. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2010 June) Vision 9.03.23.
6/15/2011 New Medical Document. 1) A fluocinolone acetonide intravitreal implant (e.g., Retisert™) may be considered medically necessary for the treatment of chronic noninfectious posterior uveitis, in one or both eyes, in patients who are intolerant of, refractory to, or not a candidate for systemic corticosteroids. All other indications are considered experimental, investigational and unproven. 2) A dexamethasone intravitreal implant (e.g., Ozurdex®) may be considered medically necessary for the treatment of macular edema with any one of the following:
All other indications are considered experimental, investigational and unproven.
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