Dexamethasone Ophthalmic Implants (Ozurdex and Dextenza)

Number: 0795

Policy

1. Aetna considers Ozurdex (dexamethasone intravitreal implant) medically necessary for the treatment of the following indications:

   1. Macular edema secondary to branch or central retinal vein occlusion
   2. Non-infectious uveitis affecting the posterior segment of the eye (e.g., pars planitis)
   3. Diabetic macular edema (DME).

2. Aetna considers Ozurdex (dexamethasone intravitreal implant) therapy not medically necessary for members with the following contraindications:

   1. Ocular or periocular infections (viral, bacterial, or fungal)
   2. Advanced glaucoma
   3. Aphakic eyes with rupture of the posterior lens capsule
   4. ACIOL (anterior chamber intraocular lens) and rupture of the posterior lens capsule.

3. Aetna considers Ozurdex experimental and investigational for the treatment of the following indications (not an all-inclusive list) because of insufficient evidence of its effectiveness for these indications:

   1. Acute zonal occult outer retinopathy (AZOOR)
   2. Coats' disease
   3. Cystoid macular edema (CME) associated with retinitis pigmentosa, sympathetic ophthalmia or syphilis-related uveitis
   4. Macular edema secondary to acute retinal necrosis, idiopathic retinal vasculitis, aneurysms, neuroretinitis (IRVAN) syndrome, or tuberculosis uveitis
   5. Non-arteritic anterior ischemic optic neuropathy
   6. Proliferative vitreoretinopathy
   7. Pseudophakic macular edema (Irvine-Gass syndrome) except for pseudophakic persons with DME
   8. Radiation maculopathy
   9. Reducing the risk of conjunctivitis from cytarabine
   10. Vasoproliferative tumor
       
       

4. Aetna considers combined cataract surgery and Ozurdex experimental and investigational for the treatment of cataract and macular edema because of insufficient evidence of the effectiveness of this approach.

5. Aetna considers combined intravitreal anti-vascular endothelial growth factor (VEGF) and Ozurdex experimental and investigational for the treatment of diabetic macular edema, and punctate inner choroidopathy because of insufficient evidence of the effectiveness of this approach.

6. Ozurdex is contraindicated and considered unproven in individuals with advanced glaucoma and ocular or periocular infections.

7. Aetna considers Dextenza (dexamethasone ophthalmic insert) medically necessary for the treatment of ocular pain following ophthalmic surgery (i.e., cataract surgery).

8. Aetna considers Dextenza experimental and investigational for all other indications (e.g., allergic conjunctivitis) (not an all-inclusive list) because of insufficient evidence of the effectiveness of this approach.

See also CPB 0719 - Fluocinolone Acetonide Intra-vitreal Implant (Retisert, Yutiq and Iluvien).

Background

Ozurdex (dexamethasone intravitreal implant) is an intravitreal implant containing 0.7 mg (700 μg) dexamethasone in the Novadur solid polymer drug delivery system. Ozurdex is preloaded into a single‐use, specially designed DDS applicator to facilitate injection of the rod‐shaped implant directly into the vitreous of the eye.

Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and migration of inflammatory cells.

Ozurdex contains a corticosteroid (dexamethasone), and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Ozurdex (dexamethasone) is also indicated for non‐infectious uveitis affecting the posterior segment of the eye and for the treatment of diabetic macular edema.

Retinal Vein Occlusion

Retinal vein occlusion is a blockage of a portion of the venous circulation that drains the retina and is second only to diabetic retinopathy as the most common retinal vascular cause of visual loss.  It generally does not occur until later in life and may have several causes, including: hypertension, atherosclerosis, diabetes, and glaucoma.  When a blockage occurs, pressure builds up in the capillaries causing hemorrhages and leakage of fluid and blood.  This can lead to macular edema (ME) and ischemia of the macula.  There are 2 basic types of retinal vein occlusion: central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO).  Central retinal vein occlusion is obstruction of the retinal vein at the optic nerve and BRVO is obstruction of a portion of the venous circulation that drains the retina. 

Central retinal vein occlusion (CRVO) is a common retinal vascular disorder. The exact etiology is unknown, however may be caused by arteriosclerotic changes in the central retinal artery or from a thrombotic occlusion of the central retinal vein. Occlusion of the central retinal vein leads to backup of the blood in the retinal venous system and increases resistance to the venous blood flow. This increased resistance causes stagnation of the blood and ischemia to the retina. Ischemic damage to the retina stimulates increase production of vascular endothelial growth factor (VEGF), and increased levels of VEGF stimulate neovascularization of the posterior and anterior segment of the eye.

Central vein occlusion can also be further categorized as either ischemic or non-ischemic. Ischemic CRVO is the more severe form and presents with severe visual loss, extensive retinal hemorrhages, and cotton‐wool spots. Poor perfusion of the retinal and patients may end up with neovascular glaucoma and painful blind eye. Nonischemic CRVO is the milder form of the disease and presents with good vision, few retinal hemorrhages and cotton‐wool spots, and good perfusion to the retina. This type may resolve fully with good visual outcome or may progress to the ischemic type. Most individuals with ischemic CRVO develop the complications of ME that ultimately lead to blindness.  The non-ischemic type maintains better blood flow to the retina through collateral circulation, thus, preventing the dreaded complications of the ischemic type. 

In branched retinal vein occlusion (BRVO) the blockage occurs in a smaller branch of the vessels that connect to the central retinal vein. Branch retinal vein occlusion occurs 3 times more often than CRVO and may include both systemic factors (e.g., hypertension) as well as local anatomic factors (e.g., arterio-venous crossings). Both types of retinal vein occlusion can lead to macular edema or growth of fragile new blood vessels.

While there are similarities in the pathogenesis and clinical nature of both forms of retinal vein occlusion, each has unique etiologies, differential diagnosis, management and prognosis. Central retinal vein occlusion is difficult to treat.  No known effective treatment is available for either the prevention or treatment of CRVO.  Pan-retinal photocoagulation (PRP) has been used in the treatment of neovascular complications of CRVO, however, no definite guidelines exist regarding the exact indication and timing of PRP.  Other treatments with varying degrees of success include: aspirin, anti-inflammatory agents, isovolemic hemodilution, plasmapheresis, systemic anti-coagulation, fibrinolytic agents, systemic corticosteroids, local anti-coagulation with intravitreal injection of alteplase, intravitreal injection of triamcinolone, and intravitreal injection of bevacizumab.

A Cochrane systematic review on the use of intravitreal steroids versus observation for CRVO-ME (Gewaily and Greenberg, 2009) found no relevant RCTs and concluded that "[t]here is inadequate evidence for the use of intravitreal steroids for CRVO-ME due to a paucity of RCTs and well-designed observational studies on the topic; therefore, it is still an experimental procedure."

The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) study, a phase III clinical trial conducted at 84 clinical sites and supported by the National Eye Institute (NEI) at the National Institutes of Health (NIH), included participants with CRVO (n = 271) and BRVO (n = 411) in 2 separate trials.  The SCORE study reported that intravitreal injections of a corticosteroid medication could reduce vision loss due to CRVO-ME and that treated patients were also 5 times more likely to regain vision after 1 year than patients who were under observation.  The study compared intravitreal triamcinolone (1 mg and 4 mg doses) versus observation for eyes with vision loss associated with CRVO-ME.  Of those participants in the observation, 1 mg, and 4 mg groups, 7 %, 27 %, and 26 % achieved the primary outcome measure of a gain in VA letter score of 15 or more from baseline to month 12, respectively.  The odds of achieving the primary outcome were 5.0 times greater in the 1 mg group than the observation group (odds ratio [OR], 5.0; 95 % confidence interval [CI]: 1.8 to 14.1; p = 0.001) and 5.0 times greater in the 4 mg group than the observation group (OR, 5.0; 95 % CI: 1.8 to 14.4; p = 0.001); there was no difference identified between the 1 mg and 4 mg groups (OR, 1.0; 95 % CI: 0.5 to 2.1; p = 0.97).  The rates of elevated intra-ocular pressure and cataract were similar for the observation and 1 mg groups, but higher in the 4 mg group.  The authors concluded that intra-vitreal triamcinolone is superior to observation for treating vision loss associated with CRVO-ME in patients who have characteristics similar to those in the SCORE-CRVO trial.  The 1-mg dose has a safety profile superior to that of the 4-mg dose.  The authors concluded that intra-vitreal triamcinolone in a 1-mg dose, following the re-treatment criteria applied in the SCORE study should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial (Ip et al, 2009).

In general, BRVO has a good prognosis.  Between 50 to 60 % of patients report a final VA of 20/40 or better without treatment.  Thus, comparative studies are necessary to determine whether improvements in VA are a result of the procedure or simply the natural course of the condition.  Laser photocoagulation, as demonstrated by the Branch Vein Occlusion Study (BVOS; Scott et al, 2009), is the gold standard for the treatment of ME and ocular neovascularization following BRVO.  However, the limited functional outcomes achievable by means of laser treatment have prompted researchers to try alternative options. 

