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

Number: 0719

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses fluocinolone acetonide intra-vitreal implant (Retisert, Yutiq and Iluvien).

1. Medical Necessity

   Aetna considers the following interventions medically necessary:

   1. Retisert (fluocinolone acetonide intravitreal 0.59 mg implant) and Yutiq (fluocinolone acetonide intravitreal 0.18 mg implant) for the treatment of chronic non-infectious uveitis (including birdshot chorioretinopathy) affecting the posterior segment of the eye in persons who do not respond to or are intolerant to conventional treatment (i.e., failed corticosteroid or immunosuppressive therapy);

      Retisert and Yutiq (fluocinolone acetonide intravitreal implant) are contraindicated and considered not medically necessary for members with active ocular or periocular infections.

   2. Iluvien (fluocinolone acetonide intravitreal implant) for the treatment of diabetic macular edema in persons who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.

      Iluvien (fluocinolone acetonide intravitreal implant) therapy is not considered medically necessary for members with the following contraindications:

      • Active ocular or periocular infections; or
      • Glaucoma with a cup to disc ratio of greater than 0.8.

2. Experimental and Investigational

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

   1. Fluocinolone acetonide intravitreal implant for the treatment of the following indications (not an all-inclusive list):
      
      
      1. Anterior uveitis;
      2. Birdshot retinochoroiditis;
      3. Central retinal vein occlusion;
      4. Cystoid macular edema;
      5. Diabetic retinal neurodegeneration;
      6. Diffused uveal melanocytic proliferation;
      7. Inflammatory vitreoretinopathy;
      8. Intermediate (pars planitis) uveitis;
      9. Paraneoplastic visual syndromes (melanoma-associated retinopathy and cancer-associated retinopathy);
      10. Radiation-induced maculopathy;
      11. Retinitis pigmentosa;
      12. Serpiginous choroditis;
      13. Sjogren’s syndrome-related keratopathy;
      14. Sympathetic ophthalmia;
      15. Uveitic glaucoma;
      16. Vogt-Koyanagi-Harada disease/uveitis.
   2. Combined approach of fluocinolone acetonide intravitreal implant, keratoprosthesis, and silicone oil placement for treatment of uveitis-associated hypotony and keratopathy.

3. Related Policies

   • CPB 0795 - Dexamethasone Ophthalmic Implants (Ozurdex and Dextenza)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
67027	Implantation of intravitreal drug delivery system (e.g., ganciclovir implant), includes concomitant removal of vitreous
67028	Intravitreal injection of a pharmacologic agent (separate procedure)
CPT codes not covered for indications listed in the CPB:
65770	Keratoprosthesis
Retisert and Yutiq:
HCPCS codes covered if selection criteria are met:
J7311	Injection, fluocinolone acetonide, intravitreal implant (Retisert), 0.01 mg
J7314	Injection, fluocinolone acetonide, intravitreal implant (Yutiq), 0.01 mg
HCPCS codes not covered for indications listed in the CPB:
C1814	Retinal tamponade device, silicone oil
ICD-10 codes covered if selection criteria are met:
E08.311, E08.3211 - E08.3219, E08.3311 - E08.3319, E08.41, E08.51, E09.311 E09.3211 - E09.3219, E09.3311 - E09.3312, E09.3411 - E09.3419, E09.3511 - E09.3559, E10.311, E10.3211 - E10.3219, E10.3311 - E10.3319, E10.3411 - E10.3419, E10.3511 - E10.3559,, E11.311, E11.3211 - E11.3219, E11.3311 - E11.3319, E11.3411 - E11.3419, E11.3511 - E11.3559, E13.11, E13.3211 - E13.3219, E13.3311 - E13.3319, E13.3411 - E13.3419, E13.3511 - E13.3559	Diabetic retinopathy with macular edema [in persons who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure]
H30.001 - H30.049	Focal chorioretinal inflammation
H30.101 - H30.139	Disseminated chorioretinal inflammation
H30.90 - H30.93	Unspecified chorioretinal inflammation [birdshot chorioretinopathy] [not covered for birdshot retinochoroiditis]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A52.71	Late syphilitic oculopathy
A54.30 - A54.39	Gonococcal infection of eye
A71.0 - A71.9	Trachoma
B02.30 - B02.39	Zoster ocular disease
B30.0 - B30.9	Viral conjunctivitis
C69.20 – C69.22	Malignant neoplasm of retina [paraneoplastic visual syndromes]
D48.7	Neoplasm of uncertain behavior of other specified sites [diffused uveal melanocytic proliferation]
H00.011 - H00.19	Hordeolum and chalazion
H01.001 - H01.029	Blepharitis
H01.00A - H01.00B	Unspecified blepharitis
H01.01A - H01.01B	Ulcerative blepharitis
H01.02A - H01.02B	Squamous blepharitis
H04.001 - H04.039	Dacryoadenitis
H04.301 - H04.339	Acute and unspecified inflammation of lacrimal passages
H04.411 - H04.439	Chronic inflammation of lacrimal passages
H05.00 - H05.049	Acute inflammation of orbit
H10.011 - H10.9	Conjunctivitis
H15.001 - H15.009	Scleritis
H15.101 - H15.129	Episcleritis
H16.001 - H16.9	Keratitis
H18.891 - H18.899	Other specified disorders of cornea [uveitis-associated keratopathy]
H20.00 - H20.049, H20.10 - H20.9	Iridocyclitis [anterior uveitis]
H31.22	Choroidal dystrophy (central areolar) (generalized) (peripapillary) [serpiginous choroiditis]
H34.8110 - H34.8192	Central retinal vein occlusion
H35.351 - H35.359	Cystoid macular degeneration
H35.52	Pigmentary retinal dystrophy [Retinitis pigmentosa]
H35.81	Retinal edema
H35.9	Unspecified retinal disorder [diabetic retinal neurodegeneration]
H40.400 - H40.434	Glaucoma secondary to eye inflammation [Uveitic glaucoma]
H44.001 - H44.029	Purulent endophthalmitis
H44.111 - H44.129, H44.19	Other endophthalmitis
H44.131 - H44.139	Sympathetic uveitis [sympathetic ophthalmia]
H44.431 - H44.439	Hypotony of eye due to other ocular disorders [uveitis-associated hypotony]
H59.031 – H59.039	Cystoid macular edema following cataract surgery
H59.40 - H59.43	Inflammation (infection) of postprocedural bleb
M35.01	Sicca syndrome with keratoconjunctivitis [Sjogren’s syndrome-related keratopathy]
T66.xxxA - T66.xxxS	Radiation sickness, unspecified [radiation-induced maculopathy]
Iluvien:
HCPCS codes covered if selection criteria are met:
J7313	Injection, fluocinolone acetonide intravitreal implant (Iluvien), 0.01 mg
HCPCS codes not covered for indications listed in the CPB:
C1814	Retinal tamponade device, silicone oil
ICD-10 codes covered if selection criteria are met:
E08.311, E08.3211 - E08.3219, E08.3311 - E08.3319, E08.41, E08.51, E09.311 E09.3211 - E09.3219, E09.3311 - E09.3312, E09.3411 - E09.3419, E09.3511 - E09.3559, E10.311, E10.3211 - E10.3219, E10.3311 - E10.3319, E10.3411 - E10.3419, E10.3511 - E10.3559,, E11.311, E11.3211 - E11.3219, E11.3311 - E11.3319, E11.3411 - E11.3419, E11.3511 - E11.3559, E13.11, E13.3211 - E13.3219, E13.3311 - E13.3319, E13.3411 - E13.3419, E13.3511 - E13.3559	Diabetic macular edema [in persons who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C69.20 – C69.22	Malignant neoplasm of retina [paraneoplastic visual syndromes]
D48.7	Neoplasm of uncertain behavior of other specified sites [diffused uveal melanocytic proliferation]
H18.891 - H18.899	Other specified disorders of cornea [uveitis-associated keratopathy]
H20.00	Unspecified acute and subacute iridocyclitis
H20.011 - H20.019	Primary iridocyclitis
H20.021 - H20.029	Recurrent acute iridocyclitis
H20.031 - H20.039	Secondary infectious iridocyclitis
H20.041 - H20.049	Secondary noninfectious iridocyclitis
H20.10 - H20.13	Chronic iridocyclitis
H20.20 - H20.23	Lens-induced iridocyclitis
H20.811 - H20.819	Fuchs' heterochromic cyclitis
H20.821 - H20.829	Vogt-Koyanagi syndrome
H20.9	Unspecified iridocyclitis
H31.22	Choroidal dystrophy
H34.8110 - H34.8192	Central retinal vein occlusion
H35.351 - H35.359	Cystoid macular degeneration
H35.52	Pigmentary retinal dystrophy [Retinitis pigmentosa]
H35.81	Retinal edema
H35.9	Unspecified retinal disorder [diabetic retinal neurodegeneration]
H40.400 - H40.434	Glaucoma secondary to eye inflammation [Uveitic glaucoma]
H44.131 - H44.139	Sympathetic uveitis
H44.431 - H44.439	Hypotony of eye due to other ocular disorders [uveitis-associated hypotony]
H59.031 – H59.039	Cystoid macular edema following cataract surgery
M35.01	Sicca syndrome with keratoconjunctivitis [Sjogren’s syndrome-related keratopathy]
T66.xxxA – T66.xxxS	Radiation sickness, unspecified [radiation-induced maculopathy]
ICD-10 codes contraindicated for this CPB:
A52.71	Late syphilitic oculopathy
A54.30 - A54.39	Gonococcal infection of eye
A71.0 - A71.9	Trachoma
B02.30 - B02.39	Zoster ocular disease
B30.0 - B30.9	Viral conjunctivitis
H00.011 - H00.19	Hordeolum and chalazion
H01.001 - H01.029	Blepharitis
H04.001 - H04.039	Dacryoadenitis
H04.301 - H04.339	Acute and unspecified inflammation of lacrimal passages
H04.411 - H04.439	Chronic inflammation of lacrimal passages
H05.00 - H05.049	Acute inflammation of orbit
H10.011 - H10.9	Conjunctivitis
H15.001 - H15.009	Scleritis
H15.101 - H15.129	Episcleritis
H16.001 - H16.9	Keratitis
H40.001 - H40.9	Glaucoma [cup to disc ratio of greater than 0.8]
H44.001 - H44.029	Purulent endophthalmitis
H44.111 - H44.129, H44.19	Other endophthalmitis
H59.40 - H59.43	Inflammation (infection) of postprocedural bleb

