Dexamethasone Ophthalmic Implant (Ozurdex) and Insert (Dextenza)

Number: 0795

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses dexamethasone ophthalmic implant (Ozurdex) and insert (Dextenza).

1. Medical Necessity

   Aetna considers the following interventions medically necessary: 

   1. Ozurdex (dexamethasone intravitreal implant) 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).

      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;
      5. Non-intact posterior lens capsule.

      Ozurdex (dexamethasone intravitreal implant) is contraindicated and considered unproven in individuals with advanced glaucoma and ocular or periocular infections.

   2. Dextenza (dexamethasone ophthalmic insert) for the treatment of the following:

      1. Ocular inflammation and pain following ophthalmic surgery;
         Note: When administered at the time of ophthalmic surgery, Dextenza (dexamethasone ophthalmic insert) is considered a supply integral to the surgery and is not separately reimbursed.
      2. Ocular itching associated with allergic conjunctivitis after failure of all of the following unless contraindicated or clinically significant adverse effects are experienced:
         
         
         1. Topical ophthalmic antihistamines with mast cell-stabilizing properties (see Appendix); and
         2. Topical ophthalmic mast cell stabilizers (see Appendix); and
         3. Topical ophthalmic corticosteroids (see Appendix).

      Aetna considers Dextenza (dexamethasone ophthalmic insert) therapy not medically necessary for members with the contraindication of active ocular infection.

2. Experimental and Investigational

   Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

   1. Ozurdex (dexamethasone intravitreal implant) for the treatment of the following indications (not an all-inclusive list) because of insufficient evidence for these indications:

      1. Acute zonal occult outer retinopathy (AZOOR)
      2. Autoimmune retinopathy
      3. Coats' disease (also known as Coats disease)
      4. Cystoid macular edema (CME) associated with retinitis pigmentosa, sympathetic ophthalmia or syphilis-related uveitis
      5. CME following cataract surgery
      6. Diabetic retinopathy
      7. Idiopathic macular telangiectasia type 1
      8. Idiopathic neuroretinitis
      9. Idiopathic posterior scleritis
      10. Macular edema secondary to acute retinal necrosis, idiopathic retinal vasculitis, aneurysms, neuroretinitis (IRVAN) syndrome, radiation, or tuberculosis uveitis
      11. Non-arteritic anterior ischemic optic neuropathy
      12. Panuveitis
      13. Post-operative CME from retinal detachment repair
      14. Post-operative inflammation in refractory uveitis undergoing cataract surgery
      15. Post-operative macular edema secondary to vitrectomy for epiretinal membrane and retinal detachment
      16. Proliferative vitreoretinopathy
      17. Pseudophakic macular edema (Irvine-Gass syndrome) except for pseudophakic persons with DME
      18. Radiation maculopathy
      19. Reducing the risk of conjunctivitis from cytarabine
      20. Uveitis-glaucoma-hyphema syndrome (Ellingson syndrome)
      21. Vasoproliferative tumor;
      22. Vogt-Koyanagi-Harada syndrome/Vogt-Koyanagi-Harada-like syndrome;
   2. Combined cataract surgery and Ozurdex (dexamethasone intravitreal implant) for the treatment of cataract and macular edema because of insufficient evidence for this approach;
   3. Combined intravitreal anti-vascular endothelial growth factor (VEGF) and Ozurdex (dexamethasone intravitreal implant) for the treatment of the following because of insufficient evidence for this approach:
      
      
      1. Diabetic macular edema
      2. Macular edema secondary to retinal vein occlusion
      3. Neovascular serous retinal pigment epithelial detachment secondary to neovascular age-related macular degeneration
      4. Punctate inner choroidopathy;

   4. Dextenza (dexamethasone ophthalmic insert) for all other indications (e.g., panuveitis) (not an all-inclusive list) because of insufficient evidence for this approach.

3. Related Policies

   • CPB 0719 - Fluocinolone Acetonide Intra-vitreal Implant (Retisert, Yutiq and Iluvien)

Background

Ozurdex (Dexamethasone Intravitreal Implant)

U.S. Food and Drug Administration (FDA)-Approved Indications

Ozurdex is a corticosteroid indicated for:

• The treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO)
• The treatment of non-infectious uveitis affecting the posterior segment of the eye
• The treatment of diabetic macular edema.

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 USA, 2022). 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 USA, 2022). 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 USA, 2022). 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 USA, 2022).

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, 2021).

Hasanreisoglu et al (2019) examined the long-term outcomes of intravitreal DEX for the treatment of non-infectious uveitis.  The study included 62 eyes of 44 patients treated with DEX implant due to non-infectious uveitis and followed-up for at least a year.  Outcome measures included BCVA, CFT, IOP, vitreous haze score, indications, immunomodulatory therapy and steroid usage before/after injection, number of injections, as well as AEs were analyzed retrospectively.  Average follow-up was 20 months (range of 12 to 64 months).  The female/male ratio was 29/15; mean age was 50 years (range of 22 to 75 years).  The most frequent uveitis etiologies were idiopathic (25 patients, 40.3 %) and Behcet’s uveitis (17 patients, 27.4 %).  The most common indication for DEX injection was CME together with resistant vitreous haze (26 eyes, 41.9 %); 22 eyes (30 %) received more than 1 DEX injection.  Mean BCVA was improved from 0.55 logMAR at baseline to 0.38, 0.32, and 0.35 after 1, 3, and 6 months, respectively (p < 0.001 for each).  Mean CFT was decreased from 386 μm at baseline to 288, 311, and 302 μm after 1, 3, and 6 months, respectively (p < 0.001 for each).  Mean IOP did not change significantly during follow-up; 5 eyes (8 %) received topical anti-glaucoma medication (IOP greater than or equal to 25 mmHg); 18 (46 %) of 39 phakic eyes underwent cataract surgery during follow-up.  Similar efficacy of the DEX implant was observed in eyes that received multiple injections.  Systemic immunomodulatory therapy did not change significantly during follow-up.  The authors concluded that intravitreal DEX injection was useful for suppressing intra-ocular inflammation, provided good visual and anatomical results in the long-term, and preserved these effects with repeated injections.  However, although it appeared safer than other intravitreal steroid treatments in terms of IOP and cataract formation, patients still require close follow-up.  These researchers stated that intravitreal DEX appeared to reduce the need for systemic steroids, but this phenomenon and its effect on systemic immunosuppressive therapies must be clarified by long-term prospective studies.  They noted that the main drawbacks of this study were its retrospective nature and small sample size (44 patients).