The SCORE-BRVO trial evaluated the use of 2 different dosages of intravitreal triamcinolone for treating vision loss from BRVO-ME and reported that laser treatment is safer than corticosteroid injections and is equally effective.  The study compared intravitreal triamcinolone (1-mg and 4-mg doses) with standard of care (i.e., grid photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage clears in eyes with dense macular hemorrhage) for eyes with vision loss associated with BRVO-ME (n = 411).  Of those participants in the standard care, 1-mg, and 4-mg groups, 29 %, 26 %, and 27 % achieved the primary outcome measure of a gain in VA letter score of 15 or more from baseline to month 12, respectively.  None of the pair-wise comparisons between the 3 groups was statistically significant at month 12.  The rates of elevated intraocular pressure and cataract were similar for the standard care and 1 mg groups, but higher in the 4 mg group.  The authors found no difference in VA at 12 months for the standard care group compared with the triamcinolone groups; however, rates of adverse events (particularly elevated intra-ocular pressure and cataract) were highest in the 4 mg group.  The authors concluded that photocoagulation as applied in the SCORE study remains the standard of care for patients with vision loss associated with BRVO-ME who have characteristics similar to participants in the SCORE-BRVO trial and that grid photocoagulation should remain the benchmark against which other treatments are compared in clinical trials for eyes with vision loss associated with BRVO-ME (Scott et al, 2009).

Several processes have been implicated in the breakdown of the blood-retinal barrier that leads to ME, including the production of inflammatory mediators (e.g., prostaglandins and interleukin-6), increased amounts of vascular permeability factors (e.g., vascular endothelial growth factor) and the loss of endothelial tight junction proteins.  Corticosteroids are thought to have beneficial effects on these processes, but delivering therapeutic concentrations of any medication to the retina while limiting systemic exposure presents a challenge.  Intra-vitreal injections of the corticosteroid triamcinolone have shown promise in the treatment of ME.  Dexamethasone, a more potent corticosteroid than triamcinolone, has been shown to produce high intra-vitreal levels of the drug, however, a short intra-ocular half-life after intra-vitreal injection (approximately 3 hours) has led to the investigation of other delivery methods.  

Ozurdex (dexamethasone intra-vitreal implant) (Allergan, Irvine, CA) was approved by the U.S. Food and Drug Administration (FDA) in June 2009 for the treatment of ME associated with CRVO or BRVO.  The rod-shaped biodegradable intra-vitreal implant contains 0.7 mg of dexamethasone and is injected directly into the eye (vitreous) through a small pars plana incision or puncture.  A solid polymer drug delivery system called Novadur (Allergan, Irvine, CA) gradually releases dexamathasone for up to 6 months.  Biodegradable polymers release the drug as they themselves degrade and are finally absorbed within the body. 

The FDA's approval of Ozurdex was based on results from 2 randomized, double-masked, multi-center clinical studies (n = 853).  The studies demonstrated a statistically significant improvement in 3 or more lines of VA in approximately 20 to 30 % of treated patients within 60 days post-implantation compared to sham.  The duration of improvement continued for approximately 30 to 90 days and was effective in both CRVO and BRVO.  The most significant adverse effect was an increase in intra-ocular pressure that occurred in 106 patients (25 %), which peaked at 60 days and returned to baseline levels by day 180.  Three patients (0.7 %) required laser or surgical procedures as a result.  Conjunctival hemorrhage occurred in 85 patients (20 %).  Ozurdex is the first FDA-approved therapy for ME related to retinal vein occlusion.  The proposed benefit of a sustained-release intra-vitreal corticosteroid insert such as Ozurdex is the potential for fewer injections.  Intra-vitreal injections have been associated with endophthalmitis, eye inflammation, increased intra-ocular pressure, and retinal detachments. 

According to the prescribing information, Ozurdex is for ophthalmic intravitreal injection. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis.

According to the prescribing information, Ozurdex is contraindicated in patients with active or suspected ocular or peri-ocular 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.  Furthermore, Ozurdex is also contraindicated in individuals with advanced glaucoma.

Intravitreal corticosteroid injection‐related effects have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection.

Ozurdex (dexamethasone intravitreal implant) should not be utilized in patients with a hypersensitivity to dexamethasone or any components of the product. The safety and effectiveness of Ozurdex in pediatric patients has not been established.

Diabetic Macular Edema

Treatment options currently available for the treatment of diabetic macular edema include photocoagulation (laser therapy), intravitreal corticosteroids and intravitreal anti‐vascular endothelial growth factor agents (VEGF).

In June 2014, Ozurdex sustained-release, biodegradable dexamethasone intravitreal implant 0.7 mg was approved by the FDA for adult patients with diabetic macular edema who have artificial lens implants or are scheduled for cataract surgery (Allergan, 2014).  The approval was based on the Macular Edema: Assessment of Implantable Dexamethasone in Diabetes (MEAD) trial, which included 2 multi-center, 3-year, sham-controlled, masked, randomized clinical studies of patients with 15 or more letters improvement in best corrected visual acuity (BCVA) from baseline.  The sustained-release biodegradable steroid implant uses a solid polymer to suppress the inflammation that causes diabetic macular edema (DME) by releasing the steroid over an extended period, without the need for monthly steroid injections.  In September 2014, the FDA approved expanded indications for Ozurdex for the treatment of the general population of patients with DME, based on ongoing review of clinical data demonstrating efficacy and safety. 

The Ozurdex implant uses a biodegradable polymer implant that releases dexamethasone over an extended period of time to suppress inflammation, which plays a key role in the development of DME (Allergan, 2014).  The most common adverse events in the studies of Ozurdex for DME included cataracts and elevated intraocular pressure.  An increase in mean intra-ocular pressure (IOP) was seen with each treatment cycle; mean pressure generally returned to baseline between treatment cycles.  The labeling states that Ozurdex should not be used in persons with glaucoma.

Injections into the vitreous in the eye, including those with Ozurdex, are associated with endophthalmitis, eye inflammation, increased IOP, and retinal detachments (Allergan, 2014).  Use of corticosteroids may produce posterior subcapsular cataracts, increased IOP, glaucoma, and may increase the establishment of secondary eye infections due to bacteria, fungi, or viruses.  The labeling for Ozurdex states that it should not be used in patients that have any infections or diseases in the eye, or surrounding eye area, including most viral diseases of the cornea and conjunctiva, including active herpes viral infection of the eye, vaccinia, varicella, mycobacterial infections, and fungal diseases

Other adverse effects among patients with DME included conjunctival blood spot, reduced vision, conjunctival swelling and/or inflammation, floaters, dry eye, vitreous detachment, vitreous opacities, retinal aneurysm, foreign body sensation, corneal erosion, inflammation of the cornea, anterior chamber inflammation, retinal tear, drooping eyelid, and high blood pressure (Allergan, 2014).

Boyer et al (2013) reported on the results of 2 RCTs to evaluate the safety and efficacy of Ozurdex dexamethasone intravitreal implant (DEX) 0.7 and 0.35 mg in the treatment of patients with DME. Two randomized, multi-center, masked, sham-controlled, phase III clinical trials with identical protocols were conducted.  Data were pooled for analysis.  Study subjects were 1,048 patients with DME, BCVA of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of greater than or equal to 300 μm by optical coherence tomography (OCT).  Patients 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 patients treated at month 36) at less than or equal to 40 scheduled visits.  Patients who met re-treatment eligibility criteria could be re-treated no more often than every 6 months.  The pre-defined primary efficacy end-point was achievement of greater than or equal to 15-letter improvement in BCVA from baseline at study end.  Safety measures included adverse events and IOP.  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 patients with greater than or equal to 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 %; p ≤ 0.018).  Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (-111.6 μm) and DEX implant 0.35 mg (-107.9 μm) than sham (-41.9 μm; p < 0.001).  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; 2 patients (0.6 %) in the DEX implant 0.7 mg group and 1 (0.3 %) in the DEX implant 0.35 mg group required trabeculectomy.  The investigators concluded that the DEX implant 0.7 mg and 0.35 mg met the primary efficacy end-point for improvement in BCVA.  The investigators stated that the safety profile was acceptable and consistent with previous reports.