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Background

The incidence of uveitis varies from 14 to 28 per 100,000.  According to the anatomical classification, about 30 to 60 % (average 47 %) are related to anterior uveitis; 6 to 30 % (average 21 %) are posterior uveitis; 7 to 15 % (average 12 %) are intermediate uveitis; and 7 to 69 % (average 20 %) are panuveitis.  A specific diagnosis can be established in more than 70 % in most series (Guex-Crosier, 1999).

Corticosteroids represent the mainstay of short-term medical therapy for ocular inflammation, especially in children (Hesselink et al, 2004).  They can be administered systemically or via periocular injections.  Song (2004) noted that corticosteroids are usually included in 1st-line therapy for the treatment of posterior uveitis because of its rapid onset of action and favorable safety profile; and systemic immunosuppressive agents also play an important role in the management of this condition.  Immunosuppressive agents take several weeks for their full effect and are considered when long-term therapy is anticipated.  When long-term therapy is anticipated, immunosuppressants may be added.  This approach allows for the reduction and eventual discontinuation of treatment with corticosteroids.  Combination therapy of various immunosuppressive agents may decrease relapse rate, however, immunosuppressants can be associated with serious side effects, and requires careful monitoring.  Moreover, the role of new therapeutic approaches in the treatment of uveitis such as anti-tumor necrosis factor alpha treatment or immunosuppression with drugs including tacrolimus, sirolimus, and interleukin-2 receptor antibodies is being investigated (Efthimiou and Markenson, 2005).  Furthermore, chlorambucil, a cytotoxic alkylating anti-neoplastic agent, has been reported to be a safe and effective alternative for preserving vision in patients with otherwise treatment resistant (i.e., systemic steroids and immunomodulatory therapy) uveitis (Miserocchi et al, 2002).

Uveitis often requires long-term medical therapy.  In a pilot study, Tanner et al (1998) examined the safety and effectiveness of posterior, sub-Tenon's steroid injections (PSTSI) in the treatment of posterior and intermediate uveitis.  A total of 28 PSTSI injections (40 mg triamcinolone) were given and the results analyzed with a 6 month prospective follow-up in 13 cases.  These investigators concluded that PSTSI significantly decreases cystoid macular edema, with a corresponding increase in visual acuity, in patients with posterior uveitis.  Also, systemic immunosuppression may be reduced or discontinued with the avoidance of associated systemic side effects, and the technique has a high level of patient acceptability.  This is in agreement with the findings of Lafranco Dafflon et al (1999) who reported that PSTSI (n = 53 with 162 injections of 40 mg triamcinolone) are very effective in restoring visual acuity in patients with chronic uveitis of the posterior segment, without systemic complications.  However, this benefit was attained at the expense of intra-ocular hypertension, a complication that was found more frequently than expected.  Mean duration of follow-up was 448 +/- 57 days.

Menezo et al (2005) evaluated the visual outcome and corticosteroid dose requirement in patients with non-infectious uveitis affecting the posterior segment treated with corticosteroids and additional second-line immunosuppression.  Seventy-two patients (141 eyes) with uncontrolled non-infectious uveitis on systemic prednisolone were treated with at least one second-line immunosuppressive agent in addition to systemic prednisolone and followed for at least 3 months.  At the end of the follow-up period (mean of 55.5 months), 70 eyes (49.6 %) had visual acuity of 6/9 or better.  There was a reduction in the mean maintenance dose of prednisolone required before the introduction of the second-line agent (19 mg/day +/- 2 SE) when compared to the mean maintenance dose of prednisolone at the end of the data collection (9 mg/day +/- 1 SE; p < 0.001).  There was also a significant reduction in the number of disease relapses requiring an increase in prednisolone dose after starting the second-line agents as compared to the year before (p < 0.02).  These investigators concluded that in patients with uveitis affecting the posterior segment, the addition of all second-line immunosuppressive therapy was effective in allowing reduction of the dose of systemic prednisolone to 10 mg/day or less, in controlling intraocular inflammation, reducing the number of relapses and in maintaining vision.  Because of their side-effects, immunosuppressive treatment should be individualized and monitored closely but its addition is beneficial in the short and longer term.

An intra-vitreal implant that can deliver fluocinolone acetonide to posterior eye tissue for up to 3 years has been developed recently (Retisert, Bausch & Lomb Inc., Rochester, NY).  Retisert is an intravitreal drug implant for the treatment of non-infectious uveitis affecting the posterior segment of the eye, which affects an estimated 175,000 people in the United States. This sight-threatening inflammatory disease primarily affects people between the ages of 20 and 50.  In May 2000, the Retisert was granted fast-track status by the United States Food and Drug Administration (FDA) and in July 2000 it received Orphan Drug designation from the FDA for posterior uveitis. On April 11, 2005, the FDA approved the single-indication orphan drug Retisert (fluocinolone acetonide intra-vitreal implant) for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. Retisert is available at a 0.59 mg fluocinolone acetonide intravitreal implant. 

In a randomized controlled trial (n = 32), Jaffe et al (2005) examined the safety and effectiveness of a fluocinolone acetonide intra-vitreal implant in the treatment of patients with a history of recurrent non-infectious posterior uveitis.  Patients were randomized to receive either a 0.59-mg or a 2.1-mg fluocinolone acetonide intra-vitreal implant.  They were observed every 4 to 6 weeks for the first 3 months and then every 3 months thereafter.  Main outcome measures were pre-operative and post-operative ocular inflammation, visual acuity (VA), anti-inflammatory medication use, and safety.  Mean follow-up duration was 683 +/- 461 days (range of 204 to 1,817).  The average number of recurrences in the 12 months before implantation was 2.5 episodes per eye.  None of these eyes experienced a recurrence for the first 2 years after implantation.  There was a reduction in systemic and local therapy use in the device-implanted eyes.  Of the patients who remained on systemic medication after implantation, nearly 70 % had a reduced dosage by the 1st year of study, and  85 % by 2nd year (reduced dosage is defined as a reduction of dosage and/or a discontinuation of a medication for patients on combination therapy).  The posterior sub-Tenon's capsule injection rate significantly decreased from a mean of 2.2 injections per eye per year to 0.07 injections per eye per year (p < 0.0001).  The most common adverse event was increases in intra-ocular pressure (IOP).  At baseline, 11.0 % of eyes used pressure-lowering agents, versus 56.1 % over the follow-up period (p = 0.005).  There were no device explantations or patients lost to follow-up during the investigation.  These investigators concluded that the fluocinolone acetonide intra-vitreal implant effectively controlled intra-ocular inflammation in the studied population.  Elevated IOP and cataracts that occurred in fluocinolone device-implanted eyes were managed by standard means.  The fluocinolone acetonide sustained drug delivery implant seems to be promising in patients with posterior uveitis who do not respond to or are intolerant to conventional treatment.