In a systematic review, Saincher and Gottlieb (2020) examined if the DEX implant is effective for treating intermediate, posterior, and panuveitis as a monotherapy or adjunctive treatment to systemic immunomodulatory therapies.  These investigators carried out a systematic review using Medline, Embase, and PubMed data-base searches with the Oxford Centre for Evidence-based Medicine Levels of Evidence criteria to select publications.  Available background information and patient data from each study was tabulated.  Outcomes studied were CRT, BCVA, intra-ocular inflammation (anterior chamber cells, vitreous haze), number of patients with prior and concomitant immunomodulatory treatments, IOP elevation (greater than or equal to 25 mmHg), and other adverse effects associated with the implant.  A total of 195 (61.51 %) patients had previous immunomodulatory treatment while 232 (64.8 %) were treated with concomitant immunomodulatory therapy with the DEX implant.  CRT decreased by an average of 198.65 μm (42.74 %); VA improved to an average of 0.451 (logMAR) or 20/57 (Snellen), which was a 43.11 % improvement from baseline; 173 (59 %) of eyes were quiescent at the end of the trials, of which 40 (13.7 %) previously inflamed eyes became quiescent.  Elevated IOP occurred in 91 (20.6 %).  The most common AEs were cataract/posterior subcapsular opacities in 47 (11.03 %) patients and conjunctival hemorrhage in 24 (5.44 %) patients.  The authors concluded that the DEX implant was an effective medication for the treatment of posterior segment uveitis, uveitic macular edema, and resulted in improved VA.  Development of elevated IOP and cataract should be closely monitored as they are tangible risks associated with the DEX implant.  This study was unable to determine whether the DEX implant was more effective as a monotherapy or as an adjunctive therapy to systemic immunomodulatory treatment.  These researchers stated that more RCTs are needed to increase the power of evidence supporting the use of the DEX implant.  They noted that the effects of the DEX implant on QOL are also unknown and need further exploration; and further research is needed to examine the DEX implant as a monotherapy for posterior uveitis.

Coats' Disease (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) states that “Cystoid macular edema can reduce central vision in later stages of retinitis pigmentosa (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 and Radiation-Induced Macular Edema

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.

Fallico and colleagues (2021a) noted that radiation maculopathy and radiation-induced macular edema are common sight-threatening complications following radiotherapy, especially that used for uveal melanoma.  While many treatment and preventive strategies have been proposed, management of these conditions is still challenging . Initially, treatments were based on the use of retinal laser, but the outcomes were poor.  Subsequently, management has shifted towards injection of intravitreal anti-VEGF or corticosteroids.  These investigators reviewed current clinical evidence, which mostly relies on small sample-sized and retrospective studies, for the management of radiation maculopathy and, in particular, radiation-induced macular edema.  At present, the 1st-line approach is usually intravitreal anti-VEGF.  Intravitreal dexamethasone implant may be an option for those with suboptimal response or contraindications to anti-VEGF agents.  Possible preventive treatments that require future study are intravitreal bevacizumab and ranibizumab, peripheral laser photocoagulation, and subtenon triamcinolone acetonide.

Furthermore, an UpToDate review on “Initial management of uveal and conjunctival melanomas” (Harbour and Shih, 2022) states that “Early clinical signs of radiation retinopathy include macular edema and ischemia, which may be demonstrable using optical coherence tomography prior to becoming funduscopically detectable … The management of radiation retinopathy, optic neuropathy, and neovascular glaucoma has been more challenging.  Radiation causes endothelial cell loss and capillary closure, leading to retinal ischemia and the elaboration of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors.  Attempted treatments have included photodynamic therapy, laser photocoagulation, oral pentoxifylline, hyperbaric oxygen, periocular or intravitreal injection of corticosteroids, and more recently, intravitreal injection of anti-VEGF agents such as bevacizumab, ranibizumab, and aflibercept.  While none of these treatments is curative or preventative, promising results have been observed for intravitreal anti-VEGF therapy in maintaining or improving visual function in some patients with radiation maculopathy”.

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.

Ozurdex for the Treatment of Idiopathic Macular Telangiectasia Type 1

Cirafici and colleagues (2021) noted that macular telangiectasia type 1 (MacTel 1) is a rare unilateral disease, characterized by telangiectatic retinal capillaries, CME, and lipid deposition occurring temporal to the fovea.  These investigators reported the findings of 3 patients who were diagnosed with idiopathic MacTel 1, and prospectively followed for a mean duration of 26 months between 2016 and 2019.  This was the 1st report of patients affected by MacTel 1 who were treated with DEX implant as a 1st-line treatment.  These researchers attempted to better characterize the disease using a multi-modal wide-field imaging and determined the effectiveness of DEX implant on MacTel 1 in terms of CMT and BCVA.  Patients underwent a comprehensive ophthalmic examination, BCVA, swept-source OCT (SS-OCT), SS-OCT angiography (SS-OCTA), ultra-widefield (UWF) color, and FA fundus photograph.  All patients presented mono-lateral reduced BCVA and ME with increased CMT evaluated by SS-OCT.  With SS-OCTA, these researchers showed that the telangiectasia-associated vascular changes originate in the deep retinal vascular plexus and as a consequence ME and exudation develop causing vision loss.  Furthermore, UWF imaging helped clinicians to highlight vascular changes typical of Coats Disease at the far retinal periphery.  All patients were treated with DEX intravitreal implant, showing a decrease in CMT and a stabilization of VA.  Due to the recurrent nature of ME, patients underwent a mean of 4 DEX implants during the follow-up period.  The authors concluded that in order to address the clinical features of this uncommon disease avoiding diagnostic errors, it might be important to use a multi-modal imaging approach.  The anatomical and functional beneficial effects of DEX implant were well evident although transient.

The authors stated that the treatment of MacTel 1 is usually centered on the resolution of ME and exudation, and long-acting steroids might be effectively used.  These researchers stated that more studies are needed to better delineate the cytokines profile and finding new therapeutic strategies.

Ozurdex for the Treatment of Idiopathic Neuroretinitis

In a single-case study, Cekic and Gulkas (2022) described the successful management of idiopathic neuroretinitis with intravitreal DEX implant.  A 34-year-old man with acute painless unilateral vision loss, optic disc swelling, and macular edema was diagnosed as idiopathic neuroretinitis, and he underwent 0.7-mg intravitreal DEX implant.  Macular edema responded quickly and VA improved from 20/50 to 20/25 within 2 weeks and to 20/20 within a month.  One month after the injection, optic disc edema disappeared.  No recurrence occurred and VA was stable at 20/20 during 3 years of follow-up.  The authors concluded that idiopathic neuroretinitis could be treated with intravitreal DEX implant.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Retinal vasculitis associated with primary ocular disorders” (Tolentino and Dana, 2020) states that “Retinal vasculitis may be the marker for or the harbinger of a systemic disease, usually a systemic inflammatory or immune disorder or an infectious disease, or may occur in isolation or as part of an ocular syndrome such as idiopathic retinal vasculitis aneurysm neuroretinitis (IRVAN) … Treatment of idiopathic retinal vasculitis is usually reserved for those who develop symptomatic decline in vision or if vasculitis is encroaching on the macula.  Systemic glucocorticoids, azathioprine, methotrexate, cyclosporine, and plasma exchange have all been used with variable efficacy, but none has been evaluated in a randomized fashion.  One retrospective study of 29 patients with vision-threatening disease found that the administration of prednisone (initial dose 1 mg/kg per day) was associated with visual improvement in 60 % of patients”.  Intravitreal DEX implant is not mentioned as a therapeutic option.