In a randomized, controlled, multi-center, double-masked, parallel-group, 12-month trial, Callanan et al (2013) evaluated Ozurdex (dexamethasone intravitreal implant [DEX implant]) 0.7 mg combined with laser photocoagulation compared with laser alone for treatment of diffuse DME.  A total of 253 patients with retinal thickening and impaired vision resulting from diffuse DME in at least 1 eye (the study eye) were enrolled.  Patients were randomized to treatment in the study eye with DEX implant at baseline plus laser at month 1 (combination treatment; n = 126) or sham implant at baseline and laser at month 1 (laser alone; n = 127) and could receive up to 3 additional laser treatments and 1 additional DEX implant or sham treatment as needed.  The primary efficacy variable was the percentage of patients who had a 10-letter or more improvement in BCVA from baseline at month 12.  Other key efficacy variables included the change in BCVA from baseline and the area of vessel leakage evaluated with fluorescein angiography.  Safety variables included adverse events and IOP.  The percentage of patients who gained 10 letters or more in BCVA at month 12 did not differ between treatment groups, but the percentage of patients was significantly greater in the combination group at month 1 (p < 0.001) and month 9 (p = 0.007).  In patients with angiographically verified diffuse DME, the mean improvement in BCVA was significantly greater with DEX implant plus laser treatment than with laser treatment alone (up to 7.9 versus 2.3 letters) at all time-points through month 9 (p ≤ 0.013).  Decreases in the area of diffuse vascular leakage measured angiographically were significantly larger with DEX implant plus laser treatment through month 12 (p ≤ 0.041).  Increased IOP was more common with combination treatment.  No surgeries for elevated IOP were required.  The authors concluded that there was no significant between-group difference at month 12.  However, significantly greater improvement in BCVA, as demonstrated by changes from baseline at various time points up to 9 months and across time based on the area under the curve analysis, occurred in patients with diffuse DME treated with DEX implant plus laser than in patients treated with laser alone.

Pacella et al (2013) evaluated the safety and effectiveness of Ozurdex in patients with persistent DME over a 6-month follow-up period.  A total of 17 patients (20 eyes) affected by DME were selected.  The mean age was 67 + 8 years, and the mean duration of DME was 46.3 + 18.6 months.  The eligibility criteria were: age greater than or equal to 18, a BCVA between 5 and 40 letters, and macular edema with a thickness of greater than or equal to 275 μm; 13 patients had also previously been treated with anti-vascular endothelial growth factor (VEGF) medication.  The mean ETDRS (Early Treatment Diabetic Retinopathy Study) value went from 18.80 + 11.06 (T0) to 26.15 + 11.03 (p = 0.04), 28.15 + 10.29 (p = 0.0087), 25.95 + 10.74 (p = 0.045), 21.25 + 11.46 (p = 0.5) in month 1, 3, 4, and 6, respectively.  The mean logMAR (logarithm of the minimum angle of resolution) value went from 0.67 + 0.23 (at T0) to 0.525 + 0.190 (p = 0.03), 0.53 + 0.20 (p = 0.034), and 0.56 + 0.22 (p = 0.12) in month 1, 3, and 4, respectively, to finally reach 0.67 + 0.23 in month 6.  The mean central macular thickness (CMT) value improved from 518.80 + 224.75 μm (at T0) to 412.75 + 176.23 μm, 292.0 + 140.8 μm (p < 0.0001), and 346.95 + 135.70 (p = 0.0018) on day 3 and in month 1 and 3, respectively, to then increase to 476.55 + 163.14 μm (p = 0.45) and 494.25 + 182.70 μm (p = 0.67) in month 4 and 6.  The authors concluded that Ozurdex produced significant improvements in BCVA and CMT from the third day of implant in DME sufferers, and this improvement was sustained until the third month. 

In a retrospective, interventional case-series study, Rishi et al (2013) evaluated the safety and effectiveness of Ozurdex in patients with recalcitrant DME.  Inclusion criteria comprised patients presenting with recalcitrant DME, 3 or more months after 1 or more treatments of macular laser photocoagulation and/or intra-vitreal anti-VEGF injections.  Exclusion criteria included history of corticosteroid-responsive IOP rise, cataract extraction, or other intra-ocular surgery within 3 months.  The main outcome measure was VA at 1 and 4 months after Ozurdex injection.  Secondary outcome measures included change in CMT on OCT and changes in IOP following Ozurdex implant.  Of 18 eyes (17 patients) with recalcitrant DME that underwent Ozurdex implant, 3 eyes (2 patients) had follow-up of more than 3 months post-injection.  Mean age of patients was 56 years.  Mean duration of diabetes mellitus was 16.6 years.  Systemic control of diabetes mellitus was good as assessed by FBS/PPBS and HbA1c.  The pre-operative mean CMT was 744.3 μm and improved to 144 and 570 μm at months 1 and 4, respectively.  Pre-operative mean BCVA was 0.6 logMAR units and improved to 0.3 and 0.46 logMAR units at month 1 and 4, respectively.  The mean follow-up was 4.3 months (range of 4 to 5 months).  The authors concluded that Ozurdex appears effective in management of recalcitrant DME.  Moreover, they stated that the results of the ongoing POSURDEX study will elaborate these effects better.

Non-Infectious Uveitis

Uveitis is inflammation of the uvea, the middle layer of the eye that consists of the iris, ciliary body and choroid. Uveitis can have many causes, including eye injury, inflammatory diseases or exposure to toxins. Uveitis is classified by location of inflammation within the uvea: anterior uveitis refers to inflammation of the iris alone (iritis) or the iris and ciliary body. Intermediate uveitis refers to inflammation of the ciliary body. Posterior uveitis is inflammation of the choroid. Diffuse uveitis or panuveitis is inflammation in all areas of the uvea.

In a review on new developments in corticosteroid therapy for uveitis, Taylor et al (2010) stated that corticosteroids remain the mainstay of the management of patients with uveitis.  Topical corticosteroids are effective in the control of anterior uveitis, but vary in strength, ocular penetration and side effect profile.  Systemic corticosteroids are widely used for the management of posterior segment inflammation that requires treatment, particularly when it is associated with systemic disease or when bilateral ocular disease is present.  However, when ocular inflammation is unilateral, or is active in 1 eye only, local therapy has considerable advantages, and peri-ocular injections of corticosteroid are a useful alternative to systemic medication and are very effective in controlling mild or moderate intra-ocular inflammation.  More recently, the injection of intra-ocular corticosteroids such as triamcinolone have been found to be effective in reducing ME and improving vision in uveitic eyes that have proved refractory to systemic or peri-ocular corticosteroids.  The effect is usually transient, lasting around 3 months, but can be repeated although the side effects of cataract and raised intra-ocular pressure are increased in frequency with intra-ocular versus peri-ocular corticosteroid injections.  This has led to the development of new intra-ocular corticosteroid devices, which are designed to deliver sustained-release drugs and obviate the need for systemic immuno-suppressive treatment.  The first such implant was Retisert, which is surgically implanted (in the operating theater) and is designed to release fluocinolone over a period of about 30 months.  More recently, Ozurdex, a "bioerodible" dexamethasone implant, which can be inserted in an office setting, has completed phase III clinical trials in patients with intermediate and posterior uveitis.  This implant lasts approximately 6 months, and has been found to be effective with a much better side effect profile than Retisert or intra-vitreal triamcinolone injection, at least for 1 injection.

Williams et al (2009) evaluated the effects of a dexamethasone intravitreous drug delivery system (dexamethasone DDS) in a randomized, prospective, single-masked, controlled trial of patients with persistent (90 days or more) ME from uveitis or Irvine-Gass syndrome (n = 41).  Patients were randomized to surgical placement of 0.35 mg or 0.7 mg dexamethasone DDS or observation.  At day 90, the primary outcome measure of a 10-letter or more BCVA improvement was achieved in the 0.35 mg group, 0.7 mg group, and the observation group (p = 0.029 versus the 0.7 mg group) in 41.7 % (5/12), 53.8 % (7/13) and 14.3 % (2/14) of patients, respectively.  Improvement in VA persisted to day 180.  A 15-letter or more improvement was achieved in 53.8 % (7/13) of 0.7 mg patients versus 7.1 % (1/14) of observed patients (p = 0.008).  There were significantly greater reductions in fluorescein leakage in treated patients than in observed patients.  Dexamethasone DDS was well- tolerated.  Throughout the study, an increase in intra-ocular pressure of 10 mm Hg or more was observed in 5 of 13 patients in the 0.7 mg group, in 1 of 12 patients in the 0.35 mg group, and in no patients in the observation group.  There were no reports of endophthalmitis.  The authors concluded that dexamethasone DDS may be a promising new treatment option for patients with persistent ME resulting from uveitis or Irvine-Gass syndrome, however, further investigation of its clinical value in this patient population is warranted. 

In September 2010, Allergan received FDA approval of its supplemental new drug application of Ozurdex for the treatment of non-infectious uveitis affecting the posterior segment of the eye.  The approval was based on the findings of a single, multi-center, masked, randomized study of 153 patients with non-infectious uveitis affecting the posterior segment of the eye.  After a single injection, the percent of patients reaching a vitreous haze score of 0 (where a score of 0 represents no inflammation) was statistically significantly greater for patients receiving Ozurdex versus sham at week 8 (primary time-point) (47 % versus 12 %).  The percent of patients achieving a 3-line improvement from baseline BCVA was 43 % for patients receiving Ozurdex versus 7 % for sham at week 8.