In a randomized, controlled, phase IIb/III, open-label, multi-center trial, Pavesio et al (2010) assessed the safety and effectiveness of Retisert compared with standard therapy in subjects with non-infectious posterior uveitis (NIPU).  Subjects with unilateral or bilateral NIPU (n = 140) received either a 0.59 mg Retisert (n = 66) or standard of care (SOC; n = 74) with either systemic prednisolone or equivalent corticosteroid as monotherapy (greater than or equal to 0.2 mg/kg daily) or, if judged necessary by the investigator, combination therapy with an immunosuppressive agent plus a lower dose of prednisolone or equivalent corticosteroid (greater than or equal to 0.1 mg/kg daily).  Main outcome measure was time to first recurrence of uveitis.  Eyes that received Retisert experienced delayed onset of observed recurrence of uveitis (p < 0.01) and a lower rate of recurrence of uveitis (18.2 % versus 63.5 %; p < or = 0.01) compared with SOC study eyes.  Adverse events frequently observed in implanted eyes included elevated IOP requiring IOP-lowering surgery (occurring in 21.2 % of implanted eyes) and cataracts requiring extraction (occurring in 87.8 % of phakic implanted eyes).  No treatment-related non-ocular adverse events were observed in the implant group, whereas such events occurred in 25.7 % of subjects in the SOC group.  The authors concluded that Retisert provided better control of inflammation in patients with uveitis compared with systemic therapy.

In a retrospective, non-comparative case series, Mahajan et al (2009) examined if the Retisert implant can achieve control of inflammation and a reduced need for oral corticosteroids or immunosuppressives in patients with sympathetic ophthalmia (SO).  A total of 8 patients with active SO were included in this study, and were followed-up for a period of 6 months to 2 years.  Main outcome measures included presence or absence of intra-ocular inflammation, VA, IOP, need for further surgery, and the need for additional use of oral or locally injected corticosteroids and/or immunosuppressives.  All patients demonstrated a significant reduction in the systemic medication needed to maintain control of inflammation.  Two patients had recurrent inflammatory episodes requiring the resumption of an oral immunosuppressive.  Vision was improved or stabilized in all 8 patients.  The authors concluded that the fluocinolone acetonide implant provides inflammatory control and reduces the dependence on systemic immunosuppression in patients with SO.  These findings need to be validated by well-designed studies. 

The most common adverse events associated with the implantation of Retisert include eye pain, procedural complications, cataract progression, which is managed by standard cataract surgery, and IOP, which is managed with the use of IOP-lowering eye drops or filtering surgery.  Contraindications for Retisert include viral diseases of the cornea and conjunctiva, ocular mycobacterial and fungal infections of the eye, and hypersensitivity to ingredients or other corticosteroids.

In a retrospective, multi-center, interventional case study, Rush and colleagues (2011) assessed outcomes in birdshot chorioretinopathy following intra-vitreal implantation of a fluocinolone acetonide-containing drug delivery device.  A total of 22 HLA-A29+ birdshot patients (36 eyes) were implanted with a sustained-release corticosteroid device and followed for up to 3 years.  Main outcome measures were Snellen acuity, intra-ocular inflammation, adjunctive therapy, cataract, ocular hypertension, or glaucoma.  Paired Wilcoxon statistics were used to analyze VA; paired McNemar statistics were employed to analyze presence or absence of other outcomes.  Nineteen of 22 patients (32 eyes) completed 12 months of follow-up with improvement in median VA (p = 0.015).  Prior to implantation, 18 of 22 patients (82 %) received immunosuppressive therapy versus 1 of 19 (5 %) by 12 months (p < 0.001).  Eyes with zero vitreous haze increased from 7 of 27 scored eyes (26 %) at baseline to 30 of 30 eyes (100 %) by 12 months (p < 0.001).  Cystoid macular edema was reduced from 13 of 36 eyes (36 %) at baseline to 2 of 32 eyes (6 %) at 12 months (p = 0.006).  Five of 24 phakic eyes at baseline exited the study before surgery; all other eyes received cataract surgery.  One hundred percent of study eyes had ocular hypertension, required IOP-lowering therapy, or had glaucoma surgery by 12 months.  The authors concluded that implantation of a fluocinolone acetonide-containing intra-ocular device in patients with birdshot chorioretinopathy can improve vision, control inflammation, and eliminate systemic therapy.

In an interventional case-series study, Hu and colleagues (2011) reported their experience of using Retisert in the treatment cystoid macular edema (CME) resulting from immune recovery uveitis (IRU) in 2 acquired immunodeficiency syndrome (AIDS) patients with a history of cytomegalovirus (CMV) retinitis.  Medical records were reviewed of 2 patients who received Retisert implantation in 3 eyes for IRU-associated inflammation and CME.  Suppression of CMV disease was achieved with oral medication in 1 patient and with simultaneous implantation of a ganciclovir implant in the other patient.  Following Retisert implantation in 3 eyes in AIDS patients on HAART, improvement in CME was seen in 2 eyes.  No CMV re-activation was detected during the several-month follow-up period.  The authors concluded that Retisert may be an effective treatment for CME in AIDS patients with IRU re-activation and a history of CMV retinitis.  Results of this case-series study need to be validated by further investigation.

Jain et al (2012) evalauted long-term visual outcomes and adverse events from a FA sustained drug delivery implant in eyes with chronic macular edema from central retinal vein occlusion (CRVO).  A total of 24 eyes of 23 subjects with vision loss associated with chronic macular edema from CRVO.  The primary outcome measure was mean Early Treatment of Diabetic Retinopathy Study (ETDRS) VA letter score at 36 months after implantation.  Secondary outcome measures included number of subjects with greater than or equal to 10-letter improvement in ETDRS letter score, central foveal thickness (CFT), total macular volume, and IOP.  At 1, 2, and 3 years after implantation, mean VA showed gains of 4.5 (p = 0.52), 8.2 (p = 0.07), and 3.4 (p = 0.64) letters, respectively, and 32 %, 56 %, and 50 % of study eyes, respectively, showed at least a 10-letter gain in ETDRS score.  At these same time points, mean CFT improved by 247 (44 %; p = 0.002), 212 (38 %; p < 0.001), and 250 μm (45 %; p < 0.001), respectively.  During the study period, all phakic eyes ultimately underwent cataract extraction, and 5 eyes underwent glaucoma surgery.  The authors concluded that the FA drug delivery system provided sustained VA and anatomic benefit in patients with macular edema from CRVO, and it has promise as a therapeutic option for selected patients with this condition.  The main complications were cataract and elevated IOP.

Kiernan and Mieler (2012) noted that diabetic macular edema (DME), CME, age-related macular degeneration (ARMD), retinal vascular occlusion (RVO) and uveitis are responsible for severe visual impairment worldwide.  In some patients with these conditions, treatment with intra-ocular corticosteroids may be beneficial.  Although off-label use of these agents has occurred for many years, novel agents including preservative-free and sustained-release intra-vitreal implants are currently being studied in clinical trials (CTs).  These investigators reviewed the use of CTs for vitreo-retinal (VR) diseases including choroidal neovascularization, CME, DME, RVO and posterior uveitis.  They also discussed the use of corticosteroids for treating VR disease, including dexamethasone, FA, intrav-itreal implants and triamcinolone acetonide.  Used alone, intra-vitreal corticosteroids may benefit disorders such as DME, RVO and uveitis compared with standard therapy.  Cases of exudative ARMD non-responsive to standard treatment may benefit from combination therapy, including usage of intra-vitreal corticosteroid injections.  Intra-operative use of these agents may aid visualization of retinal structures.  Sustained-release intra-ocular implants have been approved for posterior uveitis and RVO associated with macular edema.  In spite of this, most intra-ocular corticosteroids have a limited duration of action along with significant side effects, including cataract and glaucoma.  Currently, intra-vitreal corticosteroid usage for DME is considered off-label.

Furthermore, an UpToDate review on "Prevention and treatment of diabetic retinopathy" (Fraser and D'Amico, 2012) states that "Intravitreal triamcinolone injection (IVTA) is an option for ME of any cause.  Injection of 4 mg of triamcinolone acetonide produces a rapid reduction in macular thickness, often within days, and with a several line gain in visual acuity.  However, the treatment response in diabetic ME is transient.  As a result, repeated injections are necessary, but these responses are also transient and adverse effects may be seen .... Intravitreal and retinal implants have been designed to deliver glucocorticoids over an extended time frame.  The use of these implants is associated with even higher rates of cataract formation and glaucoma than IVTA injection.  In the aggregate, the above findings have diminished the enthusiasm for IVTA as monotherapy for chronic ME.  IVTA in combination with photocoagulation has been associated with a higher rate of sustained visual improvement than IVTA alone in some studies, but not in others.  Larger clinical trials are required to clarify whether there is a role for IVTA with photocoagulation for the management of diabetic macular edema".