Ozurdex for the Treatment of Idiopathic Posterior Scleritis

Zhao and colleagues (2021) noted that posterior scleritis is one of the most easily missed and misdiagnosed diseases in ophthalmology.  In a single-case study, these investigators treated a patient with DEX implant.  Subject was a 40-year old woman who had anxiety, palpitation, and insomnia presented with eye pain and decreased vision in the left eye.  An eye examination indicated that her VA was 40/100.  Her left eye presented with conjunctival edema, mild exophthalmos, clear cornea, KP(-), and clear aqueous humor.  In the fundus, there was a cinerous retinal protuberance.  Ultrasonography showed "T-sign" and no systemic association was detected in laboratory examination.  One month after injection of DEX implant, the patient exhibited VA of 20/20, fundus serous retinal detachment disappeared, and IOP of both eyes was at the normal level.  The authors concluded that intravitreal injection of DEX implant may be a safe and effective treatment for patients with idiopathic posterior scleritis.  Potential advantages include no exposure of the patients to the risks of systemic steroids.  Furthermore, it could avoid compliance issues of systemic administration of corticosteroids that may preclude effective treatment.  Moreover, these researchers stated that more studies with a longer period of follow-up are needed to better examine the safety and efficacy of this treatment.

Ozurdex for the Treatment of Panuveitis

Brady et al (2016) noted that uveitis is a term used to describe a heterogeneous group of intra-ocular inflammatory diseases of the anterior, intermediate, and posterior uveal tract (iris, ciliary body, choroid).  Uveitis is the 5th most common cause of vision loss in high-income countries, accounting for 5 % to 20 % of legal blindness, with the highest incidence of disease in the working-age population.  Corticosteroids are the mainstay of acute treatment for all anatomical subtypes of non-infectious uveitis and can be administered orally, topically with drops or ointments, by peri-ocular (around the eye) or intra-vitreal (inside the eye) injection, or by surgical implantation.  In a Cochrane review, these investigators examined the safety and efficacy of steroid implants in patients with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis.  They searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid Medline, Ovid Medline In-Process and Other Non-Indexed Citations, Ovid Medline Daily, Ovid OLDMedline (January 1946 to November 2015), Embase (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched April 15, 2013), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en).  These researchers did not use any date or language restrictions in the electronic search for studies.  They last searched the electronic databases on November 6, 2015.  They also searched reference lists of included study reports, citation databases, and abstracts and clinical study presentations from professional meetings.  These investigators included RCTs comparing either fluocinolone acetonide (FA) or dexamethasone intravitreal implants with standard-of-care (SOC) therapy with at least 6 months of follow-up after treatment.  They included studies that enrolled subjects of all ages who had chronic non-infectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was better than hand-motion.  Two review authors independently reviewed studies for inclusion; 2 review authors independently extracted data and assessed the risk of bias for each study.  They included data from 2 studies (619 eyes of 401 subjects) that compared FA implants with SOC therapy.  Both studies used similar SOC therapy that included administration of prednisolone and, if needed, immunosuppressive agents.  The studies included subjects from Australia, France, Germany, Israel, Italy, Portugal, Saudi Arabia, Spain, Switzerland, Turkey, the United Kingdom, and the United States.  These researchers examined both studies at high risk of performance and detection bias.  Only 1 study reported the primary outcome, recurrence of uveitis at any point during the study through 24 months.  The evidence, judged as moderate quality, showed that a FA implant probably prevented recurrence of uveitis compared with SOC therapy (risk ratio (RR) 0.29, 95 % CI: 0.14 to 0.59; 132 eyes).  Both studies reported safety outcomes, and moderate quality evidence showed increased risks of needing cataract surgery (RR 2.98, 95 % CI: 2.33 to 3.79; 371 eyes) and surgery to lower IOP (RR 7.48, 95 % CI: 3.94 to 14.19; 599 eyes) in the implant group compared with SOC therapy through 2 years of follow-up.  No studies compared DEX implants with SOC therapy.  The authors concluded that after considering both benefits and harms reported from 2 studies in which corticosteroids implants were compared with SOC therapy, these investigators were unable to conclude that the implants were superior to traditional systemic therapy for the treatment of non-infectious uveitis.  These studies exhibited heterogeneity in design and outcomes that measured efficacy.  Pooled findings regarding safety outcomes suggested increased risks of post-implant surgery for cataract and high IOP compared with SOC therapy.

Squires et al (2017) stated that non-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders.  Management includes local and systemic corticosteroids, immunosuppressants and biological drugs.  These researchers examined the clinical effectiveness and cost-effectiveness of subcutaneous adalimumab (Humira) and Ozurdex in adults with non-infectious intermediate uveitis, posterior uveitis or panuveitis.  Electronic databases and clinical trials registries including Medline, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the WHO's International Clinical Trials Registry Platform were searched to June 2016, with an update search conducted in October 2016.  Review methods followed published guidelines.  A Markov model was developed to examine the cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from a NHS and Personal Social Services (PSS) perspective over a lifetime horizon, parameterized with published evidence.  Costs and benefits were discounted at 3.5 %.  Substantial sensitivity analyses were undertaken.  Of the 134 full-text articles screened, 3 studies (4 articles) were included in the clinical effectiveness review; 2 RCTs [VISUAL I (active uveitis) and VISUAL II (inactive uveitis)] compared adalimumab with placebo, with limited standard care also provided in both arms.  Time to treatment failure (reduced VA, intra-ocular inflammation, new vascular lesions) was longer in the adalimumab group than in the placebo group, with a hazard ratio (HR) of 0.50 [95 % CI: 0.36 to 0.70; p < 0.001] in the VISUAL I trial and 0.57 (95 % CI: 0.39 to 0.84; p = 0.004) in the VISUAL II trial.  The adalimumab group showed a significantly greater improvement than the placebo group in the 25-item Visual Function Questionnaire (VFQ-25) composite score in the VISUAL I trial (MD 4.20; p = 0.010) but not the VISUAL II trial (MD 2.12; p = 0.16).  Some systemic adverse effects occurred more frequently with adalimumab than with placebo.  One RCT [HURON (active uveitis)] compared a single 0.7-mg dexamethasone implant against a sham procedure, with limited SOC also provided in both arms.  Dexamethasone provided significant benefits over the sham procedure at 8 and 26 weeks in the percentage of patients with a vitreous haze score of zero (p < 0.014), the mean BCVA improvement (p ≤ 0.002) and the percentage of patients with a greater than or equal to 5-point improvement in VFQ-25 score (p < 0.05).  Raised IOP and cataracts occurred more frequently with dexamethasone than with the sham procedure.  The incremental cost-effectiveness ratio (ICER) for 1 dexamethasone implant in 1 eye for a combination of patients with unilateral and bilateral uveitis compared with limited current practice, as per the HURON trial, was estimated to be £19,509 per quality-adjusted life-year (QALY) gained.  The ICER of adalimumab for patients with mainly bilateral uveitis compared with limited current practice, as per the VISUAL trials, was estimated to be £94,523 and £317,547 per QALY gained in active and inactive uveitis, respectively.  Sensitivity analyses suggested that the rate of blindness has the biggest impact on the model results.  The interventions may be more cost-effective in populations in which there is a greater risk of blindness.  The authors concluded that 2 RCTs of systemic adalimumab and 1 RCT of a unilateral, single DEX implant showed significant benefits over placebo or a sham procedure.  The ICERs for adalimumab were estimated to be above generally accepted thresholds for cost-effectiveness.  The cost-effectiveness of dexamethasone was estimated to fall below standard thresholds.  However, there was substantial uncertainty around the model assumptions.  In future work, primary research should compare dexamethasone and adalimumab with current treatments over the long-term and in important subgroups and consider how short-term improvements relate to long-term effects on vision.  The authors stated that the drawbacks of this study included that the clinical trials did not fully reflect clinical practice; 13 additional studies of clinically relevant comparator treatments were identified; however, network meta-analysis was not feasible.  The model results were highly uncertain because of the limited evidence base.