Pars planitis, also called peripheral uveitis or intermediate uveitis) is a relatively common ocular inflammatory condition. The major clinical findings are localized to the vitreous and posterior pole. The hallmark of the disorder is the presence of preretinal exudates over the inferior pars plana, referred to as snow banks. "Therapy consists of oral or intra/periocular injected glucocorticoids. External cryotherapy has also been used directly on the snowbanks. If these modalities fail, systemic immunosuppression, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine, has been used in some cases. Severe disease can often benefit from surgery to extract a cataract and/or to remove vitreous debris" (Tolentino and Dana, 2019).

Coats' Disease

Martínez-Castillo et al (2012) reported a case of Coats' disease managed with Ozurdex combined with retinal photocoagulation.  A 46-year old female with 20/200 VA was diagnosed with Coats' disease with secondary retinal vaso-proliferative tumor.  An initial approach was performed with an intra-vitreal injection of the sustained-release dexamethasone implant Ozurdex.  After re-attachment of the retina, the telangiectatic vessels were treated with laser photocoagulation.  The patient's VA improved to 20/25 after the intra-vitreal Ozurdex.  No further recurrences of exudation were evident through the 12-month follow-up.  The authors concluded that Ozurdex may be an effective initial therapeutic approach for Coats' disease with immediate anatomical response and visual improvement.  The results of this case study need to be validated by well-designed studies.

IRVAN Syndrome

Empeslidis et al (2013) presented the short-term favorable clinical results with Ozurdex in a patient with florid idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome.  The patient was a 26-year old man with significant bilateral deterioration of vision due to vitreous hemorrhage and neuroretinitis with a background of vasculitis and neovascularization.  The patient was initially treated with high doses of oral steroids (80 mg prednisolone), which were gradually tapered, and also received extensive argon laser photocoagulation in ischemic areas in both eyes.  Despite vigorous treatment and an initial positive response to treatment, pars plana vitrectomy was eventually needed to address the recurrent vitreous hemorrhages in the left eye.  Consequently, VA improved from 0.1 to 0.2 (Snellen) and there was no relapse of vitreous hemorrhage.  Persistent ME was noted, however, and it was decided to treat with a dexamethasone 0.7 mg intravitreal implant.  Following the dexamethasone implant OS, VA improved significantly from 0.2 to 0.5 (Snellen), the patient reported much less distortion, and there was marked reduction in central retinal thickness from 467 to 234 microns.  The patient remained in remission without any exudation in the macula at 4 months follow-up.  The authors concluded that dexamethasone 0.7 mg intravitreal implant appeared to be a safe and effective method in the treatment of ME in patients with IRVAN syndrome and could possibly be a treatment option for other cases of inflammatory induced ME.

Cystoid Macular Edema associated with Retinitis Pigmentosa

Saatci et al (2013) reported the effectiveness of Ozurdex in a patient with retinitis pigmentosa (RP) and bilateral cystoid ME unresponsive to topical carbonic anhydrase inhibitors.  A 36-year old man with bilateral cystoid ME associated with RP that was unresponsive to topical carbonic anhydrase inhibitors underwent bilateral 0.7-mg Ozurdex 2 weeks apart.  Spectral domain optical coherence tomography revealed resolution of ME 1 week following each injection in both eyes and his VA improved.  However, ME recurred 2 months later in OS (left eye) and 3 months later in OD (right eye).  Second implant was considered for both eyes.  No implant-related complication was experienced during the follow-up of 7 months.  The authors concluded that inflammatory process seems to play a role in RP.  Intravitreal dexamethasone implant may offer retina specialists a therapeutic option especially in cases unresponsive to other treatment regimens in eyes with RP-related ME.

Srour et al (2013) evaluated the anatomical and functional outcomes of Ozurdex in patients with ME secondary to RP.  A total of 3 patients (4 eyes), aged 24 to 46 years, presented with refractory ME secondary to RP were included in this study.  Ozurdex was administered to treat ME.  The anatomical (CMT) and functional (BCVA) outcomes as well as adverse events were recorded.  All patients completed 6 months follow-up.  After Ozurdex therapy, all patients showed regression of ME.  At baseline, mean CMT was 443 ± 185 μm (range of 213 to 619 μm); ME improved to 234 ± 68 μm (range of 142 to 307 μm) at 1 month, to 332 ± 177 μm (range of 139 to 513 μm) at 3 months, and to 305 ± 124 μm (range of 144 to 447 μm) at 6 months.  Recurrent ME was recorded in 2 patients (both patients at 3 months from Ozurdex therapy).  Re-treatment with intravitreal Ozurdex was performed in 2 patients. Mean BCVA improved form 20/160 (range of 20/50 to 20/200) (baseline) to 20/100 (range of 20/40 to 20/125) at 1 month, to approximately 20/125 (range of 20/100 to 20/200) at 3 months, and to approximately 20/125 (range of 20/100 to 20/160) at 6 months.  No serious ocular and systemic adverse events were observed during the study period.  The authors concluded that Ozurdex provided anatomic and functional improvements and may represent a valuable treatment option for patients with ME secondary to RP.  These preliminary findings need to be validated by well-designed studies.

In a pilot study, Sudhalkar and colleagues (2017) determined the utility of the intravitreal dexamethasone implant as therapy for cystoid macular edema (CME) secondary to retinitis pigmentosa (RP) recalcitrant to carbonic anhydrase inhibitor therapy over 2 years.  This was a prospective, case-series study.  Patients who showed either an incomplete or no response to topical dorzolamide for at least 1 month and oral acetazolamide therapy for at least 15 days were recruited for the study with informed consent.  A complete anterior and posterior segment examination was performed including fundus fluorescein angiography (FFA), OCT scan and electroretinogram (ERG) to confirm the diagnosis.  The dexamethasone implant was injected using a standardized technique.  Follow-ups were scheduled on days 1, 7, and 30 and then monthly thereafter for 2 years.  The primary outcome measure was the change in corrected distance VA (CDVA) and central subfield thickness (CST) at months 1, 6, 12, 18, and 24.  The secondary outcome measure was complications, if any.  Appropriate statistical analysis was done.  A total of 5 patients (2 men; 6 eyes; median age of 49 years) were recruited for the study.  All patients required at least 2 injections over 2 years.  All patients demonstrated significant improvement in CDVA (p = 0.004) as well as CST measurements (p = 0.0038) over 2 years.  No complications were noted.  The authors concluded that intravitreal dexamethasone implant provided significant improvement in CDVA and CST measurements in patients with recalcitrant CME secondary to RP.  This was a small study (n = 5); its findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Retinitis pigmentosa: Treatment” (Garg, 2017) states that “Cystoid macular edema can reduce central vision in later stages of RP.  The most successful treatment thus far is the oral carbonic anhydrase inhibitor, acetazolamide.  Acetazolamide increases fluid absorption across the retinal pigment epithelium.  In the absence of macular edema, carbonic anhydrase inhibitors do not improve vision or alter the course of electroretinography (ERG) degradation in patients with RP”.  It does not mention dexamethasone intravitreal implant as a therapeutic option.

Cataract and Macular Edema

Sze and colleagues (2015) examined the safety and effectiveness of intra-vitreal dexamethasone implant in patients with cataract and ME undergoing phacoemulsification and intra-ocular lens (IOL) implantation. A total of 24 eyes with ME secondary to DME and RVO were retrospectively reviewed. These eyes underwent phacoemulsification with IOL implantation and intra-vitreal dexamethasone implant 0.7 mg at the same setting between September 2012 and September 2013. Demographic data, BCVA, CMT, (IOP, surgical time, and complications were recorded. Twelve eyes had DME and 12 eyes had RVO (10 central RVO and 2 branch RVO). Median baseline logMAR BCVA was 1.0 (Snellen 20/200) and mean baseline CMT was 530.2 ± 218.9 µm. Median follow-up duration was 13 months. At last follow-up, median VA improved significantly to 0.523 (Snellen 20/66) (p = 0.003) and CMT decreased to 300.7 ± 78.1 µm (p = 0.000). Median surgical time was 23 minutes. There were no intra-operative complications. In 12 eyes, ME recurred, requiring further treatment, and median time to recurrences was 21 weeks. One eye had raised IOP after second dexamethasone implant for recurrent ME. No major complication such as vitreous hemorrhage, retinal detachment, or endophthalmitis occurred. The authors concluded that combined cataract surgery with intra-vitreal dexamethasone implant appeared to be safe and effective in treating patients with cataract and ME in this small case series. Moreover, they stated that a larger prospective study with longer follow-up is needed to demonstrate the long-term benefit of this combined procedure.