Tlucek and associates (2012) reviewed the effect of the fluocinolone acetonide implant in subjects with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), an inherited autoimmune uveitis.  A retrospective case series was assembled from patients with ADNIV who received fluocinolone acetonide implants.  Visual acuity and features of ADNIV, including inflammatory cells, neovascularization, fibrosis, and CME, were reviewed.  Nine eyes of 5 related patients with ADNIV with uncontrolled inflammation were reviewed.  Follow-up ranged from 21.7 to 56.7 months.  Visual acuity at implantation ranged from 20/40 to hand motion.  Pre-operatively, 8 eyes had vitreous cells (a 9th had diffuse vitreous hemorrhage).  Eight eyes had CME, 7 had an epi-retinal membrane, and 3 had retinal neovascularization.  Following implantation, vitreous cells resolved in all eyes and neovascularization regressed or failed to develop.  Central macular thickness improved in 4 eyes.  During the post-operative course, however, VA continued to deteriorate, with VA at the most recent examination ranging from 20/60 to no light perception.  There was also progressive intra-ocular fibrosis and phthisis in 1 case.  Four eyes underwent cataract surgery.  Six of the 7 eyes without previous glaucoma surgery had elevated IOP at some point, and 3 of these required glaucoma surgery.  The authors concluded that the fluocinolone acetonide implant may inhibit specific features of ADNIV such as inflammatory cells and neovascularization, but does not stabilize long-term vision, retinal thickening, or fibrosis.  All eyes in this series required cataract extraction, and more than 50 % required surgical intervention for glaucoma.  They stated that further studies may identify additional therapies and any benefit of earlier implantation.

In a comparative case-series study, Arcinue et al (2013) evaluated the safety and effectiveness of the fluocinolone acetonide (Retisert) implant compared with the dexamethasone (Ozurdex) implant in patients with non-infectious uveitis.  A total of 27 eyes received either the fluocinolone acetonide (FA) (n = 16) or dexamethasone (n = 11) implant.  Chart review of patients at the Massachusetts Eye Research and Surgery Institution (MERSI) was done and patients were selected and matched according to age, sex, and type of uveitis.  Eyes that received either the FA or dexamethasone implant, with follow-up ranging from 6 months to 2 years, were included.  Main outcome measure was the recurrence rate of uveitis after implantation.  There were no significant differences in the baseline demographic characteristics.  The majority of cases were idiopathic panuveitis, with 36.4 % and 31.3 % of eyes in the Ozurdex and Retisert groups, respectively.  Recurrence rates of uveitis were 1.7 and 0.5 per 100 person-months in the Retisert and Ozurdex groups, respectively, with Retisert-implanted eyes 3.16 times more at risk of recurrence; however, this difference was not statistically significant (p = 0.41).  No significant differences were seen in terms of improvement in inflammatory score and best-corrected visual acuity (BCVA).  The median survival time for a 2nd implant was 13 and 28 months for the Ozurdex and Retisert groups, respectively (p = 0.0028).  Eyes with the Ozurdex were 5 times more likely to receive a 2nd implant (p = 0.02).  No eyes in the Ozurdex group needed additional glaucoma medications, surgery, or laser compared to 44 % of eyes in the Retisert group.  Eyes with the Retisert implant had a statistically higher rate of having more glaucoma medications, surgery, or laser (p = 0.02).  In the Ozurdex group, 50 % of phakic eyes at baseline had cataract progression and subsequent surgery compared with 100 % of Retisert phakic eyes.  Eyes with the Retisert implant are 4.7 times more at risk of cataract progression (p = 0.04).  The authors concluded that the dexamethasone (Ozurdex) implant seems comparable to the fluocinolone acetonide (Retisert) implant in preventing recurrence of non-infectious uveitis and in improving inflammation and BCVA.  However, there were higher rates of cataract progression and need for glaucoma medications, laser, and surgery with the Retisert implant.

On October 16, 2018, the FDA approved Yutiq, an intravitreal 0.18 mg fluocinolone acetonide implant for patients with chronic noninfectious posterior uveitis by EyePoint Pharmaceuticals. The implant is supplied in a sterile single-dose preloaded injector that can be administered in an office setting. Yutiq is intended to prevent uveitis flares by releasing 0.18 mg of fluocinolone acetonide over a period of 3 years. The drug is housed within proprietary nonbioerodible drug delivery technology (i.e., Durasert) that has also been utilized Iluvien, Retisert and Vitrasert. The approval was based on data from 2 randomized, multicenter, sham-controlled, double-masked phase 3 clinical trials with up to 3 years of follow-up (NCT01694186 and NCT02746991). Both studies met primary endpoints, demonstrating significantly lower rates of uveitis recurrence compared with sham at 6 and 12 months. Overall, the insert was well tolerated. Mean IOP increased by 2 mmHg in the treatment group, and did not change within the sham group. Cataract surgery was performed in 18% of patients receiving Yutiq and 8.6% for sham.

Jaffe et al (2019; NCT01694186) state to assess the safety and efficacy of an intravitreal fluocinolone acetonide (FA) insert to manage inflammation associated with chronic noninfectious posterior uveitis. Multicenter, randomized, prospective, doubled-masked, sham-controlled, 3-year phase 3 clinical trial. One hundred twenty-nine participants with recurrent noninfectious posterior uveitis were assigned randomly to FA insert (n = 87) or sham injection (n = 42). The more severely affected eye in participants with bilateral disease was designated as the study eye. The insert (FA, 0.18 mg) was injected into the vitreous cavity; sham injection mimicked the insert delivery procedure. Ophthalmic examinations, optical coherence tomography (OCT), and ocular tolerability and discomfort assessments were conducted; study visits were on days 7 and 28 and months 2, 3, 6, 9, and 12. Uveitis recurrence was treated as needed. The 6-month recurrence rate was the primary outcome measure. The 6-month (28% and 91%) and 12-month (38% and 98%) uveitis recurrence rates were significantly lower (P < 0.001) with FA insert vs. sham, respectively. Fewer recurrences per study eye (mean, 0.7 vs. 2.5), lower incidence of 15-letter or more decrease in best-corrected visual acuity (14% vs. 31%), and reduced systemic (19% vs. 40%) and local (7% vs. 62%) uveitis adjunctive treatments were observed with FA insert vs. sham, respectively. Of the 42 FA study eyes that were phakic at baseline, 14 (33%) required cataract surgery during the first 12 months of the study. Over the same period, 1 phakic sham injection eye (5%) required cataract surgery. Post hoc analysis showed a significant increased risk for cataract development among study eyes treated with FA insert compared with those treated with sham injection (33% vs. 12%, respectively; odds ratio, 3.7; P < 0.01). Intraocular pressure-lowering treatment use was similar between groups. No deaths, treatment-related study discontinuations, or unanticipated safety signals were observed through 12 months. The authors concluded that chronic noninfectious posterior uveitis was managed successfully in this study population; FA insert eyes experienced fewer uveitis recurrence episodes, required fewer adjunctive treatments, and demonstrated less visual acuity loss compared with sham eyes. The FA insert treatment group showed higher rates of cataract; delivery by injection was not associated with an increase in ocular adverse events or any other safety measures not typically associated with local steroid use, suggesting the procedure is appropriate for an office setting. Study limitations include enrollment of participants without severe active inflammation at the time of the initial study treatment and lack of stratification by uveitis etiology. Evaluation of the therapeutic effect of FA insert in uveitic eyes with more significant active ocular inflammation than that included in the current study and in the uveitis subset stratified by anatomic location, cause, or both likely would yield additional useful information to the practicing clinician, particularly considering the ceiling effect for possible visual acuity improvements based on BCVA letters gained, a constraint that likely disproportionately affected the FA insert treatment group.

Diabetic Macular Edema

Diabetic macular edema, the primary cause of vision loss associated with diabetic retinopathy, is a disease affecting the macula, the part of the retina responsible for central vision (Alimera Sciences, 2014). When the blood vessel leakage of diabetic retinopathy causes swelling in the macula, the condition has progressed to diabetic macular edema. Diabetic macular edema  occurs when blood vessels in the retina of patients with diabetes begin to leak into the macula, the part of the eye responsible for detailed central vision. These leaks cause the macula to thicken and swell, progressively distorting acute vision. Duration of diabetes is the greatest risk factor for increased retinopathy and is associated with an increased prevalence of diabetic macular edema. The appearance of retinopathy is associated with an upregulation of vascular endothelial growth factor (VEGF) causing an increase in permeability of vessels leading to leakage of fluid. As retinopathy worsens, an up-regulation of multiple cytokines (inflammatory factors) takes place. Corticosteroids offer a broad effect on down regulation of multiple cytokines associated with diabetic macular edema that persists.

Diabetic macular edema occurs when blood vessels in the retina of patients with diabetes begin to leak into the macula, the part of the eye responsible for detailed central vision. These leaks cause the macula to thicken and swell, progressively distorting acute vision.

Diabetic macular edema is classified into 2 types:

• Focal macular edema: caused by vascular abnormalities (primarily microaneurysms), which tend to leak fluid.
• Diffuse macular edema: caused by dilated capillaries in the retina.