Saincher and Gottlieb (2020) stated that while proven to be effective for treating ME associated with CRVO and DME, the effects of the DEX implant for treatment of intermediate, posterior, and panuveitis uveitis are not well established in the literature.  In a systematic review, these investigators examined if the DEX implant (Ozurdex) is effective for treating intermediate, posterior, and panuveitis as a monotherapy or adjunctive treatment to systemic immunomodulatory therapies.  This review used Medline, Embase, and PubMed database searches with the Oxford Centre for Evidence-based Medicine Levels of Evidence criteria to select publications.  Available background information and patient data from each study was tabulated.  Outcomes studied were CRT, BCVA, intra-ocular inflammation (anterior chamber cells, vitreous haze), number of patients with prior and concomitant immunomodulatory treatments, IOP elevation (greater than or equal to 25 mmHg), and other adverse effects associated with the implant.  A total of 195 (61.51 %) patients had previous immunomodulatory treatment while 232 (64.8 %) were treated with concomitant immunomodulatory therapy with the DEX implant.  CRT decreased by an average of 198.65 μm (42.74 %); VA improved to an average of 0.451 (logMAR) or 20/57 (Snellen) which was a 43.11 % improvement from baseline; 173  (59 %) of eyes were quiescent at the end of the trials, of which 40 (13.7 %) previously inflamed eyes became quiescent.  Elevated IOP occurred in 91 (20.6 %).  The most common AEs were cataract/posterior subcapsular opacities in 47 (11.03 %) patients and conjunctival hemorrhage in 24 (5.44 %) patients.  The authors concluded that the DEX implant was an effective medication for the treatment of posterior segment uveitis, uveitic ME, and resulted in improved VA.  Development of elevated IOP and cataract should be closely monitored as they are tangible risks associated with the DEX implant.  This study was unable to determine whether the DEX implant was more effective as a monotherapy or as an adjunctive therapy to systemic immunomodulatory treatment.  It did not mention the effectiveness of the DEX implant for panuveitis.  These researchers stated that the DEX implant caused elevated IOP in a minority of cases; thus, it is important to monitor IOP over duration of effect of the DEX implant.  Subconjunctival hemorrhage and posterior subcapsular cataract are possible AEs.  They stated that more RCTs are needed to increase the power of evidence supporting the use of the DEX implant.  The effects of the DEX implant on QOL are also unknown and need further exploration; further research is needed to examine the DEX implant as a monotherapy for posterior uveitis.

Ozurdex for the Treatment of Post-Operative Cystoid Macular Edema from Retinal Detachment Repair

In a retrospective review, Thanos and colleagues (2018) examined the effectiveness of DEX implant as the treatment for recalcitrant ME following successful rhegmatogenous retinal detachment (RRD) repair.  These researchers reviewed medical records of 17 consecutive patients (17 eyes) with recalcitrant ME associated with RRD repair who were treated with a single, or multiple injections of an intravitreal dexamethasone 0.7-mg implant (Ozurdex) at 2 centers.  Main outcomes of the study were change in logarithm of the minimum angle of resolution VA, measurement of CFT, and macular cube volume as measured by spectral domain OCT (SD-OCT) and frequency of complications.  The mean age was 67 years (range of 51 to 78 years).  All 17 patients received previous topical therapy and 12 of them had previous administration of intravitreal triamcinolone with persistence of ME.  Baseline mean BCVA was 20/100 (logarithm of the minimum angle of resolution 0.75; range of 0.18 to 1.3 ± 0.37) in the affected eyes.  There was a statistically significant improvement in BCVA at 1 month (p < 0.001) and 3 months (p = 0.01).  Mean baseline CFT was 505 μm, and mean macular cube volume was 10.62 mm.  There was a statistically significant decrease in CFT and macular cube volume at 1 month (505 to 290 μm, p = 0.013 and 10.62 to 9.13 mm, p < 0.0001) and 3 months (p = 0.01).  All patients developed recurrence of ME at 3 months, which required re-treatment.  The average number of implants was 4 (range of 1 to 14).  No adverse effects such as retinal detachment or endophthalmitis occurred; 2 patients experienced an increase in IOP that was controlled with topical therapy.  The authors concluded that ME that occurred in eyes following successful repair of RRD can be chronic and recalcitrant; and may be safely and successfully treated with the DEX implant.