Post-Lensectomy-Vitrectomy Aphakia

Bansal et al (2012) reported the behavior of intra-vitreal Ozurdex implant in eyes with post-lensectomy-vitrectomy (PLV) aphakia.  These researchers carried out a retrospective chart review of 3 eyes with PLV aphakia (3 patients with uveitis) who received intravitreal injection of Ozurdex for cystoid macular edema (1 eye), persistent inflammation (1 eye), and ocular hypotony (1 eye).  Final outcome was assessed in terms of effectiveness, stability, and tolerance of the implant.  Following implantation of the Ozurdex, an initial improvement was seen in all 3 eyes.  However, the implant migrated into the anterior chamber (AC) at 1 week in 2 eyes and at 5 weeks in 1 eye, and wandered between the AC and vitreous cavity with changing postures of the patient.  Two eyes developed corneal edema, of which 1 eye underwent implant removal from the AC.  The authors concluded that Ozurdex implant should be contraindicated in eyes with PLV aphakia to avoid its deleterious effect on the corneal endothelium.

Non-Arteritic Anterior Ischemic Optic Neuropathy

Alten and associates (2014) evaluated structural and functional outcomes of intra-vitreal dexamethasone implant (IDI) in 3 patients presenting with non-arteritic anterior ischemic optic neuropathy. Intra-vitreal dexamethasone implant was administered once in 3 patients. Best-corrected visual acuity, perimetry, volume spectral-domain OCT scan of the optic disc (ODV), retinal nerve fiber layer (RNFL) scan and visually evoked potential (VEP) measurements were assessed at baseline and after 1 and 3 months. Mean BCVA was 20/100 in patient 1 (patient 2: 20/100; patient 3: 20/50) at baseline, 20/60 (patient 2: 20/400) at 1 month and 20/80 (20/400; 20/60) at 3 months. Mean deviation in perimetry developed from -4.90 dB (-22.09 dB; -8.68 dB) to -7.60 dB (-30.75 dB) and -14.23 dB (-30.59 dB; -7.17 dB); ODV and RNFL decreased during follow-up; VEP measurements showed a reduction in amplitudes during the entire observation period. The authors concluded that all patients showed a reduction in papilla edema over time, however, a functional improvement was not observed.

Proliferative Vitreoretinopathy

Banerjee and co-workers (2013) stated that proliferative vitreo-retinopathy (PVR) is the commonest cause of late anatomical failure in rhegmatogenous retinal detachment. Visual and anatomical outcomes remain poor despite advances in vitreo-retinal surgical techniques with reported primary failure rates of up to nearly 50 %. Numerous adjunctive medications have been evaluated in clinical trials with no agent gaining widespread acceptance and use. This study was designed to investigate the benefits of using a slow-release dexamethasone implant delivered intra-operatively in patients undergoing vitrectomy surgery for retinal detachment with established PVR. For the study, 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR will be randomized to receive either standard treatment or study treatment in a 1:1 treatment allocation ratio. Both groups will receive the standard surgical treatment appropriate for their eye condition and routine peri-operative treatment and care, differing only in the addition of the supplementary adjunctive agent in the treatment group. The investigated primary outcome measure was stable retinal re-attachment with removal of silicone oil without additional vitreo-retinal surgical intervention at 6 months. The authors concluded that this is the first RCT to investigate the use of an adjunctive slow-release dexamethasone implant in patients undergoing vitrectomy surgery for retinal detachments with PVR.

Kuo and colleagues (2015) investigated a new sustained-release formulation of dexamethasone (Ozurdex) for inhibiting PVR and its effect on the expression of retinal glial reaction and inflammation in experimental PVR eyes. These researchers used 30 pigmented rabbits for this study. One week after gas compression, the eyes were injected with 5 × 10(4) retinal pigment epithelial cells into the vitreous cavity to induce PVR. Concurrently, 1 eye also received an intra-vitreal injection of Ozurdex; the other eye was used as a control. Proliferative vitreo-retinopathy was graded by indirect ophthalmoscopy on days 1, 3, 7, 14, 21, and 28. The expression of the retinal glial reaction and inflammation in experimental PVR eyes were evaluated by Western blot analysis. Severity of PVR increased gradually and peaked after 14 days, and no differences in PVR severity between the study and control groups were observed at any time-point. The expression of glial fibrillary acid protein (GFAP) increased on days 7 and 14 in both the PVR control and study groups. While the use of Ozurdex in the study group showed less GFAP expression, this difference was insignificant. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 significantly increased on days 7 and 14 in PVR control eyes. There was a significant difference in TNF-α between PVR control eyes and Ozurdex-treated eyes on days 7 (p < 0.001) and 14 (p = 0.019). Ozurdex in the study group showed lower IL-6 expression; however, this difference was not significant on days 7 (p = 0.063) and 14 (p = 0.052). The authors concluded that intra-vitreal injection of Ozurdex suppressed the expression of inflammatory markers; however, it did not mitigate the severity of experimental PVR in this animal model.

Radiation Maculopathy

Bui and colleagues (2014) stated that radiation maculopathy is the most common cause of severe vision loss after radiotherapy of uveal melanoma. To-date, no effective therapy exists. These researchers reported a novel approach to the treatment of radiation maculopathy using Ozurdex (dexamethasone intra-vitreal implant). This was a retrospective case series of 2 patients who developed radiation maculopathy after radiotherapy for uveal melanoma and was treated with Ozurdex. Clinical outcomes included VA, central foveal thickness by OCT, IOP, and cataract formation. Both patients were of Caucasian descent. Patient 1 received charged-particle radiation, whereas patient 2 received iodine-125 brachytherapy for medium-sized uveal melanoma located in the mid-peripheral retina. Radiation maculopathy developed 47 months and 18 months after radiation exposure in patient 1 and 2, respectively. Both patients initially received bevacizumab monotherapy followed by alternating therapy with bevacizumab and intra-vitreal triamcinolone. Secondary to a limited response, the patients were treated with Ozurdex implants. One patient had visual improvement, and both patients experienced a prolonged time frame of anatomical stability. Adverse effects included a rise in the IOP, which was controlled by topical hypotensive agents and posterior subcapsular cataract formation in patient 1. The authors concluded that Ozurdex intra-vitreal implant provided a prolonged period of anatomical stabilization in recalcitrant cases of radiation maculopathy in patients who have failed multiple intra-vitreal bevacizumab injections and had only a partial response to intra-vitreal triamcinolone. Moreover, they stated that larger prospective studies are needed to determine the extent of visual benefit.

Macular Edema Secondary to Acute Retinal Necrosis

Majumder and colleagues (2016) reported 2 cases of acute retinal necrosis in immunocompetent patients, complicated by CME and treated with Ozurdex implant.  Two patients diagnosed with acute retinal necrosis were treated with intravenous acyclovir.  Both of them developed CME following resolution of viral retinitis.  Ocular condition of the 1st patient was further complicated by central serous chorioretinopathy.  Under unavoidable circumstances, CME in both the patients was treated with intravitreal dexamethasone implant with great caution.  Resolution of CME without recurrence of viral retinitis was noted in the long-term follow-up.  The authors concluded that the findings of this study should be interpreted cautiously, and extreme caution should be exercised prior deciding the management with a corticosteroid implant in patients with viral retinitis.  However, intravitreal dexamethasone implant can be a useful option in selected patients with CME in acute retinal necrosis.

Lowering the Risk of Conjunctivitis in Individuals Receiving Cytarabine

Matteucci and colleagues (2006) examined the effectiveness of dexamethasone plus diclofenac eye drops as prophylaxis for conjunctivitis induced by high-dose (HD) cytarabine (Ara-C).  A total of 60 patients were randomized to receive either dexamethasone (group A, n = 29) or dexamethasone plus diclofenac (group B, n = 31).  Conjunctivitis was experienced by 13/29 (45 %) patients in group A, and 4/31 (13 %) patients in group B (p < or = 0.009); 12 out of 13 patients in group A who developed ocular toxicity had grade 2 to 3 conjunctivitis whereas only 1 of 4 patients affected in group B experienced a similar grade of conjunctivitis.  The authors concluded that the incidence and severity of HD Ara-C-induced conjunctivitis were significantly reduced by combined dexamethasone/diclofenac prophylaxis.  This was a small study, which showed that combined dexamethasone/diclofenac prophylaxis provided better results than dexamethasone prophylaxis in lowering the incidence of conjunctivitis in patients receiving cytarabine.  These findings need to be validated by well-designed studies.  More importantly, the study did not study Ozurdex (dexamethasone intravitreal implant).