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

Iluvien (fluocinolone acetonide intravitreal implant) 0.19 mg is a sustained release intravitreal implant approved by the FDA to treat DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (Alimera Sciences, 2014). Each Iluvien implant is designed to release submicrogram levels of fluocinolone acetonide for 36 months. The Iluvien approval was based on clinical trial data that showed that at month 24 after receiving the Iluvien implant, 28.7 percent of patients (p value .002) experienced an improvement from baseline in their best corrected visual acuity on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart of 15 letters or more. Patients treated with Iluvien experienced a statistically significant improvement in visual acuity compared to the control group by week three of follow up, and maintained a statistically significant advantage over the control through completion of the trial at month 36.

Iluvien is available as a non‐bioerodable intravitreal implant containing 0.19 mg fluocinolone acetonide in a sustained‐release drug delivery system. Iluvien is injected in the back of the patient's eye with an applicator that employs a 25-gauge needle, which allows for a self-sealing wound (Alimera Sciences, 2014). In the FAME Study, a phase 3 clinical study of Iluvien, the most frequently reported adverse drug reactions included cataract development and increased ocular pressure. Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. The labeling of Iluvien states that patients should be monitored following the injection. Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids are not recommended to be used in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection. The implant may migrate into the anterior chamber if the posterior lens capsule is not intact. Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber. The labeling advises patients to have follow-up eye examinations at appropriate intervals following treatment with Iluvien.

Safety and effectiveness of Iluvien in pediatric patients has not been established. Iluvien is contraindicated in patients with ocular or periocular infections, glaucoma with a cup to disc ratio of greater than 0.8 and known hypersensitivity to fluocinolone acetonide or any components of the product.

In 2 randomized, sham injection-controlled, double-masked, multi-center clinical trials, Campochiaro et al (2012) evaluated the long-term safety and effectiveness of intra-vitreal inserts releasing 0.2 μg/day (low-dose) or 0.5 μg/day (high-dose) fluocinolone acetonide (FAc) in patients with DME.  Subjects with persistent DME despite greater than or equal to 1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393).  Subjects received study drug or sham injection and after 6 weeks were eligible for rescue laser.  Based on re-treatment criteria, additional study drug or sham injections could be given after 1 year.  Main outcome measures included percentage of patients with improvement of greater than or equal to 15 letters from baseline.  Secondary outcomes included other parameters of visual function and foveal thickness.  At month 36, the percentage of patients who gained greater than or equal to 15 in letter score using the last observation carried forward method was 28.7 % (low-dose) and 27.8 % (high-dose) in the FAc insert groups compared with 18.9 % (p = 0.018) in the sham group, and considering only those patients still in the trial at month 36, it was 33.0 % (low-dose) and 31.9 % (high-dose) compared with 21.4 % in the sham group (p = 0.030).  Pre-planned subgroup analysis demonstrated a doubling of benefit compared with sham injections in patients who reported duration of DME greater than or equal to 3 years at baseline; the percentage who gained greater than or equal to 15 in letter score at month 36 was 34.0 % (low- dose; p < 0.001) or 28.8 % (high-dose; p = 0.002) compared with 13.4 % (sham).  An improvement greater than or equal to 2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7 % (low-dose) and 10.1 % (high-dose) compared with 8.9 % in the sham group.  Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients.  The incidence of incisional glaucoma surgery at month 36 was 4.8 % in the low-dose group and 8.1 % in the high-dose insert group.  The authors concluded that in patients with DME FAc inserts provide substantial visual benefit for up to 3 years and would provide a valuable addition to the options available for patients with DME.

The National Institute for Health and Clinical Excellence’s clinical practice guideline on “Fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy” (NICE, 2013) stated that “Fluocinolone acetonide intravitreal implant is recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if: the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme."

Kempen and colleagues (2017) noted that a randomized clinical trial comparing fluocinolone acetonide implant versus systemic corticosteroids and immunosuppression for treatment of severe non-infectious intermediate, posterior, and panuveitides did not result in a significant difference in VA at 2 and 4.5 years; longer-term outcomes are not known.  These researchers compared the association between intra-vitreous fluocinolone acetonide implant versus systemic therapy and long-term visual and other outcomes in patients with uveitis.  This study was a no pre-specified 7-year observational follow-up of the Multicenter Uveitis Steroid Treatment (MUST) randomized clinical trial.  Follow-up was conducted in tertiary uveitis sub-specialty practices in the United States (21), the United Kingdom (1), and Australia (1).  Of 255 patients 13 years or older with intermediate, posterior, or panuveitis (active within less than or equal to 60 days) enrolled in the MUST trial between December 6, 2005, and December 9, 2008, 215 consented to ongoing follow-up through at least 7 years post-randomization (last visit, February 10, 2016).  Participants had been randomized to receive a surgically placed intra-vitreous fluocinolone acetonide implant or systemic corticosteroids supplemented by immunosuppression.  When both eyes required treatment, both eyes were treated.  Primary outcome was change from baseline in BCVA in uveitic eyes (5 letters = 1 VA chart line; potential range of change in letters read, -121 to +101; minimal clinically important difference, 7 letters), analyzed by treatment assignment accounting for non-independence of eyes when patients had 2 uveitic eyes.  Secondary outcomes included potential systemic toxicities of corticosteroid and immunosuppressive therapy and death; 7-year data were obtained for 161 uveitic eyes (70 % of 90 patients assigned to implant) and 167 uveitic eyes (71 % of 90 patients assigned to systemic therapy) (77 % women; median age at enrollment, 48 [interquartile range [IQR], 36 to 56] years).  Change in mean VA from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95 % confidence interval [CI]: 2.1 to 12) letters.  Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10 %, with the exceptions of hyperlipidemia (6.1 % versus 11.2 %), hypertension (9.8 % versus 18.4 %), osteopenia (41.5 % versus 43.1 %), fractures (11.3 % versus 18.6 %), hospitalization (47.6 % versus 42.3 %), and antibiotic-treated infection (57.4 % versus 72.3 %).  The authors concluded that in 7-year extended follow-up of a randomized trial of patients with severe intermediate, posterior, or panuveitis, those randomized to receive systemic therapy had better VA than those randomized to receive intra-vitreous fluocinolone acetonide implants.  Study interpretation was limited by loss to follow-up.

Vogt-Koyanagi-Harada Disease

Vogt-Koyanagi-Harada (VKH) disease is a multi-system disorder, characterized by the T-cell-mediated autoimmune process directed against melanocytic antigens in the ocular, nervous, auditory and integumentary systems.  The ocular hallmarks of the disease involve severe bilateral panuveitis associated with exudative retinal detachment.  In an interventional case series study, Khalifa and colleagues (2009) described the use of Retisert in 2 patients with VKH disease requiring high-dose systemic corticosteroid therapy to control their inflammation and bilateral serous retinal detachments.  Upon tapering of systemic corticosteroids, 1 patient had recurrent serous retinal detachments and the other patient's anterior chamber and vitreous inflammation returned.  The authors concluded that their experience with Retisert in VKH has been mixed with an inability to fully taper off of systemic corticosteroids.

Heo and colleagues (2016) examined the safety and effectiveness of fluocinolone acetonide intravitreal implant in patients with Vogt-Koyanagi-Harada disease.  They carried out a post-hoc, subgroup analysis on patients with Vogt-Koyanagi-Harada using data sets from 2 multi-center randomized trials on fluocinolone acetonide implant.  Each subject received fluocinolone acetonide implantation in 1 eye and standard-of-care treatment in the fellow eye and was followed for 3 years.  A total of 30 patients (mean age of 38.5 years) were included.  The cumulative rate of uveitis recurrence for 3 years was significantly reduced in implanted eyes compared with fellow eyes (33 % versus 87 %; p < 0.001).  The reduction of daily corticosteroid dose was well-maintained (12.8 mg before implantation versus 3.7 mg after implantation; p = 0.001), but final vision was similar to pre-operative vision in the implanted eyes (p = 0.082) and in the fellow eyes (p = 0.187).  Post-operative elevation of IOP was more frequent in the implanted eyes than in the fellow eyes (70 % versus 20 %; p < 0.001).  Cataract progression occurred in all phakic implanted eyes.  The authors concluded that fluocinolone acetonide intravitreal implant reduced uveitis recurrence rate and the dosage of systemic corticosteroid and immunosuppressant requirement in patients with Vogt-Koyanagi-Harada.  However, they stated that cataract and IOP elevation developed frequently.  The clinical benefits of fluocinolone acetonide intravitreal implant in patients with Vogt-Koyanagi-Harada disease needs to be further investigated.

Vitrectomized Eyes with Diabetic Macular Edema

Meireles and colleagues (2017) stated that limited data are available on the effectiveness of the 0.2 μg/day fluocinolone acetonide (FAc) implant in eyes with prior vitrectomy.  In a retrospective study involving 6 centers from 4 European countries, these researchers presented a collection of 26 vitrectomized eyes treated with the 0.2 μg/day FAc implant.  They analyzed the safety and effectiveness data from patients (26 eyes from 25 patients) with DME and a prior vitrectomy that had been treated with one 0.2 μg/day FAc implant.  Prior intravitreal therapies included anti-VEGF (mean of 3.8 injections) and steroids (mean of 1.9 injections).  Pars plana vitrectomy (PPV) was performed in these eyes primarily for abnormalities of vitreo-retinal interface, followed by proliferative diabetic retinopathy and vitreous hemorrhage.  The 0.2 μg/day FAc implant was injected 24.2 months, on average, after PPV and the mean duration of follow-up after injection was 255 days (range of 90 to 759 days).  The mean change in BCVA was +11.7 ETDRS letters (range of -19 to +40 letters; p < 0.0004) and the mean change in CFT was -233.5 μm (range of -678 to 274 μm; p < 0.0001).  The mean change in IOP from baseline at the last visit was +1.4 mm Hg (range of -9 to +8 mm Hg; p = 0.0090); 8 eyes initiated or continued IOP lowering medications.  The authors concluded that these data suggested the 0.2 μg/day FAc implant is effective in vitrectomized patients with an acceptable safety profile.  Moreover, they stated that further studies are needed to confirm the current findings and to evaluate the effect of the 0.2 μg/day FAc implant over a longer period of follow-up.

The authors noted that the main drawback of this study related to the collection and reporting of retrospective data with a relatively small number of patients (n = 25) and short period of follow-up (mean of 255 days)) post-therapy with Iluvien.  Another drawback was the reporting of non-standardized data, which were collected in real-life clinical practice.  However, sustained, and statistically significant, therapeutic effects were observed in this small cohort over a 2-year period and appeared to be consistent with results reported in larger randomized controlled trials (RCTs).  They stated that future studies should consider whether the difference in biochemical composition of the vitreous in vitrectomized eyes and non-vitrectomized eyes affects the pharmacokinetic profile of Iluvien and consequently its effectiveness.  Another area of interest is to examine if PPV enhances the performance of Iluvien when performed after Iluvien, and therefore at any stage in the disease process, as has been described by Kumar et al.  These investigators stated that this study described the most clinically significant cohort of vitrectomized eyes treated with a 0.2 μg/day FAc implant.  Results showed there were statistically significant improvements in VA and a concurrent decrease of the macular edema.  The current study is important as the FAME trial excluded patient eyes with prior vitrectomy and so the real-life data are now needed.  This lack of the data and clinical need mean that there is no consensus on how to use DME therapies to manage vitrectomized eyes with DME, and there is no treatment pathway on to guide physicians.  Hence, current real-life practice data are revealing how these eyes are being managed now but also informing future best practice.

Uveitic Glaucoma

Zivney and colleagues (2016) noted that glaucoma is a known complication of uveitis, and may require glaucoma tube shunt implantation for IOP control.  The success of glaucoma tube shunt (Ahmed) implantation in the setting of a local ocular steroid depot in uveitic glaucoma remains unknown.  These researchers examined if patients who underwent combined Ahmed implantation and fluocinolone acetonide (Retisert) implantation have superior outcomes compared to patients with Ahmed implants only in the setting of uveitic glaucoma.  All participants were studied retrospectively and underwent Ahmed implantation alone or with existing/concurrent Retisert implantation (combined group) at a single academic institution.  The main outcome measures were IOP, VA, number of IOP-lowering medications, and adverse events (AEs) at 6 months after Ahmed implantation.  Secondary outcome measures included AEs and surgical success at 6 months after Ahmed implantation.  Mean IOP at 6 months after Ahmed implantation was 15.3 ± 4.8 and 15.1 ± 4.9 mm Hg in the Ahmed only group (n = 17) and the combined group (n = 17), respectively (p = 0.89).  The mean number of IOP-lowering medications at 6 months after Ahmed implantation was 1.7 ± 1.0 and 1.8 ± 1.0 in the Ahmed only group and the combined group, respectively (p = 0.86).  Mean VA at 6 months after Ahmed implantation was 0.35 ± 0.29 and 0.42 ± 0.33 log mean angle of resolution in the Ahmed only group and the combined group, respectively (p = 0.50).  No significant differences in surgical success or AEs were noted between the 2 groups.  The authors concluded that at 6 months, no significant differences in mean IOP, mean number of IOP-lowering medications, VA, surgical success, or AEs were noted between Ahmed implantation alone or combined Ahmed and Retisert implantation in patients with uveitic glaucoma.  These investigators stated that further studies with larger sample sizes, longer follow-up, and prospective evaluation may provide more insight into patient outcomes after Ahmed implantation with or without the presence of a Retisert implant.

Central Retinal Vein Occlusion

Coelho and colleagues (2019) reported a case with non-ischemic CRVO that was successfully treated with a single sustained-release fluocinolone acetonide intravitreal implant.  After a course of repeated injections of shorter-acting corticosteroid, the affected eye presented a VA of 20/200 and a central subfield foveal thickness of 587 µm.  After fluocinolone acetonide in intravitreal implant and during a follow-up period of 12 months, a continuous and sustained increase in VA until 20/25 with significant anatomical improvements and an acceptable safety profile was observed.  The authors concluded that these findings showed that fluocinolone acetonide intravitreal implant might be an effective therapeutic option in macular edema secondary to non-ischemic CRVO.  Moreover, these researchers stated that larger, prospective, phase-III clinical trials with longer follow-up are needed to confirm the pharmacokinetics and long-term benefits of fluocinolone acetonide intravitreal implant 190 µg in both CRVO and branch retinal vein occlusion (BRVO).

Diffused Uveal Melanocytic Proliferation

Gemperline and Smith (2020) reported on a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) treated with intravitreal steroid implants.  Patient was treated with intravitreal steroid implants (both dexamethasone 0.7 mg [intravitreal dexamethasone implants] and fluocinolone acetonide 0.18 mg [intravitreal fluocinolone acetonide implants]) and monitored every 2 weeks to 4 weeks with OCT.  Intravitreal dexamethasone implants improved VA and central retinal thickness (CRT) for 10 weeks, was best from 4 to 6 weeks, and recurred by 14 weeks after treatment.  Intravitreal fluocinolone acetonide implants improved VA and CRT for 20 weeks after treatment without edema recurrence.  No retinal detachments were observed over 1 year of treatment.  The authors concluded that intravitreal steroid implants resulted in VA improvement and CRT reduction for up to 20 weeks and may protect against retinal detachments in patients with BDUMP.

Radiation-Induced Maculopathy

In a retrospective study, Kaplan and associates (2017) examined the effect of adjuvant intravitreal triamcinolone acetonide (ITA) for radiation-induced maculopathy (RM) recalcitrant to high-dose bevacizumab in patients with choroidal melanoma following plaque radiotherapy.  A total of 8 eyes of 8 patients with RM secondary to plaque radiotherapy for choroidal melanoma, recalcitrant to high-dose bevacizumab (3.0 mg) were retrospectively evaluated; ITA (4 mg/0.1 ml) was carried out at 4-week to 16-week intervals as an adjunct to continued bevacizumab therapy.  Change in CFT as measured by OCT and change in VA were the main outcome measures.  At the time of diagnosis of choroidal melanoma, VA was 20/20 to 20/50 in 88 % (n = 7) and 20/60 to 20/200 in 12 % (n = 1).  The mean radiation dose to the fovea was 81 Gy (median of 75.2 Gy; range of 22.72 to 132.8 Gy).  The mean onset to RM was 25 months after plaque therapy (median of 25 months; range of 12 to 44 months).  At the time of initiation of ITA, VA was 20/20 to 20/50 in 38 % (3/8), and 20/60 to 20/200 in 62 % (5/8).  After initiation of ITA, VA was stable or improved in 100 % of patients (n = 8) at 3 months, 88 % at 6 months, 88 % at 9 months and 75 % at 12 months.  Mean CFT was 417 µm at ITA initiation, 339 µm at 1 month, 355 µm at 6 months, 339 µm at 9 months and 359 µm at 1 year.  The authors concluded that ITA can be added to preserve vision and decrease macular edema in patients with RM recalcitrant to high-dose anti-VEGF agents.  Moreover, these researchers stated that larger, prospective, registry and confirmatory studies with longer follow-up and differing dose regimens are needed to validate these preliminary findings.  The main drawbacks of this study were its retrospective design and small sample size (n = 8).

Zimmermann and colleagues (2020) examined the effectiveness of continuous delivery of low-dose corticosteroids for the treatment of RM.  A total of 52 men and 3 women (age of 37 to 68 years) who presented with RM following 106Ru-plaque brachytherapy or stereotactic radiation therapy (STx) with photons using a hypo-fractionated schedule of 5 × 10 Gy were included in this trial.  All subjects were treated with triamcinolone injections in 1st-line and proved to be refractory to steroids.  In addition, 2 patients had received Ozurdex implants as a 2nd-line treatment, though without any clinical benefit; FAc slow-release implants were injected, and patients were followed-up to monitor clinical improvement.  All patients responded to therapy by means of a decrease in macular edema.  In 4 of 5 (80 %) patients, VA improved, and 1 patient showed stable VA.  No toxic effects or complications were observed.  The authors concluded that slow-release implants of FAc are a promising therapeutic option to benefit anatomical structures of the fovea and visual function.  These researchers stated that slow-release implants with FAc reduced the frequency of intravitreal injections and the therapeutic burden.

Sjogren's Syndrome-Related Keratopathy

Wasielica-Poslednik and colleagues (2019) presented the findings of a severe case of Sjogren's syndrome-related keratopathy following fluocinolone acetonide 190-μg intravitreal implant (Iluvien) therapy.  The case entailed a 52-year-old Caucasian woman with Sjogren's syndrome secondary to autoimmune hepatitis and primary sclerosing cholangitis who was admitted to the authors’ emergency department owing to bilateral corneal ulcers and corneal perforation in the left eye following exposure keratopathy in an artificially induced coma.  Within the following months, recurrent fulminant keratolysis with perforations required multiple penetrating keratoplasties and amniotic membrane transplants in both eyes.  With new signs of severe keratolysis, an intravitreal fluocinolone acetonide implant was injected off-label in the left eye, and a 3rd penetrating keratoplasty was carried out 2 weeks later.  In the 6 months of follow-up after the last penetrating keratoplasty, no more surgical interventions were needed in the eye with the fluocinolone acetonide implant.  The corneal surface remained stable, and IOP was normal.  During this time-frame, 2 further penetrating keratoplasties, 1 vitrectomy, and 5 amniotic membrane transplants were carried out in the fellow eye owing to relapsing keratolysis and perforations.  The authors concluded that to the best of their knowledge, this was the 1st report of fluocinolone acetonide intravitreal therapy in a patient with corneal disease.  In the 6-month follow-up period, no surgical intervention was needed in the eye with the fluocinolone acetonide implant, whereas further penetrating keratoplasties and amniotic membrane transplants were performed in the fellow eye.  These researchers stated that intravitreal fluocinolone acetonide may be considered as a potential adjunctive therapy in severe cases of autoimmune corneal disease.  These preliminary findings need to be validated by well-designed studies.

Off-Label Uses of Fluocinolone Acetonide Intravitreal Implant

Marques and colleagues (2021) noted that CME due to Irvine-Gass syndrome (IGS) is one of the common causes of painless visual impairment post-cataract extraction.  The treatment of recurrent cases remains unstandardized.  In a retrospective, 36-month, case-series study, these researchers examined the safety and effectiveness of fluocinolone acetonide intravitreal implant (0.2 µg/day; ILUVIEN) in the off-label treatment of recurrent CME due to IGS.  Consecutive eyes of patients with recurrent CME due to IGS who underwent a single intravitreal injection of fluocinolone acetonide intravitreal implant were included; BCVA (logMAR), central macular thickness (CMT, µm) and safety (IOP, mmHg) at baseline and at 6, 12, 24 and 36 months post-administration of the fluocinolone acetonide intravitreal implant were recorded.  A total of 5 eyes from 3 patients were included.  The duration of CME was 67.8 ± 25.9 months and all 5 eyes received more than 2 intravitreal injections of a corticosteroid (triamcinolone and/or dexamethasone implant) prior to fluocinolone acetonide intravitreal implantation.  At baseline (median - IQR), BCVA was 0.3-0.3; CMT was 492.0 to 38.0; and IOP was 16.0 to 0.  By Month 36, BCVA was 0.4 to 0.3; CMT was reduced to 369.0 to 324.0 and IOP was 17.0 to 3.0; 4 of 5 eyes had increased IOP and were managed with IOP-lowering eye-drops.  The authors concluded that the current cases highlighted the potential of FAc to provide recurrence-free periods and a reduced need for intravitreal therapies for up to 3 years.  Moreover, these researchers stated that prospective, larger studies with more patients and longer follow-up are needed to substantiate the current findings and to assess the reproducibility of the current results..  The drawbacks of this study included the retrospective nature of the study, and small patient number (n = 3 patients).

Ansari and associates (2021) noted that treatment of juvenile idiopathic arthritis (JIA)-associated uveitis necessitates the use of long-term corticosteroids or immunosuppressive agents, each of which poses their own significant side effect profile.  Initial treatment requires intensive topical glucocorticoids, with a step-up approach employing immunosuppressive agents for those cases with poor response or high-risk complications such as macular edema.  To-date, there is minimal evidence to support a specific approach to such complicated subgroups.  In a retrospective, case-report, these investigators presented the 1st case to successfully employ the 0.19 mg FAc implant (ILUVIEN) as a novel device for prolonged intravitreal administration of disease-modifying agents for patients with JIA complicated by uveitis.  This report described a 20-year old woman diagnosed with oligoarticular JIA complicated by chronic uveitis and associated CME.  Considering factors including the patient's non-compliance, age, lens status, non-steroid response, and good response to short-term intravitreal steroid therapy, the 0.19 mg FAc intravitreal implant was deemed an appropriate step-up therapeutic option.  At 12-month follow-up, the left eye (OS) showed an improvement in VA to 6/15 - 1 from 6/60 + 1 (0.42 from 0.98 logMAR) (pre-insertion) and a reduction in CRT of 199 μm from 471 μm.  The right eye (OD), treated 10 months later, showed an improvement in VA to 6/7.5 from 6/24 - 1 (0.10 from 0.56 LogMAR) and a reduction in CRT of 327 μm 6 months after treatment.  The authors concluded that in this case, the 0.19 mg FAc implant provided safe and effective long-term treatment of JIA-associated uveitis and secondary CMO.  This potentially offers an alternative approach to complex cases that show good response to short-term corticosteroid use.  Moreover, these investigators stated that definitive safety and effectiveness can only be truly determined by larger clinical trials, which they believe are needed.

Ribeiro and Falcao (2021) stated that corticosteroids are used in a variety of ophthalmological diseases.  One challenge faced by ophthalmologists is to deliver corticosteroids to the posterior segment of the eye with efficacy and safety.  Sustained-release corticosteroid implants may be the answer to this problem.  The 0.19 mg Fac implant (Iluvien) releases FAc for 36 months, and it is approved for the treatment of diabetic macular edema (DME) and non-infectious uveitis.  In a systematic review, these researchers examined which other diseases FAc implant is being used off-label.  They carried out a literature search in the following 3 electronic databases: PubMed, Scopus, and Web of Science (from January 1, 2000, to September 20, 2020), using the following query: ("Fluocinolone Acetonide" OR Iluvien®) AND ("eye" OR "ocular" OR "intravitreal)".  A total of 11 papers were included, and the use of FAc implant was analyzed in the following diseases: radiation-induced maculopathy (RM); paraneoplastic visual syndromes (melanoma-associated retinopathy (MAR) and cancer-associated retinopathy (CAR)); Sjogren's syndrome-related keratopathy; retinal vein occlusion (RVO); CME; diabetic retinal neurodegeneration (DRN); and retinitis pigmentosa (RP).  The authors concluded that FAc implant may be a potential treatment for these diseases; however, the level of scientific evidence of the included studies in this review was limited.  These researchers stated that further high-quality studies with well-defined methodologies, larger cohorts and longer follow-ups are needed to provide a greater level of understanding of the safety and efficacy of the potential use of this implant in other ocular diseases.

Birdshot Retinochoroiditis

In a retrospective, single-center, case-series study, Ajamil-Rodanes et al (2022) reported outcomes and effectiveness of Iluvien (FA 0.19-mg intra-vitreal implant) in controlling retinal and choroidal inflammation in 11 patients with birdshot retinochoroiditis.  The primary effectiveness endpoint was improvement in vascular leakage on fluorescein angiography, effect on CME and resolution of hypo-fluorescent lesions on indocyanine green angiography (ICGA); secondary measures were improvements on pattern and full-field electroretinogram (PERG; ERG) parameters.  Safety outcome measures were elevation of IOP and cataract genesis.  A total of 15 eyes received Iluvien implant with an average follow-up of 31 months (range of 12 to 36 months).  Before implantation of Iluvien, 5 (33.3 %) eyes had received dexamethasone intra-vitreal implant 0.7 mg (Ozurdex).  Fluorescein angiography showed evidence of vascular leakage in all eyes at baseline.  Between month 6 and 12, fluorescein angiography showed that 73.4 % of eyes had no leakage, this increased to 84.6 % by month 24; 3 eyes in this trial had CME at baseline.  Six months after Iluvien implantation, all eyes achieved complete CME resolution.  One year after insertion of the implant, the characteristic hypo-fluorescent lesions on ICGA were unchanged in all cases.  There was baseline ERG evidence indicating a high incidence of peripheral cone system dysfunction and most showed PERG evidence of macular dysfunction.  Retinal function improved and macular function improved or was stable in the majority following treatment.  The authors concluded that the findings of this study demonstrated the possible therapeutic effect of Iluvien in the management of birdshot-related vascular leakage, CME and retinal dysfunction; however, choroidal lesions appeared to persist with no detectable response to treatment.  Moreover, these researchers proposed that further studies should be carried out to confirm these findings.  These studies should be prospective in design, and ideally multi-center.

The authors stated that this study had several drawbacks.  First, it was a retrospective study.  Second, this trial included a relatively small number of cases (n = 15 eyes) and these investigators could not exclude that possibility of erroneous findings of type 1 and type 2 bias.  Third, the retrospective nature of the study meant that these researchers could not exclude bias, especially as some patients received concomitant immunosuppressive drug therapy.

Combined Keratoprosthesis, Silicone Oil Placement, and Fluocinolone Acetonide Implant for Treatment of Uveitis-Associated Hypotony and Keratopathy

In a retrospective study, Mosenia et a l(2022) described a case series of combined Boston Type 1 keratoprosthesis with pars plana vitrectomy, silicone oil placement, and intravitreal FA 0.59-mg implant (Retisert); and reported its safety and effectiveness in preventing phthisis bulbi in patients with uveitis-associated hypotony and concurrent corneal edema.  This trial included patients with chronic uveitis, corneal decompensation and concurrent hypotony who underwent the combined approach between 2015 and 2020.  A total of 3 patients were treated using the combined approach.  Intra-ocular pressure following placement of keratoprosthesis was estimated by scleral pressure and were measured using pneumatonometry in the inferotemporal quadrant to compare with corneal pressure measurements before insertion of the keratoprosthesis.  Post-operative recovery was unremarkable in all cases and the patients' corneal condition remained stable on follow-up.  No patient developed phthisis, retro-prosthetic membrane, or infectious endophthalmitis.  Average IOP 1 year after intervention was 2.7 to 6.4 mmHg higher compared to a year prior.  The authors concluded that the combined approach described was potentially safe and effective in preventing phthisis and membrane formation in uveitis-associated hypotony and keratopathy.  Moreover, these researchers stated that while inferotemporal scleral pneumatonometry is a promising method for measuring IOP in those with keratoprosthesis, this has not been validated in eyes with hypotony. They stated that future investigation can focus on further characterizing the impact of this intervention on IOP.

Radiation Retinopathy-Related Cystoid Macular Edema

In a retrospective study, Singaravelu et al (2023) examined the effectiveness of a 0.18-mg intravitreal FA implant (Yutiq) as a therapeutic option for patients with radiation retinopathy-related CME.  This review included 7 patients treated for uveal melanoma who developed radiation retinopathy-related CME.  They were initially treated with intravitreal anti-VEGF and/or steroid injections and then transitioned to intravitreal FA implant.  Primary outcomes include BCVA, central subfield thickness (CST), and number of additional injections.  After FA implant insertion, BCVA and CST remained stable in all patients.  The variance in BCVA decreased from 75.5 ETDRS letters (range of 0 to 199 letters) to 29.8 (range of 1.2 to 134) following FA implant insertion.  Mean CST was 384 μm (range of 165 to 641) and 354 μm (range of 282 to 493) before and after FA implant insertion, resulting in a 30 μm mean reduction.  The number of intravitreal injections (average of 4.9, range of 2 to 10) decreased following intravitreal FA implant insertion with only 2 patients requiring 1 additional FA implant (average of 0.29, range of 0 to 1) over a mean of 12.1 months (range of 0.9 to 18.5) follow-up.  The authors concluded that intravitreal FA implant was an effective treatment for radiation retinopathy-related CME.  The slow release of steroid allowed for sustained control of macular edema, which correlated with stable VA and decreased injection burden for patients.

Serpiginous Choroiditis

In a retrospective, longitudinal study, Miserocchi et al (2017) examined the safety and effectiveness of dexamethasone (DEX) intravitreal implant in patients with active serpiginous choroiditis (SC) already receiving maximal tolerated systemic immunosuppressive therapy.  This trial included patients receiving 0.7-mg DEX intravitreal implant for active SC despite maximal systemic immunosuppression.  Medical history was reviewed over a period of 18 months for each patient.  These researchers diagnosed SC activity using direct fundus examination and blue-light fundus auto-fluorescence.  Primary outcomes were the rate of disease control and functional changes at end of follow-up.  Secondary outcomes were the incidence of injection-related AEs and the success of immunosuppression tapering at the last examination.  These investigators examined 8 eyes of 7 patients; SC activity was controlled with 1injection in 5 eyes, 2 injections in 1 eye, and 3 injections in 2 eyes (total of 13 implants).  BCVA at the end of the investigational period improved in 2 eyes (25 %), remained stable in 4 eyes (50 %) and decreased in 2 eyes (25 %); and 3 eyes showed transient increase in IOP and 2 eyes disclosed cataract progression.  The average dosage of systemic prednisone at baseline and after DEX intravitreal implant decreased from 8.8 mg to 2.8 mg/day.  The authors concluded that DEX intravitreal implant may be an effective therapeutic option to control active SC lesions in patients in whom increased systemic corticosteroid therapy is contraindicated.  Moreover, these investigators stated that prospective, controlled studies are needed to confirm these findings and to define the best therapeutic approach for this severe sight-threatening disease.

The authors stated that this study had several drawbacks, mainly due to its retrospective design, the small number of patients (n = 7), and the absence of a control group.  These researchers also acknowledged that, owing to the study design, the differences of immunosuppressive therapy at baseline might have influenced the results.

In a single-case study, Siddiqui et al (2022) described an alternative treatment for a patient with SC who was intolerant to systemic therapies.  This case report entailed a 57-year-old woman with SC who was treated for 7 years with various therapies including systemic steroids, immunosuppressive agents, and repeated dexamethasone intravitreal implants.  The patient was intolerant of systemic therapies and her condition would flare if dexamethasone injections were performed less frequently than every 8 weeks, making a viable long-term treatment plan problematic.  Following 1 injection of the FA 0.18-mg intravitreal implant, the subject experienced sustained control for 20 months.  The authors conclude that real-world treatment of SC is complex as long-term control is needed, and associated side effects of the therapies provided may limit sustained use.  These investigators proposed that the FA 0.18-mg intravitreal implant may be considered as an alternative long-term therapeutic option for SC for some patients, especially those are intolerant to systemic therapies.  The findings of this single-case study need to be validated by well-designed studies.

Steroid-dependent Macular Edema Related to Retinitis Pigmentosa

Jomaa et al (2022) noted that macular edema (ME) can be observed in 20 % of patients with RP and is often responsible of central vision impairment.  Intra-ocular administration of corticosteroids (either triamcinolone or DEX implant) has been found to be effective in that indication.  In a single-case study, these researchers described the 1st report of a successful bilateral administration of FA implant in a patient with steroid-dependent ME associated to RP.  This case entailed a 34-year-old woman with RP who was referred for a 1-year bilateral persistent ME.  She had been refractory to topical or to general carbonic anhydrase inhibitors.  Bilateral off-label administration of 0.7-mg DEX implant (Ozurdex) was therefore decided.  Effectiveness and tolerance were very good in both eyes.  Still, every 4-month injections were needed to keep the macula dry.  Off-label use of 0.19-mg FA implant (Iluvien) was then proposed and injected, first, in the right eye and, 2 years after, in the left eye.  No recurrences of the edema were observed from then on (i.e., for 3 years in the right eye and for 1 year in the left eye).  The authors concluded that intravitreal FA could represent a promising means in the therapeutic management of persistent steroid-dependent ME related to RP.

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Appendix

For the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye:

Retisert (0.59 mg fluocinolone acetonide): Surgically insert 1 implant tablet into the posterior segment of the affected eye. The implant releases fluocinolone acetonide at an initial rate of 0.6 mcg/day, decreasing over the first month to 0.3 to 0.4 mcg/day at steady state, and lasting approximately 30 months. If there is a recurrence of uveitis after the implant is depleted, the implant may be replaced.

Yutiq (0.18 mg fluocinolone acetonide): Inject 1 implant intravitreally. Monitor the patient for elevated intraocular pressure and endophthalmitis. The implant is designed to release fluocinolone acetonide at an initial rate of 0.25 mcg/day, and lasting 36 months.

For the treatment of diabetic macular edema:

Iluvien (0.19 mg fluocinolone acetonide): Inject 1 implant (containing 0.19 mg fluocinolone acetonide) intravitreally. Monitor the patient for elevated intraocular pressure and endophthalmitis. The implant is designed to release fluocinolone acetonide at an initial rate of 0.25 mcg/day, and lasting 36 months.

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References