In a retrospective, case-control series, Pole and associates (2021) examined risk factors, imaging characteristics, and treatment responses of CME following RRD repair.  This trial included patients who underwent pars plana vitrectomy (PPV) and/or scleral buckling (SB) for RRD, with at least 6 months of follow-up.  Clinical and surgical parameters of patients with and without CME (nCME), based on SD-OCT, were compared.  Of 99 eyes enrolled, 25 had CME while 74 had nCME.  Patients with CME underwent greater numbers of surgeries (p < 0.0001).  After adjusting for number of surgeries, macula-off RRD (p = 0.06), proliferative vitreoretinopathy (PVR) (p = 0.09), surgical approach (PPV and/or SB, p = 0.21), and tamponade type (p = 0.10) were not statistically significant, although they all achieved significance on uni-variate analysis (p = 0.001 or less).  Intra-operative retinectomy (p = 0.009) and post-operative pseudophakia or aphakia (p = 0.008) were more frequent in the CME group, even after adjustment.  Characteristics of cCME on OCT included diffuse distribution, confluent cysts, and absence of subretinal fluid or intra-retinal hyper-reflective foci.  Macular thickness improved significantly with intra-vitreal triamcinolone (p = 0.016), but not with anti-VEGF agents (P = 0.828) or DEX implant (p = 0.125).  After adjusting for number of surgeries and macular detachment, final VAs remained significantly lower in the CME versus nCME group (p = 0.012).  The authors concluded that risk factors of CME included complex retinal detachment repairs requiring multiple surgeries, and pseudophakic or aphakic lens status.  Although chronic CME was associated with poor therapeutic response, corticosteroids were the most effective studied treatments.

The authors stated that this study had several drawbacks.  The retrospective analysis precluded standardized imaging and treatment protocols.  Significant loss to follow-up likely led to under-reporting of chronic post-RRD CME and an inability to accurately determine incidence.  The high percentage of CME likely related to inclusion of eyes that had initial RRD repairs prior to the inclusion period and multiple referrals for complex cases.  These researchers were unable to determine after which surgery CME appeared due to inconsistent timing and absence of OCT acquisition between surgeries; or missing outside records.  A small number of eyes received anti-VEGF injections, and greater numbers may show CME improvement.  These investigators stated that a prospective, larger study examining complex macular surgeries is needed.

Ozurdex for the Treatment of Post-Operative Inflammation in Refractory Uveitis Undergoing Cataract Surgery

In a retrospective, single-center study, Li and colleagues (2021) examined the effectiveness of Ozurdex after phacoemulsification and IOL implantation in refractory uveitis patients.  This trial was carried out for refractory pan-uveitis patients who underwent cataract surgery combined with intravitreal Ozurdex implantation.  The main outcome measurements were BCVA, CRT, grade of anterior chamber cell (AAC), IOP, and systemic/ocular AEs.  A total of 10 eyes of 7 patients were included; BCVA showed significant improvement at 1 month (p = 0.004), 3 months (p = 0.0004), and 6 months (p = 0.001) post-operation.  There were no statistically significant differences in the post-operative CRT among follow-up groups (p > 0.05).  No significant differences were observed in the baseline IOP when compared to 1, 3, and 6 month(s) (all p > 0.05) post-operation.  One patient developed a transient elevated IOP post-injection; 2 eyes (20 %) developed posterior capsular opacifications and underwent neodymium-doped yttrium aluminum garnet (Nd:YAG) laser capsulotomy.  In 6 patients (8 eyes, 71.4 %), the systemic steroid usage was reduced to below 10 mg/day.  Patients experienced a mean of 1.4 ± 0.52 recurrences of inflammation in the 6 months before operation and 0.7 ± 0.48 in the 6 months post-operation.  The mean recurrence time was 13 ± 0.58 weeks (range of 12 to 14 weeks) post-operation.  In 5 of 7 patients (7 out of 10 eyes), inflammation relapse developed post-operatively.  Only 1 patient (2 eyes) needed increased amounts of oral corticosteroids.  Intra-ocular inflammation recurrence in the remaining patients was controlled by topical steroids.  The authors concluded that Ozurdex was considered a safe and effective approach to control post-operative inflammation in cataract surgery for patients with refractory uveitis in this study.  After the disappearance of Ozurdex's anti-inflammatory effects over time, in most cases the recurrent inflammation could be controlled by topical steroids.  Moreover, these researchers stated that the main drawback of this trial was it was a small case-series study (n = 7 patients), and a study with larger cohorts of patients and longer follow-up period is needed to further confirm these preliminary findings.

Ozurdex for the Treatment of Post-Operative Macular Edema Secondary to Vitrectomy for Epiretinal Membrane and Retinal Detachment

In a systematic review and meta-analysis, Parisi and colleagues (2021) examined the efficacy of DEX for the treatment of macular edema secondary to vitrectomy for epiretinal membrane (ERM) and retinal detachment (RD).  Studies reporting clinical outcomes of DEX use for the treatment of macular edema secondary to ERM and RD vitrectomy were searched on PubMed and Embase databases.  The primary outcome was BCVA change between baseline and post-DEX treatment, reported as MD with 95 % CI.  In particular, post-DEX data included 1-month, 3-month, 6-month, and 12-month follow-up, if available.  Mean CMT change was examined as a secondary outcome.  Post-implant AEs, including rise in IOP and development of cataract, were reported as well.  A total of 5 uncontrolled studies, 1 non-randomized controlled study, and 1 RCT were included, with a total of 5 cohorts and 3 cohorts in the ERM group and RD group, respectively.  Considering the last available follow-up, a significant improvement in post-implant BCVA was found in the overall population, irrespective of the indication for vitrectomy (MD = -0.28, 95 % CI: -0.37 to -0.20; p < 0.001), but with significant heterogeneity.  In both groups, mean BCVA significantly improved following the implant (in the ERM group, MD = -0.31, 95 % CI: -0.40 to -0.22; in the RD group, MD = -0.22, 95 % CI: -0.41 to -0.03), with no difference between the 2 groups (p = 0.41).  However, there was significant heterogeneity in both groups.  Considering the last available follow-up, a significant CMT reduction was observed in the overall population, irrespective of the indication for vitrectomy (MD = -129.75, 95 % CI: -157.49 to -102.01; p < 0.001).  In the ERM group, a significant CMT reduction was shown following DEX (MD = -133.41, 95 % CI: -155.37 to -111.45; p < 0.001), with no heterogeneity.  In the RD group, mean CMT reduction was borderline significant (MD = -128.37, 95 % CI: -253.57 to -3.18; p = 0.040), with significant heterogeneity.  No difference in CMT improvement was observed between the 2 groups (p = 0.94).  The authors concluded that this meta-analysis showed that DEX yielded a significant improvement in visual and anatomical outcomes, even if limited by significant heterogeneity.  These investigators stated that DEX represents an effective treatment for post-operative macular edema secondary to ERM and RD vitrectomy.

The authors stated that this review/meta-analysis had several drawbacks.  First, significant heterogeneity was found for BCVA analysis in both groups and for CMT analysis in the rhegmatogenous RD group.  The presence of high heterogeneity limited the quality of the evidence provided.  The reason for it could be related to the retrospective nature of most of the included studies and to the fact that different eligibility criteria and clinical variables could have been considered by the included studies.  Furthermore, no analysis was carried out on potential AEs, such as rise in IOP and development of cataract, due to the limited number of cases reported.  Finally, a relatively small number of studies was included.