Ozurdex for the Treatment of Acute Zonal Occult Outer Retinopathy (AZOOR)

Kuo and colleagues (2017) noted that acute zonal occult outer retinopathy (AZOOR), a rare disorder affecting the outer retina, was first described by Gass in 1993 as a syndrome with rapid loss of 1 or more extensive zones of the outer retinal segments.  It is characterized by photopsia, minimal funduscopic changes, and electroretinographic (ERG) abnormalities.  The efficacy of systemic steroids in treating AZOOR has been previously described and advocated by the concept of autoimmune retinopathy.  However, the use of intravitreal of sustained-released steroid had not been mentioned to date.  In this single-case study, a 34-year old man had sudden onset of central scotoma and photopsia in the left eye.  His visual acuity (VA) continued to deteriorate.  The visual field defect demonstrated bilateral enlarged blind spots and altitudinal defects.  Fluorescein angiography (FA) showed non-specific retinal inflammation, and an ERG illustrated decreased amplitude of the b wave in both eyes.  Optical coherence tomography (OCT) examinations revealed para-foveal loss of the photo-receptor inner/outer segment (IS/OS) junction.  Therefore, AZOOR was diagnosed.  Although his vision did not improve under the initial treatment of systemic corticosteroid and calcium channel blocker, remarkable improvement was noticed after the intravitreal injection (IVI) of Ozurdex, consistent with the recovered IS/OS junction disruption.  These investigators stated that during the 13-month follow-up, subject’s condition remained stable.  However, these researchers could not rule out the residual or delayed effects from the systemic steroid treatment received prior to the administration of Ozurdex or the possibility of spontaneous recovery.  Thus, they stated that the reliability of intravitreal injection treatment with sustained released steroid need further elucidation with future clinical research of AZOOR.

Barnes and associates (2018) reported on the use of intravitreal steroids in the management of AZOOR.  Retrospective case series of 9 eyes of 5 patients with AZOOR who received intravitreal triamcinolone acetonide (IVTA), dexamethasone intravitreal implant, and/or fluocinolone acetonide implant.  Treatment response was determined by reported symptoms and multi-modal imaging findings.  Patients were observed for at least 1 year following intravitreal steroid treatment (range of 14 months to 63 months).  A total of 7 eyes received IVTA, 6 eyes received the dexamethasone intravitreal implant, and 1 eye received the fluocinolone acetonide implant.  All patients experienced disease stability or improvement based on symptomatic response and multi-modal imaging findings after intravitreal steroids; 1 eye developed central serous retinopathy, and another eye a choroidal neovascular membrane; 5 of 9 eyes experienced ocular hypertension.  All phakic eyes developed cataracts.  The authors concluded that intravitreal steroids effectively achieved disease stability in patients with AZOOR.  This was a small study (6 eyes received Ozurdex) with relatively short-term follow-up (1 year).

Ozurdex for the Treatment of Macular Edema Secondary to Tuberculosis Uveitis

Hasanreisoglu and colleagues (2019) noted that tuberculosis-associated uveitis remains a diagnostic and therapeutic challenge.  After diagnosis of tuberculosis and initiation of anti-tuberculosis therapy for tuberculosis uveitis, the clinical responses are favorable.  However, at 4 to 6 weeks of the therapy, there commonly occurs paradoxical deterioration due to an increase in inflammation which is often accompanied by cystoid macular edema (CME).  Thus, adjuvant administration of anti-inflammatory regimen should be considered.  For this purpose, systemic and peri-ocular steroids, systemic and intravitreal immunosuppressive agents have been tested.  Nevertheless, there is no report in the literature about intravitreal DEX implants for the treatment of this inflammatory condition.  These investigators presented a case of tuberculosis uveitis whose ocular inflammation is partially modified by systemic and peri-ocular steroid injections and then well-controlled by the intravitreal DEX implant.  The authors concluded that intravitreal DEX implant injection appeared to be a safe and potent option for the treatment of macular edema secondary to tuberculosis uveitis.

Ozurdex for the Treatment of Cystoid Macular Edema (CME) Associated with Sympathetic Ophthalmia or Syphilis-Related Uveitis

In a retrospective, interventional, controlled study, Kakkassery et al (2017) determined the safety, efficacy, and predictive outcome factors for intravitreal DEX in pseudophakic cystoid macular edema (PCME).  Patients included had to have clinically significant PCME and have been treated with the DEX between 2012 and 2015.  Charts and 1-year data were selected consecutively, and efficacy and safety were abstracted; VA and central foveal thickness (CFT) were analyzed.  A total of 19 patient data sets were analyzed.  After treatment with DEX, mean VA increased significantly by 0.2 logMAR (p = 0.034), while the mean CFT was reduced significantly by 162.79 μm (p < 0.001); 5 patients receiving a combination of DEX/bevacizumab have not experienced a higher mean VA gain or CFT reduction compared to 14 patients receiving DEX alone.  Decision rules, when to combine DEX with bevacizumab, have not been defined before the study.  Only post-treatment VA gains in the non-hypertensive subgroup (n = 11) were significantly better (p = 0.026).  Analysis of data from diabetes patients (n = 4) versus non-diabetics yielded no significant differences in efficacy.  There have been no adverse events (AEs) within follow-up time.  The authors concluded that the use of DEX in PCME showed significant improvements in VA and CFT.  The VA appeared to show greater improvements in patients without hypertension.  Moreover, they stated that the use of DEX implants in PCME should be further investigated in larger patient populations to confirm these findings.

The authors stated that this pilot study had several drawbacks.  The layout of a retrospective study always includes a selection bias.  The number of patients screened was normally higher than the sample finally chosen for inclusion.  The small sample size (n = 14 with DEX alone) and geographic aspect represent a further drawback.  The drawbacks mentioned earlier could be assumed for all retrospective data referenced above.  Apart from 1 RCT, all datasets discussed were also neither randomized nor controlled.  The treatment decision especially for an intravitreal administration of a DEX implant alone or with combined bevacizumab had not been clearly defined and there might be a negative bias for the decision to give additive bevacizumab.  Also, the different group size of DEX implant alone or with combined bevacizumab weakened the significance of the data.  Even more, DEX implant with combined bevacizumab was more frequently used in PCME patients with diabetes.

Lautredou et al (2018) reported the successful utilization of adjunctive repeat intravitreal corticosteroid therapy for the treatment of CME in syphilis-related uveitis.  A HIV-positive patient with treated ocular syphilis who developed refractory CME was treated with repeat intravitreal corticosteroid therapy including DEX intravitreal implants.  Treatment led to the resolution of CME and improvement in VA.  The authors concluded that intravitreal corticosteroid therapy may be a viable adjunctive treatment for refractory CME in patients with treated syphilitic uveitis.  Corticosteroid-induced exacerbation of infection is unlikely in patients with an adequate serologic treatment response.  Moreover, these researchers noted that to their knowledge there was only 1 case report in the literature where DEX implant was used as adjuvant treatment for CME secondary to syphilitic uveitis.

Wocker and Januschowski (2019) presented the case of a 39-year old woman with CME of the left eye in the context of sympathetic ophthalmia.  The right eye underwent several surgical interventions of both cornea and retina after ocular trauma and was enucleated after first clinical signs compatible with sympathetic ophthalmia and after exclusion of other infectious/non-infectious etiologies.  The patient was treated with para-bulbar triamcinolone injections and intravitreal injections of a dexamethasone slow-release implant with a good clinical course with respect to the macular edema.  A steroid response did not occur over the treatment period of more than 12 months.  This was  single-case study; its findings need to be further investigated.

Ozurdex for the Treatment of Vasoproliferative Tumor

Temblador-Barba and colleagues (2018) reported the case of a 19-year old woman who presented a vasoproliferative tumor.  It caused complications, such as epi-retinal membrane, macular edema, vitreous hemorrhage, and exudative retinal detachment.  The patient was treated with 3 injections of intravitreal bevacizumab, an intravitreal DEX implant, tocilizumab, and double freeze-thaw cryotherapy.  The authors concluded that therapeutic options were: observation, if it is small, if it is a peripheral lesion, and if there seems to be no threat to vision.  If it requires treatment, laser photocoagulation, intravitreal bevacizumab, trans-conjunctival cryotherapy, trans-pupillary thermotherapy, photodynamic therapy, brachytherapy plaques and surgery are the different options available.  Recently, tocilizumab and intravitreal DEX implants have been reported to be beneficial.

Combined Intravitreal Anti-Vascular Endothelial Growth Factor (VEGF) and Ozurdex

In a retrospective cohort study, Lin and co-workers (2017) evaluated the safety and efficiency in macular edema patients who concurrently received a single injection of a dexamethasone intravitreal implant (DEX, 0.7 mg) and ranibizumab (2.3 mg).  Medical records from 2012 to 2016 were reviewed.  Patients who received concurrent DEX and ranibizumab injections with a follow-up period of at least 3 months were enrolled in the study group.  An age- and gender-matched group received ranibizumab injections and was designated the control group; BCVA, CMT and IOP were included in the analysis.  Steroid-induced ocular hypertension (SIOH) is defined as either an elevation of more than 10 mmHg from baseline or a single IOP measurement of more than 30 mmHg.  A total of 26 patients were enrolled in the current study with 13 patients in each group.  Both the BCVA (p = 0.04) and CMT (p < 0.01) achieved significant improvement after the follow-up period in the study group.  The IOP increased after the injection but no significant elevation was observed throughout the follow-up period in the study group (p = 0.15).  For SIOH, 1 patient in the study group had an elevated IOP of 10 mmHg (7.7 %) at 2 post-operative months, and no single IOP measurement of more than 30 mmHg was obtained; 5 patients (38.5 %) in the study group received medical treatment that successfully retarded their IOP elevation, and no individuals required surgical management.  In the control group, there were no significant fluctuations concerning BCVA, CMT, and IOP, and no ocular hypertension was observed.  According to the inter-group analysis, the CMT and BCVA recovered more significantly in the study group than in the control group.  The authors concluded that concurrent injection of DEX and ranibizumab was a preliminary method that showed effectiveness in treating ME.  Furthermore, safety was also guaranteed, with moderate levels of severity and transient IOP elevation being observed.  Moreover, they stated that a future large-scale study that include different anti-angiogenic agents, such as aflibercept, is needed to evaluate the long-term safety and effectiveness of this combined treatment.

The authors stated that this study had several drawbacks.  First, the small numbers of patients, with only 13 patients in each group, would diminish the statistical power of the study with a 22 % chance of type-II error.  Second, the retrospective nature could limit the consistency, and some data, including underlying diseases, may be incomplete.  Lastly, the concurrent ranibizumab injection in the study group might influence the outcomes compared to previous studies.

Mehta and colleagues (2018) stated that he combination of steroid and anti- VEGF intravitreal therapeutic agents could potentially have synergistic effects for treating DME.  On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes.  Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects.  Ina Cochrane review, these investigators evaluated the effects of intravitreal agents that block VEGF activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DME.  They searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid Medline; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP.  The date of the search was February 21, 2018.  These researchers included RCTs of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DME.  They included people with DME of all ages and both sexes.  They also included trials where both eyes from 1 participant received different treatments.  These investigators used standard methodological procedures recommended by Cochrane; 2 authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria.  The primary outcome was change in BCVA between baseline and 1 year.  Secondary outcomes included change in CMT, economic data and quality of life (QOL).  They considered adverse effects including intra-ocular inflammation, raised IOP and development of cataract.

There were 8 RCTs (703 participants, 817 eyes) that met inclusion criteria with only 3 studies reporting outcomes at 1 year.  The studies took place in Iran (3 studies), USA (2 studies), Brazil (1 study), Czech Republic (1 study) and South Korea (1 study); 7 studies used the unlicensed anti-VEGF agent bevacizumab and 1 study used licensed ranibizumab.  The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DME after anti-VEGF monotherapy and received 3 monthly doses of ranibizumab prior to allocation.  The anti-VEGF agent was combined with intravitreal triamcinolone in 6 studies and with an intravitreal DEX implant in 2 studies.  The comparator group was anti-VEGF alone in all studies; 2 studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm.  While the authors judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.  When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DME, these researchers found no meaningful clinical difference in change in BCVA (MD -2.29 VA letters, 95 % CI: -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95 % CI: -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at 1 year.  There was very low-certainty evidence on intra-ocular inflammation from 8 studies, with 1 event in the anti-VEGF/steroid group (313 eyes) and 2 events in the anti-VEGF group (322 eyes).  There was a greater risk of raised IOP (Peto OR 8.13, 95 % CI: 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95 % CI: 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy.  There was low-certainty evidence from 1 study of an increased risk of systemic AEs in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95 % CI: 0.61 to 2.86; 103 eyes).  One study compared anti-VEGF/steroid versus macular laser therapy.  At 1 year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95 % CI: -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95 % CI: -68.93 to 36.93; 80 eyes; low-certainty evidence).  There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95 % CI: 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95 % CI: 2.86 to 31.51; 100 eyes).  One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at 1 year.  There was no evidence of a meaningful difference in BCVA between treatments at 1 year (MD 0 VA letters, 95 % CI: -6.1 to 6.1, low-certainty evidence).  Likewise, there was no meaningful difference in the mean CMT at 1 year (MD - 9 μm, 95 % CI: -39.87 μm to 21.87 μm between the anti-VEGF/steroid group and the steroid group.  There was very low-certainty evidence on raised IOP at 1 year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95 % CI: 0.16 to 3.55).  No included study reported impact of treatment on patients' QOL or economic data.  None of the studies reported any cases of endophthalmitis.

The authors concluded that combination of intravitreal anti-VEGF plus intravitreal steroids did not appear to offer additional visual benefit compared with monotherapy for the treatment of DME; at present the evidence for this is of low-certainty.  There was an increased rate of cataract development and raised IOP in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone.  Patients were exposed to potential side effects of both these agents without reported additional benefit.  The majority of the evidence came from studies of bevacizumab and triamcinolone used as primary therapy for DME.  There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least 1 year follow-up.  It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.

Krick and Bressler (2018) presented some recent clinically relevant results from Diabetic Retinopathy Clinical Research (DRCR) Network trials that may guide management of DME or proliferative diabetic retinopathy (PDR).  Among eyes with DME and VA 20/50 or worse, aflibercept, on average, had greater improvement in VA over 2 years compared with bevacizumab or ranibizumab.  Aflibercept is associated with higher rates of improvements in diabetic retinopathy severity among eyes with PDR and vision-impairing DME at baseline compared with bevacizumab or ranibizumab.  Among eyes with persistent central-involved DME after at least 6 anti-VEGF injections, no difference in mean VA improvement was observed between eyes that received continued ranibizumab and sham injections versus ranibizumab and intravitreal sustained dexamethasone drug-delivery system, especially for phakic eyes.  For eyes with PDR, ranibizumab was associated with lower rates of developing PDR-worsening events compared with pan-retinal photocoagulation, especially among eyes that did not receive ranibizumab for central-involved DME at baseline.  Ranibizumab was cost-effective for PDR for eyes with, not without, vision-impairing central-involved DME, highlighting challenges when safety and efficacy results were at odds with cost-effectiveness results.  The authors concluded that aflibercept for DME, in certain circumstances, was more likely to have superior VA and anatomical outcomes compared with bevacizumab or ranibizumab.  No vision benefits were apparent, especially for phakic eyes, by adding intravitreal corticosteroids for persistent DME following anti-VEGF injections.

Tsaousis and associates (2018) presented a case-series study of 3 women (mean age of 48.33 ± 16.16 years) with punctate inner choroidopathy (PIC).  These researchers reported the outcomes after an essentially long follow-up period of up to 14 years and provided evidence of the effectiveness of intravitreal injections of bevacizumab (1.25 mg/0.05 ml) and dexamethasone (0.7 mg) in PIC patients with choroidal neovascular membrane formation.  This was a retrospective case series of 3 patients with PIC who were treated with intravitreal injections of bevacizumab; 2 patients also received intravitreal dexamethasone.  Once a choroidal neovascular membrane (CNVM) developed, the outcome was poor with a BCVA of 6/60 or counting fingers in the affected eyes.  Patients were followed-up for 5, 14 and 8 years, respectively.  The authors concluded that the use of dexamethasone 0.7 mg in PIC yielded encouraging results and long periods of stability.  When CNVM complicated the primary disease, the prognosis was unfavorable, especially if the macula integrity had already been considerably affected.  On the contrary, aggressive early therapy and continued monthly monitoring could prevent severe fibrosis, as showed in previous reports.  They stated that further studies with a larger number of PIC patients are needed to examine the role of intravitreal injections of dexamethasone 0.7 mg and anti-VEGF agents in PIC complicated with CNVM.  The main drawback of this study were its small sample size (n = 2 for intravitreal dexamethasone implant plus intravitreal bevacizumab), the non-randomized nature, and the lack of post-perspective study design.

Dextenza (dexamethasone ophthalmic insert)

On December 3, 2018, Ocular Therapeutix, Inc. announced the U.S. FDA approval of Dextenza (dexamethasone ophthalmic insert) 0.4 mg for intracanalicular use for the treatment of ocular pain following ophthalmic surgery.

Dextenza is a corticosteroid intracanalicular insert placed in the punctum and into the canaliculus. The insert is designed to deliver a dexamethasone 0.4 mg dose to the ocular surface for up to 30 days without preservatives. Dextenza resorbs and exits the nasolacrimal system without the need for removal. Dextenza is intended for single-use only.