In a systematic review and meta-analysis, Fallico and associates (2021b) examined the effectiveness of vitrectomy combined with DEX versus vitrectomy without DEX in patients with ERM.  Studies that compared ERM vitrectomy with and without DEX with a follow-up greater than or equal to 3 months were included.  The primary outcome was mean BCVA change between eyes undergoing ERM vitrectomy combined with DEX (DEX group) and eyes undergoing ERM vitrectomy alone (control group) at 3 months.  Secondary outcomes included mean BCVA change at 6 months and mean OCT-CMT change at both 3-month and 6-month follow-up; MDs with their 95 % CI were calculated.  Meta-analyses were based either on random effect model or fixed effect model according to heterogeneity.  A total of 4 studies were included.  At 3 months, ERM vitrectomy combined with DEX yielded a greater visual gain compared to vitrectomy alone (MD = 9.7; 95 % CI: 2.6 to 16.8; p = 0.01).  However, significant heterogeneity was found.  A sensitivity analysis excluding the only retrospective non-randomized study confirmed a greater visual gain in the DEX group (MD = 7.1; 95 % CI: 2.7 to 11.6; p < 0.01), with no heterogeneity.  At 6 months, a non-significant but borderline difference in visual gain was found between in the 2 groups (MD = 5.1; 95 % CI: -0.3 to 10.5; p = 0.06), with no heterogeneity.  Three-month analysis of CMT revealed a greater reduction in the DEX group (MD = -80.2; 95 % CI: -149.1 to 11.2; p = 0.02), but with significant heterogeneity.  A sensitivity analysis excluding the only retrospective non-randomized study allowed to reduce heterogeneity, but no difference in 3-months CMT change was found between the 2 groups (MD = -50.0; 95 % CI: -106.2 to 6.2; p = 0.08).  At 6 months, no difference in CMT change was shown between the 2 groups (MD = -48.5; 95 % CI: -120.5 to 23.5; p = 0.19), with significant heterogeneity.  The authors concluded that DEX in eyes undergoing vitrectomy for ERM provided a better visual outcome at 3 months compared to ERM vitrectomy without the implant, with limited evidence of better anatomic outcome as well.  Moreover, these researchers stated that further carefully designed studies are needed to examine if DEX would ensure a significant long-term visual benefit as a result of a faster reduction of macular thickening.

Ozurdex for the Treatment of Uveitis-Glaucoma-Hyphema Syndrome (Ellingson Syndrome)

Badakere et al (2016) stated that uveitis-glaucoma-hyphema (UGH) syndrome is a rare but potentially serious cataract surgery complication following IOL implantation in the anterior chamber or mal-positioned posterior chamber IOLs.  It is extremely rare to have this complication in an eye with intact posterior capsule and a well placed in-the-bag IOL.  These investigators reported the case of a 48-year old man who presented with blurred vision after an uneventful cataract surgery in the right eye, and who was treated for anterior uveitis.  The anterior chamber inflammation persisted despite intense treatment with topical steroids for 2 months, and the IOP was high.  The posterior chamber IOL was in the bag and well covered by a capsulorrhexis margin.  Dilated gonioscopy revealed inferior capsular bag hyphema secondary to the superior haptic displacement due to a tear in the equatorial bag.  The authors concluded that this case highlighted the importance of dilated gonioscopy and a rare possibility of UGH syndrome in an eye with a well-placed IOL.

Sousa et al (2016) reported the case of a patient who developed UGH syndrome following an uneventful cataract surgery and discussed risk factors, diagnostic challenges, management options, and clinical implications.  Clinical manifestations of UGH syndrome include elevated IOP, anterior chamber inflammation, and recurrent hyphema or micro-hyphema.  Uveitis-glaucoma-hyphema Plus syndrome also includes accompanying vitreous hemorrhage.  Although classically associated with rigid anterior chamber lOLs, cases of mal-positioning and subluxated posterior chamber lOLs had also been described as possible triggers.  These investigators reported the case of a 70-year old man who developed UGH Plus syndrome after an uneventful cataract surgery with an lOL implanted in the capsular bag.  During post-operative follow-up, persistent intra-ocular inflammation, increased IOP, hyphema, and vitreous hemorrhage were consistent with this diagnosis.  Slit-lamp examination demonstrated progressive localized iris atrophy, compatible with chafing of the posterior iris by the IOL haptic as the trigger for UGH syndrome.  A pars plana vitrectomy was carried out and a retro-pupillary IOL was implanted.  No further complications occurred during follow-up.  The authors concluded that given the increasing prevalence of single-piece lOLs implanted in the capsular bag, it is important to recognize UGH syndrome as a rare but potentially serious complication.  Moreover, these researchers stated that topical steroid medication and aggressive IOP-lowering treatment were usually of limited use as they do not address the stimulus for inflammation.

Zemba (2017) stated UGH syndrome (Ellingson syndrome) is a rare condition caused by the mechanical trauma of an IOL mal-positioned over adjacent structures (iris, ciliary body, iridocorneal angle), leading to a spectrum of iris transillumination defects, micro-hyphemas and pigmentary dispersion, concomitant with increased IOP.  In patients with UGH syndrome, topical and systemic medication (corticosteroids along with IOP-lowering medication) reduced the IOP, controlled the anterior inflammation and brought symptomatic relief in the short-term.

Ozurdex for the Treatment of Vogt-Koyanagi-Harada Syndrome / Vogt-Koyanagi-Harada-Like Syndrome

Polo and colleagues (2020)described the case of a 58-year old woman with a personal history of metastatic melanoma under treatment with trametinib and dabrafenib, as well as a decrease in bilateral VA.  On examination, it was observed that she had an anterior uveitis, vitritis, serous retinal detachment, vasculitis and disc edema in both eyes.  She was diagnosed with a Vogt-Koyanagi-Harada-like syndrome secondary to MAP kinase pathway inhibition.  In addition to the withdrawal of the oncology drugs, systemic and topical corticosteroids were prescribed, but this treatment only achieved a partial improvement of the disease when biological therapy was re-introduced.  A bilateral intravitreal DEX implant was added, which led to a favorable improvement in her symptomatology, as well as in the findings of complementary tests.  Intra-ocular inflammation was a complication described following treatment with trametinib and dabrafenib.  An accurate diagnosis, added to corticosteroid treatment, systemic and intravitreal, resulted in optimal results.  The findings on intravitreal DEX need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Ocular side effects of systemically administered chemotherapy” (Liu et al, 2022) states that “Ipilimumab has rarely been associated with bilateral severe uveitis, which can lead to exudative retinal detachment in a mode similar to that seen with Vogt-Koyanagi-Harada syndrome (VKH).  This can be vision threatening and should prompt immediate drug discontinuation.  Treatment with topical corticosteroid drops has controlled anterior uveitis, and vision usually improves.  As patients typically have concurrent systemic autoimmune toxicities, systemic corticosteroids have also typically been used in these cases.  While the uveitis appears to be manageable with corticosteroids, cessation of therapy must be considered in the setting of systemic autoimmune toxicity … If uveitis occurs in combination with other immune-mediated adverse reactions (e.g., cutaneous [vitiligo, poliosis, alopecia], auditory [tinnitus], or neurologic [cerebrospinal fluid pleocytosis, meningismus), consider a VKH-like syndrome, which has been observed in patients treated with ipilimumab and may require treatment with systemic steroids to reduce the risk of permanent vision loss”.  Intravitreal DEX implant is not mentioned as a therapeutic option.

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 (mean difference [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.

Combined Intravitreal Anti-VEGF and Ozurdex for the Treatment of Macular Edema Secondary to Retinal Vein Occlusion

In a prospective, non-randomized, case-series study, Harb and colleagues (2021) examined the effectiveness of the combination therapy of intravitreal aflibercept 2-mg (Eylea) and Ozurdex versus dexamethasone alone in providing better VA in eyes with macular edema (ME) secondary to retinal vein occlusion (RVO).  A total of 74 eyes of 74 patients with treatment-naïve ME secondary to RVO were included in this trial; and were studied over a 12-month follow-up period.  Patients in the dexamethasone monotherapy group were treated with an initial Ozurdex injection while patients in the combination therapy group were treated with an Eylea injection followed 2 weeks later by an Ozurdex injection.  The treatment was repeated as needed; BCVA, CMT, and IOP were examined periodically’ the primary outcome measure was the BCVA.  Secondary outcome measures included CMT, number of re-treatments, and safety parameters.  At 1 year, the primary endpoint was met.  Patients receiving combined therapy had better mean VA changes from baseline compared to those receiving monotherapy (0.369 ± 0.221 logarithm of the minimum angle of resolution [logMAR] versus 0.218 ± 0.171 logMAR; p = 0.002).  The secondary endpoints were not met since there were no significant differences in mean reductions in CMT (272.67 ± 82.35 versus 248.11 ± 159.73; p = 0.412) and the mean number of re-treatments was similar in the 2 groups (1.75 ± 1.13 versus 1.42 ± 0.64; p = 0.126).  The authors concluded that aflibercept with dexamethasone implants achieved better visual outcomes compared to dexamethasone monotherapy with no significant differences in intravitreal re-treatment rates at the 1st year in eyes with ME secondary to RVO.  These investigators stated that this treatment modality provided imperative results that met the study's primary endpoint, making it a practical substitute that warrants a starting point for further research.

The authors stated that according to the findings of this study, associating anti-VEGF with dexamethasone implants showed encouraging results.  Efficacy outcomes were better than those obtained with dexamethasone monotherapy while the need to re-treat patients by anti-VEGF injections still met that obtained with dexamethasone monotherapy.  However, further studies must be carried out to ascertain the best therapeutic regimen that would reduce the number of injections of both the anti-VEGF and the dexamethasone while providing a better VA than anti-VEGF monotherapy alone.  Despite being among the few trials to have examined the effectiveness of combining aflibercept and dexamethasone implants, this study had several limitations worth mentioning.  In fact, having a small sample size, the relatively short duration of follow-up, and the absence of an anti-VEGF monotherapy control group were the major drawbacks; thus, the need of a large and comparative randomized clinical trial between combination and anti-VEGF monotherapy is of great value in order to be able to draw clear-cut conclusions.

Combined Intravitreal Anti-VEGF and Ozurdex for the Treatment of Neovascular Serous Retinal Pigment Epithelial Detachment Secondary to Neovascular Age-Related Macular Degeneration

Limon and Akcay (2021) examined the add-on effect of simultaneous DEX implant to bevacizumab for treatment of neovascular serous retinal pigment epithelial detachment (PED) secondary to neovascular age-related macular degeneration (nAMD).  A 72-year old man was previously treated with intravitreal bevacizumab and aflibercept for neovascular serous PED secondary to nAMD.  Because of the recurrences in neovascular PED, subject was treated with simultaneous intravitreal injection of bevacizumab and DEX implant.  At the initial visit, the patient's the BCVA in the left eye was 20/800.  His left eye had neovascular serous PED with a height of 1,100 µm and a largest linear diameter of ,3953 µm accompanied by subretinal fluid.  He received 4 intravitreal bevacizumab and 5 intravitreal aflibercept injections.  Although there was a decrease in PED sizes from time to time during the 16-month treatment period, PED height was 926 µm and PED greatest linear diameter was 5,820 µm at the end of 16th month.  Later, the patient could not have an injection for 3 months (he could not come to his controls during the pandemic period), and when he arrived 3 months later, the PED height was 910 µm and the greatest linear diameter was 5,830 µm.  With a single simultaneous intravitreal injection of bevacizumab and DEX implant, the PED regressed to 168 µm in height after 3 months.  The BCVA increased to 20/200.  No clinical toxic effects were observed, and IOP did not rise for 3 months after injection.  The authors concluded that simultaneous intravitreal bevacizumab and DEX implant injection safely and effectively treated treatment-resistant neovascular serous PED.  These researchers stated that this approach may be a novel alternative therapy for the treatment-resistant neovascular serous PED secondary to nAMD; however, further studies are needed to evaluate its safety and effectiveness.

Autoimmune Retinopathy

In a retrospective study, Hou et al (2023) examined clinical outcomes of autoimmune retinopathy (AIR) in the patients treated with intravitreal dexamethasone implant (IDI).  A total of 21 eyes of 11 AIR patients treated with at least 1 injection of IDI were r reviewed.  Clinical outcomes before and after treatment, including BCVA, OCT, fundus auto-fluorescence (FAF), full-field ERG (ff-ERG), and visual field (VF) at last visit within 6 and/or 12 months, were recorded.  Among all the patients, 3 had cancer-associated retinopathy (CAR) and 8 had non-paraneoplastic-AIR (npAIR) with mean follow-up of 8.52 ± 3.03 months (range of 4 to 12 months).  All patients achieved improved or stable BCVA within 6 and/or 12 months after the treatment.  CME in 2 eyes and significant retinal inflammation in 4 eyes were markedly resolved after single injection.  CFT in all eyes without CME, ellipsoid zone (EZ) on OCT in 71.4 % of eyes, ERG response in 55 % of eyes, and VF in 50 % of eyes were stable or improved within 6 months after treatment.  At last visit within 12 months, both BCVA and CFT remained stable in the eyes treated with either single or repeated IDI; however, progression of EZ loss and damage of ERG response occurred in some patients with single IDI.  The authors concluded that clinical outcomes, including BCVA and parameters of OCT, ERG, and VF, were stable or improved after IDI in the majority of AIR patients.  Local treatment of AIR with IDI was a good option to initiate the management or an alternative for the patients' refractory to the systemic therapy but with limited side effect.  Moreover, these researchers stated that the drawbacks of this study included the retrospective design, comparably small number of cases (rare disease), lack of control group, and irregular follow-up visits.  They stated that larger case numbers with careful longer-term of follow-up, control groups with blank, or other treatment approaches (e.g., systemic steroid) are needed to further confirm the conclusion or indicate the difference between local and systemic use of steroid.

Furthermore, an UpToDate review on “Paraneoplastic visual syndromes” (Dalmau and Rosenfeld, 2023) does not mention Ozurdex/dexamethasone intravitreal implant as a therapeutic option.

Combined Cataract Surgery and Ozurdex

Ina retrospective study, Deng et al (2023) examined the long-term results of patients with chronic uveitis-induced cataract by phaco-emulsification with IOL implantation and intravitreal injection of Ozurdex.  The trial included 32 eyes of 26 patients treated with DEX implant due to chronic uveitis-induced cataract and followed-up for at least 1 year; BCVA, CMT, IOP, anterior chamber reaction, intra-operative and post-operative complications and uveitis recurrence were analyzed.  A successful surgery was carried out in all patients.  The average follow-up period was 12 months.  The female/male ratio was 13/13.  Mean age was 45.65 ± 3.83 years (range of 26 to 65 years).  Etiologically, rheumatic arthritis occurred in 6 patients (18.75 %), ankylosing spondylitis in 4 (12.50 %), HLA-B27 associated uveitis in 3 (9.38 %), Vogt-Koyanagi-Harada-associated uveitis in 4 (12.50 %) , Behcet's disease in 2 (6.25 %), and 7 (21.88 %) suffered from unknown diseases.  All 32 eyes had varying degrees of improvement at 12 months after surgery, with 2 eyes showing BCVA of 0.1 or below (6.25 %), 6 having 0.1 to 0.5 (18.75 %), 18 of 0.5 to 1.0 (56.25 %), and 6 of 1.0 or above (18.75 %).  No cases with increased IOP were observed.  The values of mean CMT increased at day 1, decreased at 1 month, 3 months after surgery and increased at 6, 12 months after surgery.  No severe uveitis reactions, such as fibrinous exudates in the anterior chamber and exudative membrane formation on the anterior surface of the IOL, were observed after surgery.  The authors concluded that the present studies demonstrated that intravitreal injection of Ozudex during cataract operation could provide a new option for the clinical treatment of uveitis-induced cataract.  Moreover, these researchers stated that this study was a retrospective case analysis.  They stated that since a control group was not included in this study, further multi-center studies by different tertiary centers are needed to analyze the beneficial effects of intravitreal injection of Ozudex on different subtypes of uveitis.  Furthermore, a larger sample size and long-term follow-up are needed to determine its long-term effectiveness. The follow-up period should be extended to observe long-term post-operative reactions including macular changes in future studies.

Diabetic Retinopathy

Yilmaz et al (2022) noted that diabetic retinopathy (DRP) is the most common retinal vascular disease leading to blindness.  There is limited data regarding the off-label drug use for DRP and DME in the literature.  These investigators examined the applications for off-label drug use in patients with DME and DRP in Turkey in terms of demographic and clinical characteristics.  Applications for off-label drug use from hospitals across Turkey to the Turkish Medicines and Medical Devices Agency (TMMDA) for DRP in 2018 were reviewed retrospectively.  A total of 112 approved applications for 167 eyes were included in this study.  The mean age of the cases was 61.24 ± 10.23 years, of which 57.1 % were males and 42.9 % were females.  Of these applications, 41.1 % were for aflibercept (n = 46), 33.9 % for ranibizumab (n = 38), and 25 % for dexamethasone implant (n - 28).  There was no application for bevacizumab.  In terms of referring hospitals, public university hospitals were in the 1st place with a rate of 70.5 %.  The most common reasons for applications were drug-switching request and failure to complete loading dose, respectively.  The authors concluded that DRP treatment could sometimes be challenging.  The effectiveness of the intravitreal drugs may decrease over time and drug-switching may be necessary.  In Turkey, intravitreal drugs are only approved and reimbursed for DRP patients in case of macular edema.  Off-label drug use may be preferred in non-approved indications and for reasons such as the need for additional drug doses to the determined limits.  However, permission must be obtained from TMMDA for off-label drug use in Turkey.  The authors concluded that anti-VEGF drugs are the 1st-line therapeutic options for DME.  TMMDA currently approves stepwise therapy for DME, initiated with bevacizumab.  Bevacizumab administration does not require approval for off-label application.  Furthermore, ranibizumab, aflibercept, and dexamethasone implant are reimbursed only in case of failure to respond to 3 doses of bevacizumab injection.  This report provided information regarding off-label drug preferences and drug use regulations in DRP treatment in Turkey.  These researchers noted that the limitations of this study were the retrospective study design and the inability to provide data on the use of bevacizumab and triamcinolone because they did not require permission.  Moreover, these investigators stated that, to their best knowledge, there is no study in the English literature regarding the off-label use of approved drugs such as aflibercept, ranibizumab and dexamethasone implant in the treatment of DRP. 

Furthermore, an UpToDate review on “Diabetic retinopathy: Prevention and treatment” (D'Amico and Shah, 2023) does not mention Ozurdex/dexamethasone intravitreal implant as a therapeutic option.

Dextenza (Dexamethasone Ophthalmic Insert)

U.S. Food and Drug Administration (FDA)-Approved Indications

Dextenza is a corticosteroid indicated for:

• The treatment of ocular inflammation and pain following ophthalmic surgery
• The treatment of ocular itching associated with allergic conjunctivitis.

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.

On October 11, 2021, the United States Drug and Food Administration (FDA) granted approval of Supplemental New Drug Application (sNDA) to expand the use of Dextenza (dexamethasone ophthalmic insert) with an additional indication for the treatment of ocular itching associated with allergic conjunctivitis. This FDA approval was based on efficacy data from three randomized multicenter, double-masked, parallel group, vehicle-controlled studies utilizing a repeat conjunctival allergen challenge model in participants (n=255) with a positive history of ocular allergies and positive skin test reaction to perennial and seasonal allergens. In all three studies, the Dextenza group demonstrated lower mean ocular itching scores in comparison to the vehicle group at all time points throughout the 1-month course of the study. Additionally, two of the three studies demonstrated a higher proportion of participants having statistically significant reductions in ocular itching on day 8, at 3 minutes, 5 minutes and 7 minutes post-challenge in the Dextenza group in comparison to the vehicle group (Ocular Therapeutix, 2021a; 2021b Ocular Therapeutix, 2021; 2024).

Appendix

OTC: over-the-counter.

Source: Hamrah and Dana, 2022; Varu et al, 2019

References