FDA approval was based on results found in three randomized, multicenter, double-masked, parallel group, vehicle-controlled trials in which patients received Dextenza or its vehicle (placebo) immediately upon completion of cataract surgery. In all three trials, Dextenza had a higher proportion of patients than the vehicle group who were pain free on post-operative Day 8. On post-operative Day 14, in two of the three studies, Dextenza had a higher proportion of patients than the vehicle group who had an absence of anterior chamber cells that was statistically significant (Ocular Therapeutix, 2019).

Tyson et al (2019) state that sustained-release intracanalicular dexamethasone insert has been shown to be safe and effective for the treatment of postoperative ocular inflammation and pain following cataract surgery.  A prospective multicenter randomized parallel-arm double masked vehicle-controlled phase 3 study was conducted at 21 sites in the United States. A total of 438 adult patients with planned clear corneal cataract surgery were randomized (1:1) to receive dexamethasone insert or placebo, and the treatment was placed in the canaliculus of the eye immediately after surgery (Day 1). The primary efficacy endpoints were complete absence of anterior chamber cells at Day 14 and complete absence of pain at Day 8. The authors found that at Day 8, significantly more patients had an absence of ocular pain in the dexamethasone insert arm compared with placebo (p < .0001). At Day 14, significantly more patients had an absence of anterior chamber cells in the dexamethasone insert arm compared with placebo (p < .0001). The dexamethasone insert arm showed no increase compared with placebo in incidence of all adverse events or ocular adverse events. Twice as many placebo patients required rescue therapy, compared with treated patients at Day 14. The study was able to successfully meet both primary endpoints. In addition, patients receiving the dexamethasone insert experienced a decrease in inflammation after surgery as early as Day 4 through Day 45, and a decrease in pain as early as one day after surgery (Day 2) through Day 45. The study found that the dexamethasone insert was well-tolerated, and the adverse events profile was similar to placebo.

Dextenza is contraindicated in patients with active corneal, conjunctival or canalicular infections, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella; mycobacterial infections; fungal diseases of the eye, and dacryocystitis.

The most commonly reported adverse reactions (approximately 6-10% of patients) were anterior chamber inflammation and elevations in intraocular pressure.

Dextenza and Allergic Conjunctivits

Torkildsen et al. (2017) report on the results of a phase 2, randomized, double-masked, vehicle-controlled clinical trial evaluating the efficacy and safety of Detenza in a model of allergic conjunctivitis. Fifty-nine subjects (n=28 Dextenza group, n=31 vehicle group) with a positive conjunctival allergen challenge (CAC) were randomized to receive Dextenza or PV (vehicle insert). Challenges occurred over 42 days, with efficacy assessed at 14 (primary endpoint visit), 28, and 40 days postinsertion. Outcome measures included the evaluation of ocular itching, redness, tearing, chemosis, eyelid swelling, rhinorrhea, and congestion. At 14 days postinsertion, Dextenza was statistically superior to PV, with least square mean differences for ocular itching of -0.76, -0.97, and -0.87 at 3, 5, and 7 min post-CAC, and for conjunctival redness of -0.46, -0.66, and -0.68 at 7, 15, and 20 min post-CAC. Clinical significance, defined as a 1-U decrease from PV, was not met for primary efficacy. Secondary endpoints, including number of subjects reporting itching and conjunctival redness, indicated superior performance of Dextenza compared with vehicle. Eleven Dextenza-treated (35.5%) and 10 vehicle-treated (30.3%) subjects each experienced a single adverse event. The authors state that this phase 2 study demonstrated preliminary efficacy and safety data of Dextenza for the treatment of allergic conjunctivitis.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Ozurdex:
CPT codes covered if selection criteria are met:
67027	Implantation of intravitreal drug delivery system (eg, ganciclovir implant), includes concomitant removal of vitreous
67028	Intravitreal injection of a pharmacologic agent (separate procedure)
Other CPT codes related to the CPB:
66820, 66821, 66830, 66840 - 66940, 66982, 66984, 66985	Cataract surgery [not covered when combined with Ozurdex]
HCPCS codes if selection criteria are met:
J7312	Injection, dexamethasone, intravitreal implant, 0.1 mg [Ozurdex]
Other HCPCS codes related to the CPB:
J2778	Injection, ranibizumab, 0.1 mg
J9308	Injection, ramucirumab, 5 mg
J9035	Injection, bevacizumab, 10 mg
J9098	Injection, cytarabine liposome, 10 mg
J9100	Injection, cytarabine, 100 mg
ICD-10 codes covered if selection criteria are met:
E08.311, E08.3211 - E08.3219, E08.3311 - E08.3319, E08.3411 - E08.3419, E08.3511 - E08.3559, E09.311, E09.3211 - E09.3219, E09.3311 - E09.3319, E09.3411 - E09.3419, E09.3511 - E09.3559, E10.311, E10.3211 - E10.3219, E10.3311 - E10.3319, E10.3411 - E10.3419, E10.3511 - E10.3559, E11.311, E11.3211 - E11.3219, E11.3311 - E11.3319, E11.3411 - E11.3419, E11.3511 - E3559, E13.311, E13.3211 - E3219, E13.3311 - E13.3319, E13.3411 - E13.3419, E13.3511 - E13.3559	Diabetic macular edema
H30.20 - H30.23	Posterior cyclitis
H30.001 - H30.819, H30.90 - H30.93	Chorioretinal inflammation [neruoretinitis] [choriorentinitis]
H30.891 - H30.899	Other chorioretinal inflammations [noninfectious posterior uveitis]
H34.8110 - H34.8192	Central retinal vein occlusion
H34.821 - H34.823	Venous engorgement
H34.8310 - H34.8392	Tributary (branch) retinal vein occlusion
H34.9	Unspecified retinal vascular occlusion
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A18.54	Tuberculous iridocyclitis [Macular edema secondary to tuberculosis uveitis]
B39.0 - B39.9	Histoplasmosis
D49.81	Neoplasm of unspecified behavior of retina and choroid [vasoproliferative tumor]
H00.031 - H00.039	Abscess of eyelid
H01.001 - H01.029	Blepharitis
H01.00A - H01.00B	Unspecified blepharitis
H01.01A - H01.01B	Ulcerative blepharitis
H01.02A - H01.02B	Squamous blepharitis
H04.001 - H04.029	Dacryoadenitis
H04.301 - H04.329	Dacroyocystitis
H04.331 - H04.339	Acute lacrimal canaliculitis
H04.411 - H04.419	Chronic dacryocystitis
H04.421 - H04.429	Chronic lacrimal canaliculitis
H05.011 - H05.019	Cellulitis of orbit
H05.021 - H05.022	Osteomyelitis of orbit
H05.031 - H05.039	Periostitis of orbit
H05.041 - H05.049	Tenonitis of orbit
H05.10 - H05.129	Chronic inflammatory disorders of orbit
H10.011 - H10.9	Conjunctivitis
H16.001 - H16.149	Keratitis
H25.0 - H26.9	Cataract
H27.00 - H27.03	Aphakia [rupture of the posterior lens capsule and anterior chamber intraocular lens]
H32	Chorioretinal disorders in disease classified elsewhere [Ocular histoplasmosis syndrome (OHS)]
H35.00	Unspecified background retinopathy [acute zonal occult outer retinopathy (AZOOR)]
H35.021 - H35.029	Exudative retinopathy [Coats' disease]
H35.20 - H35.23	Proliferative vitreo-retinopathy
H35.381 - H35.389	Toxic maculopathy [radiation maculopathy]
H35.81	Retinal edema [covered only with branch or central retinal vein occlusion]
H35.89	Other specified retinal disorders [macular edema secondary to acute retinal necrosis]
H40.30x+ - H40.53x+	Glaucoma secondary to eye trauma, inflammation and other eye disorders
H40.60x+ - H40.63x+	Glaucoma secondary to drugs
H44.001 - H44.009	Purulent endophthalmitis
H44.131 - H44.139	Sympathetic uveitis
H47.011 - H47.019	Ischemic optic neuropathy
H59.031 - H59.039	Cystoid macular edema following cataract surgery
M72.6	Necrotizing fasciitis
Z96.1	Presence of intraocular lens [not covered for aphakic eyes with rupture of posterior lens capsule and anterior chamber intraocular lens]
Dextenza (dexamethasone ophthalmic insert):
Other CPT codes related to the CPB:
67028	Intravitreal injection of a pharmacologic agent (separate procedure)
HCPCS codes covered if selection criteria are met:
J1096	Dexamethasone, lacrimal ophthalmic insert, 0.1 mg
ICD-10 codes covered if selection criteria are met:
G89.18	Other acute postprocedural pain [ocular pain following ophthalmic surgery]
H57.10 - H57.13	Ocular pain [ocular pain following ophthalmic surgery]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
H10.10 - H10.13	Acute atopic conjunctivitis
H10.45	Other chronic allergic conjunctivitis

The above policy is based on the following references: