| Coverage Policy Manual | |
| Policy #: | 2010046 |
| Category: | Pharmacy |
| Initiated: | December 2010 |
| Last Review: | April 2024 |
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| Intravitreal, Punctum Corticosteroid Implants and Ranibizumab (e.g., Susvimo) | |
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| Description: |
Uveitis
Uveitis encompasses various conditions, of infectious and noninfectious etiologies, that are characterized by inflammation of any part of the uveal tract of the eye (iris, ciliary body, choroid). Infectious etiologies include syphilis, toxoplasmosis, cytomegalovirus retinitis, and candidiasis. Noninfectious etiologies include sarcoidosis, Behçet syndrome, and “white dot” syndromes such as multifocal choroiditis or “birdshot” chorioretinopathy. Uveitis may be idiopathic, have a sudden or insidious onset, a duration that is limited (less than 3 months) or persistent, and a course that may be acute, recurrent, or chronic. The classification scheme recommended by the Uveitis Study Group and the Standardization of Uveitis Nomenclature Working Group is based on anatomic location. Individuals with anterior uveitis typically develop symptoms such as light sensitivity, pain, tearing, and redness of the sclera. In posterior uveitis, which comprises approximately 5% to 38% of all uveitis cases in the United States, the primary site of inflammation is the choroid or retina (or both). Individuals with intermediate or posterior uveitis typically experience minimal pain, decreased visual acuity, and the presence of floaters (bits of vitreous debris or cells that cast shadows on the retina). Chronic inflammation associated with posterior segment uveitis can lead to cataracts, glaucoma, and structural damage to the eye, resulting in severe and permanent vision loss.
The primary goal of therapy for uveitis is to preserve vision. Noninfectious uveitis typically responds well to corticosteroid treatment. Immunosuppressive therapy (e.g., antimetabolites, alkylating agents, T-cell inhibitors, tumor necrosis factor inhibitors) may also be used to control severe uveitis. Immunosuppressive therapy is typically reserved for individuals who require chronic high-dose systemic steroids to control their disease. While effective, immunosuppressants may have serious and potentially life-threatening adverse effects, including renal and hepatic failure and bone marrow suppression.
Macular Edema After Retinal Vein Occlusion
Retinal vein occlusions are classified by whether the central retinal vein or one of its branches is obstructed. Central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) differ in pathophysiology, clinical course, and therapy. CRVOs are categorized as ischemic or nonischemic. Ischemic CRVOs are referred to as severe, complete, or total vein obstruction, and account for 20% to 25% of all CRVOs. Macular edema and permanent macular dysfunction occur in virtually all individuals with ischemic CRVO, and in many individuals with nonischemic CRVO. BRVO is a common retinal vascular disorder in adults between 60 and 70 years of age and occurs approximately 3 times more often than CRVO.
Intravitreal injections of triamcinolone are used to treat macular edema associated with CRVO, with a modest beneficial effect on visual acuity. The treatment effect lasts about 6 months and repeat injections may be necessary. Cataracts are a common side effect, and steroid-related pressure elevation occurs in about one-third of individuals, with 1% requiring filtration surgery. Macular photocoagulation with grid laser improves vision in BRVO but is not recommended for CRVO. Although intravitreal injections of triamcinolone have also been used for BRVO, the serious adverse events have stimulated the evaluation of new treatments, including intravitreal steroid implants or the intravitreal injection of antivascular endothelial growth factor.
Diabetic Macular Edema
Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness in adults. The 2 most serious complications for vision are diabetic macular edema (DME) and proliferative diabetic retinopathy. At its earliest stage (nonproliferative retinopathy), microaneurysms occur. As the disease progresses, blood vessels that nourish the retina are blocked, triggering the growth of new and fragile blood vessels (proliferative retinopathy). Severe vision loss with proliferative retinopathy arises from leakage of blood into the vitreous. DME is characterized by swelling of the macula due to gradual leakage of fluids from blood vessels and breakdown of the blood-retinal barrier. Moderate vision loss can arise from the fluid accumulating in the center of the macula (macular edema) during the proliferative or nonproliferative stages of the disease. Although proliferative disease is the main blinding complication of diabetic retinopathy, macular edema is more frequent and is the leading cause of moderate vision loss in people with diabetes.
Tight glycemic and blood pressure control is the first line of treatment to control diabetic retinopathy, followed by laser photocoagulation for individuals whose retinopathy is approaching the high-risk stage. Although laser photocoagulation is effective at slowing the progression of retinopathy and reducing visual loss, it does not restore lost vision. Alternatives to intravitreal implants include intravitreal injection of triamcinolone acetonide, which is used as off-label adjunctive therapy for DME. Angiostatic agents such as injectable vascular endothelial growth factor inhibitors, which block stages in the pathway leading to new blood vessel formation (angiogenesis), have demonstrated efficacy in DME.
Age-Related Macular Degeneration
Age-related macular degeneration is a degenerative disease of the retina that results in loss of central vision with increasing age. Two different forms of degeneration, known as dry and wet, may be observed. The dry form (also known atrophic or areolar) is more common and is often a precursor to the wet form (also known as exudative neovascular or disciform). The wet form is more devastating and characterized by serous or hemorrhagic detachment of the retinal pigment epithelium and development of choroidal neovascularization, which greatly increases the risk of developing severe irreversible loss of vision. Choroidal neovascularization is categorized as classic or occult.
Effective specific therapies for exudative or wet age-related macular degeneration are an intravitreous injection of a vascular endothelial growth factor inhibitor, possibly thermal laser photocoagulation (in selected individuals), and photodynamic therapy.
Intravitreal Implants
Intravitreal implants deliver a continuous concentration of a pharmacologic agent to the eye over a prolonged period. The goal of therapy is to reduce inflammation in the eye while minimizing the adverse events of the therapeutic regimen.
Selection of the route of corticosteroid administration (topical, systemic, periocular, or intraocular injection) is based on the cause, location, and severity of the disease. Each therapeutic approach has drawbacks. For example, topical corticosteroids require frequent (e.g., hourly) administration and may not adequately penetrate the posterior segment of the eye due to their poor ability to penetrate ocular tissues. Systemically administered drugs penetrate poorly into the eye because of the blood-retinal barrier, and high-dose or long-term treatments may be necessary. Long-term systemic therapies can be associated with substantial adverse events such as hypertension and osteoporosis, while repeated (every 4-6 weeks) intraocular corticosteroid injections may result in pain, intraocular infection, globe perforation, fibrosis of the extraocular muscles, reactions to the delivery vehicle, increased intraocular pressure, and cataract development.
Corticosteroid implants are biodegradable or nonbiodegradable. Nonbiodegradable systems are thought to be preferable for treating chronic, long-term disease, while biodegradable products may be preferred for conditions that require short-term therapy. Although the continuous local release of steroid with an implant may reduce or eliminate the need for intravitreal injections and/or long-term systemic therapy, insertion or surgical implantation of the device carries risks, and the device could increase ocular toxicity due to increased corticosteroid concentrations in the eye over a longer duration. With any route of administration, cataracts are a frequent complication of long-term corticosteroid therapy.
Intraocular corticosteroid implants being evaluated include:
Retisert is a sterile implant that consists of a tablet containing fluocinolone acetonide 0.59 mg, a synthetic corticosteroid that is less soluble in aqueous solution than dexamethasone. The tablet is encased in a silicone elastomer cup with a release orifice and membrane; the entire elastomer cup assembly is attached to a suture tab. Following implantation (via pars plana incision and suturing) in the vitreous, the implant releases the active drug at a rate of 0.3 to 0.4 μg/d over 2.5 years.
Fluocinolone acetonide intravitreal implant (e.g., ILUVIEN); Alimera Sciences) is a rod-shaped device made of polyimide and polyvinyl alcohol. It is small enough to be placed using a 25-gauge applicator. It is expected to provide sustained delivery of fluocinolone acetonide for up to 3 years.
Dexamethasone intravitreal implant (e.g., Ozurdex (previously known as Posurdex; biodegradable; Allergan, Irvine, CA) is composed of a biodegradable copolymer of lactic acid and glycolic acid with micronized dexamethasone. This implant is placed into the vitreous cavity through the pars plana using a customized, single-use, 22-gauge applicator. The implant provides intravitreal dexamethasone for up to 6 months. The mean number of Ozurdex injections reported in the literature is 4.2 injections per year, and more than 6 consecutive injections have been reported.
Fluocinolone acetonide intravitreal implant (e.g., YUTIQ™) containing 0.18 mg in a drug delivery system. It is an intravitreal micro-insert designed to release 0.25 mcg/day over the course of 36 months for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.
Dexamethasone intracanalicular insert (e.g., Dextenza®; Ocular Therapeutix™) is a rod-shaped hydrogel device that is designed to deliver a sustained and tapered release of 0.4 mg of dexamethasone over 4 weeks. Following ophthalmic surgery, it is inserted through the inferior punctum into the canaliculus of the operative eye. To allow for visualization and retention monitoring, the hydrogel device is conjugated with fluorescein. No removal is required as the device is designed to resorb and exit the nasolacrimal system independently.
Ranibizumab injection (e.g., Susvimo) is a recombinant humanized IgF1 kappa isotype monoclonal antibody fragment for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelia growth factor-A (VEGF-A).
Regulatory Status
In 2009, Dexamethasone 0.7 mg intravitreal implant (e.g., Ozurdex®; Allergan) was approved by the U.S. Food and Drug Administration for the treatment of macular edema following BRVO or CRVO. Subsequently, in September 2010, the indication was expanded to include treatment of noninfectious uveitis affecting the segment of the eye. In 2014, the indication was again expanded to include treatment of DME.
In September 2014, Fluocinolone acetonide 0.19 mg intravitreal implant (e.g., Iluvien®; Alimera Sciences) was approved by the Food and Drug Administration for the treatment of DME in individuals previously treated with a course of corticosteroids and without a clinically significant rise in intraocular pressure.
In November 2014, Fluocinolone acetonide 0.59 mg intravitreal implant (e.g., Retisert™; Bausch & Lomb) was approved by the Food and Drug Administration for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye.
In October 2018, Fluocinolone acetonide intravitreal micro-insert 0.18 mg (e.g., Yutiq; Eyepoint) was approved by the U.S. Food and Drug Administration for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.
In November 2018, Dexamethasone 0.4 mg intracanalicular implant (e.g., Dextenza®) was approved by the Food and Drug Administration for the treatment of ocular inflammation and pain following ophthalmic surgery.
On October 18, 2022, Roche announced on an investor call that it was voluntarily removing its ocular implant ranibizumab (e.g., Susvimo) from the market due to safety concerns related to the implant’s septum, or the seal on the port delivery that keeps medicine from leaking out once it has been injected. Roche plans to return ranibizumab to the market after it adjusts the manufacturing process and resolves the safety concerns. There is no definitive timeline at this point.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective August 1, 2022, Prior Approval will be required for Ranibizumab Implant.
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson, or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
Effective October 2023
INITIAL APPROVAL STANDARD REVIEW [ranibizumab injection (e.g., Susvimo) for up to 6 months]:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
CONTINUED APPROVAL for 1 year for ranibizumab injection (e.g., Susvimo):
Dosage and Administration
Dosing per FDA Guidelines
Flucinolone acetonide intravitreal implant (e.g., Retisert)
Flucinolone acetonide intravitreal implant (e.g., Yutiq)
Fluocinolone acetonide intravitreal implant (e.g., Iluvien)
Dexamethasone intravitreal implant (e.g., Ozurdex)
Dexamethasone ophthalmic insert (e.g., Dextenza)
Ranibizumab (e.g., Susvimo)
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (e.g., Retisert®), 0.18 mg (e.g., Yutiq®), 0.19 mg (Iluvien®), Dexamethasone intravitreal implant 0.7mg (e.g., Ozurdex™), Dexamethasone ophthalmic insert (e.g., Dextenza), or Ranibizumab (e.g., Susvimo), for any indication or circumstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (e.g., Retisert®), 0.18 mg (e.g., Yutiq®), 0.19 mg (Iluvien®), Dexamethasone intravitreal implant 0.7mg (e.g., Ozurdex™), punctum dexamethasone insert 0.4 mg (e.g., Dextenza®), or Ranibizumab (e.g., Susvimo), for any indication or circumstance not described above is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective August 1, 2022, Prior Approval will be required for Ranibuzumab Implant.
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
Effective October 18, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
2. The use of a fluocinolone acetonide intravitreal implant 0.18 mg (e.g., Yutiq) meets primary coverage criteria for effectiveness and is covered for the treatment of:
3. The use of a fluocinolone acetonide intravitreal implant 0.19 mg (e.g., Iluvien®) meets primary coverage criteria for effectiveness and is covered:
4. The use of a dexamethasone intravitreal implant (e.g., Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
5. The use of a punctum dexamethasone ophthalmic insert (e.g., Dextenza®) 0.4 mg meets primary coverage criteria that there be scientific evidence of effectiveness and is covered for the treatment of:
6. For those individuals who received ranibizumab (e.g., Susvimo™) for treatment of neovascular (wet) age-related macular degeneration (nAMD) as of October 18, 2022, a prior approval will be required for continuation.
CONTINUED APPROVAL for 1 year:
Dosage and Administration:
For Ophthalmic intravitreal injection:
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (e.g., Retisert®), 0.18 mg (e.g., Yutiq®), 0.19 mg (Iluvien®) or Dexamethasone intravitreal implant 0.7mg (e.g., Ozurdex™) does not meet primary coverage criteria or for members with contracts without primary coverage criteria is considered investigational for the treatment of:
The use of a punctum dexamethasone insert 0.4 mg (e.g., Dextenza®) for all other indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication not described above.
The use of ranibizumab (e.g., Susvimo) for Neovascular (wet) age-related macular degeneration (nAMD) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, the above indications are considered investigational.
Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective August 1, 2022 - October 17, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (e.g., Retisert®) meets primary coverage criteria for effectiveness and is covered for the treatment of:
The use of a fluocinolone acetonide intravitreal implant 0.18 mg (e.g., Yutiq) meets primary coverage criteria for effectiveness and is covered for the treatment of:
The use of a fluocinolone acetonide intravitreal implant 0.19 mg (e.g., Iluvien®) meets primary coverage criteria for effectiveness and is covered:
The use of a dexamethasone intravitreal implant (e.g., Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
The use of a punctum dexamethasone ophthalmic insert (e.g., Dextenza®) 0.4 mg meets primary coverage criteria that there be scientific evidence of effectiveness and is covered for the treatment of:
The use of ranibizumab (e.g., SusvimoTM) meets primary coverage criteria that there be scientific evidence of effectiveness and is covered for the treatment of:
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
CONTINUED APPROVAL for 1 year:
Dosage and Administration:
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (e.g., Retisert®), 0.18 mg (e.g., Yutiq®), 0.19 mg (Iluvien®) or Dexamethasone intravitreal implant 0.7mg (e.g., Ozurdex™) does not meet primary coverage criteria or for members with contracts without primary coverage criteria is considered investigational for the treatment of:
The use of a punctum dexamethasone insert 0.4 mg (e.g., Dextenza®) for all other indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication not described above.
For contracts without primary coverage criteria, the above indications are considered investigational.
Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective April 2020 to July 31, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (d.g., Retisert®) meets primary coverage criteria for effectiveness and is covered for the treatment of:
The use of a fluocinolone acetonide intravitreal implant 0.18 mg (e.g., Yutiq) meets primary coverage criteria for effectiveness and is covered for the treatment of:
The use of a fluocinolone acetonide intravitreal implant 0.19 mg (e.g., Iluvien®) meets primary coverage criteria for effectiveness and is covered:
The use of a dexamethasone intravitreal implant (e.g., Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
The use of a punctum dexamethasone ophthalmic insert (e.g., Dextenza®) 0.4 mg meets primary coverage criteria that there be scientific evidence of effectiveness and is covered for the treatment of:
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (e.g., Retisert®), 0.18 mg (e.g., Yutiq®), 0.19 mg (e.g., Iluvien®) or Dexamethasone intravitreal implant 0.7mg (e.g., Ozurdex™) does not meet primary coverage criteria or for members with contracts without primary coverage criteria is considered investigational for the treatment of:
The use of a punctum dexamethasone insert 0.4 mg (e.g., Dextenza®) for all other indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication not described above.
For contracts without primary coverage criteria, the above indications are considered investigational.
Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective April 2019 to March 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (Retisert®) meets primary coverage criteria for effectiveness and is covered for the treatment of:
The use of a fluocinolone acetonide intravitreal implant 0.18 mg (Yutiq) meets primary coverage criteria for effectiveness and is covered for the treatment of:
The use of a fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien®) meets primary coverage criteria for effectiveness and is covered:
The use of a dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of a fluocinolone acetonide intravitreal implant 0.59 mg (Retisert®), 0.18 mg (Yutiq), 0.19 mg (Iluvien®) or Dexamethasone intravitreal implant 0.7mg (Ozurdex™) does not meet primary coverage criteria or for members with contracts without primary coverage criteria is considered investigational for the treatment of:
For contracts without primary coverage criteria, the above indications are considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective Prior to April 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Dosage and administration:
For Ophthalmic intravitreal injection:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For contracts without primary coverage criteria, the above indications are considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective March 2018 - February 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For contracts without primary coverage criteria, the above indications are considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective March 2017 – February 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
Dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For contracts without primary coverage criteria, the following indications are considered investigational:
Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective Prior to March 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For contracts without primary coverage criteria, the following indications are considered investigational:
Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective July 2014 – September 2014
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Dexamethasone intravitreal implant (Ozurdex) does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For contracts without primary coverage criteria, the following indications are considered investigational:
Investigational services are contract exclusions in most member benefit certificates of coverage.
Effective prior to July 2014
Dexamethasone intravitreal implant (Ozurdex) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following indications:
Dexamethasone intravitreal implant (Ozurdex) does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For contracts without primary coverage criteria, the following indications are considered investigational:
Investigational services are contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
This evidence review was created in June 2010 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through January 14, 2020.
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, Two domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
SUMMARY OF EVIDENCE
Uveitis
For individuals with chronic noninfectious intermediate or posterior uveitis who receive an intravitreal fluocinolone acetonide implant (0.59 mg), the evidence includes 4 RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Two of the 4 RCTs compared 2 doses of implants, and 2 trials compared implants with systemic steroids (and immunosuppression when indicated). All trials supported the efficacy of intravitreal fluocinolone acetonide implants in preventing recurrence and improving visual acuity over 4-year follow-up. The head-to-head trial comparing implants with systemic corticosteroids did not show substantial superiority in the overall effectiveness of either approach. After 24 and 54 months of follow-up, visual acuity improved from baseline in the implant groups compared with the systematic therapy groups by +6.0 and +3.2 letters (p=0.16) and +2.4 and 3.1 letters (p=0.073), respectively. However, nearly all phakic patients receiving implants developed cataracts and required cataract surgery. Further, most also developed glaucoma, with 75% of patients requiring IOP-lowering medications and 35% requiring filtering surgeries. Systemic adverse events such as hyperlipidemia, diabetes, osteoporosis, fractures, and blood count/chemistry abnormalities were infrequent and not statistically distinguishable between groups. The incidence of hypertension was greater in the systemic therapy group (27%) than in the implant group (13%), but rates of antihypertensive treatment initiation did not differ. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals with noninfectious intermediate or posterior uveitis who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of this trial at 8 weeks showed that the implant was effective in reducing inflammation (the proportion of eyes with no inflammation was 47% and 12% with implant and sham, respectively) and resulted in clinically meaningful improvement in vision at week 8 compared with sham controls (the proportion of patients with a gain of ≥15 letters in best-corrected visual acuity from baseline was »40% with implants and 10% with sham). Further, at week 26, patients treated with implants reported meaningful increases in vision-related functioning. The major limitation of this trial was its lack of long-term follow-up. Use of implants resulted in higher incidences of cataracts and elevated IOP. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Macular Edema
For individuals with macular edema after retinal vein occlusion who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes 2 RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Compared with sham controls, implants resulted in clinically meaningful improvements in visual acuity within 1 to 3 months postimplant and improvement in vision occurred faster. The difference in the proportion of patients with gain of 15 or more letters in best-corrected visual acuity from baseline was more than 10% in favor implants vs sham in both studies at 30, 60 and 90 days, but not at 180 days postimplant. Use of implants resulted in higher incidences of cataracts and elevated IOP. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals with macular edema after retinal vein occlusion who receive an intravitreal fluocinolone acetonide implant (0.59 mg), no studies were identified. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.
Diabetic Macular Edema
For individuals with refractory (persistent or recurrent) DME who receive an intravitreal fluocinolone acetonide implant (0.59 mg), the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Compared with the standard of care (as needed laser or observation), a greater proportion of patients with implants reported clinically significant improvement in vision at 6 months (1.4% vs 16.8% respectively) and subsequent time points assessed but not at or beyond 30 months of follow-up. Ninety percent of patients with phakic eyes who received implants required cataract surgery, and 60% developed elevated IOP. Due to the substantial increase in adverse events and availability of agents with better tolerability profiles (eg, anti-VEGF inhibitors), implant use in DME is questionable. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with DME who receive an intravitreal fluocinolone acetonide implant (0.19 mg), the evidence includes 2 RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Implant-treated eyes showed clinically meaningful improvements in the vision at 2 and 3 years postimplant. The percentage of patients who gained 15 letters or more was 28.7% in the implant group vs 18.9% in the sham group at 3 years. Subgroup analysis showed greater improvements in visual acuity in patients who were pseudophakic compared with those who were phakic (difference in mean change in number of letters at 2 years from baseline was 5.6 letters in pseudophakic patients vs 1 letter in phakic patients). A major limitation of these implants is that nearly 80% all phakic patients will develop cataracts and will require cataract surgery. Further, IOP was elevated in 34% of patients who received this implant compared with 10% of controls. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals with DME who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes 3 RCTs. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Compared with sham control, 2 identically designed RCTs showed clinically meaningful improvements in vision with dexamethasone implants that peaked at 3 months and maintained 39 months (with retreatment). The difference in the proportion of patients with a gain of 15 or more letters in best-corrected visual acuity from baseline was 9.3% and 13.0% in the 2 trials, respectively, favoring implant vs sham at 39 months postimplant. Subgroup analysis of these trials showed greater improvements in visual acuity in patients who were pseudophakic compared with those who were phakic. Results of a small RCT showed that, compared with bevacizumab, implant-treated patients at 1 year had similar improvement rates on the primary end point, but experienced greater rates of vision loss (0% vs 10.9%), greater frequency of side effects such as cataracts (4.8% vs 13%) and elevated IOP (0% vs 19.6%), all respectively. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals with DME who receive an intravitreal dexamethasone implant (0.7 mg) plus anti-VEGF therapy, the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. One small RCTs with a one-year follow-up demonstrated that combination implants plus bevacizumab compared with bevacizumab alone resulted in a similar gain in visual acuity (5.4 letters vs 4.9 letters), but a greater frequency of side effects with combined treatment. Use of dexamethasone implants resulted in higher incidence of cataracts and elevated IOP. A larger RCT with adequate power is needed to confirm these findings. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with DME who receive an intravitreal dexamethasone implant (0.7 mg) plus laser photocoagulation, the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. One RCT with 1-year follow-up demonstrated that combination implants plus laser photocoagulation compared with laser photocoagulation alone resulted in better visual acuity (as measured by a gain of ≥10 letters) at 9 months but not at 12 months. However, the generally accepted standard outcome measure for change is 15 or
more letters, and this standard was not used in this trial. The use of dexamethasone implants resulted in higher incidences of cataracts and elevated IOP. Further, a differential loss to follow-up, lack of power calculations for sample size estimation, and lack of intention-to-treat analysis preclude interpretation of results. A larger RCT with adequate power is needed to confirm these findings. The evidence is insufficient to determine the effects of the technology on health outcomes.
Age-Related Macular Degeneration
For individuals with age-related macular degeneration who receive an intravitreal dexamethasone implant (0.7 mg) plus anti-VEGF inhibitor, the evidence includes an RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of this trial did not demonstrate clinically meaningful reductions in the ranibizumab injection-free interval between combined treatments (34 days) and anti-VEGF alone (29 days; p=0.016). Further, IOP was elevated in a greater proportion of patients receiving implants without any additional clinical benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
Other Conditions
For individuals with birdshot retinochoroidopathy refractory or intolerant to standard therapy who receive an intravitreal fluocinolone acetonide implant (0.59 mg) or intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Multiple observational studies have noted improvements in anatomic and visual acuity outcomes. Long-term follow-up for efficacy and safety is limited. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with refractory or intolerant birdshot retinopathy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with cystoid macular edema related to retinitis pigmentosa who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes observational studies and multiple case reports. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The RCT found improved mean visual acuity and eye anatomy outcomes with intravitreal dexamethasone compared tothe control eyes, but these differences were not sustained at 6 months. The comparative observational studies included 269 patients (range, 60 to 135) and also lacked responder analysis of the proportion of patients with a 15-or-more letter improvement. One case series evaluated the proportion of patients with a 3-line improvement in best-corrected visual acuity; although 88% of patients achieved this outcome at 2 months, the proportion with improvement was not sustained at 6 months (27.8%). Additional blinded, multicenter RCTs are needed that compare intravitreal dexamethasone to another established treatment. The trials should be adequately powered for measuring proportion of patients in whom vision had improved by 15 letters or more. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with idiopathic macular telangiectasia type 1 who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple case reports. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Case reports have noted mix results for visual acuity and inflammation-related outcomes. Long-term follow-up for efficacy and safety is limited. Better quality studies with long-term follow-up are needed to permit conclusions on the efficacy of corticosteroid implants in patients with idiopathic macular telangiectasia type 1. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with postoperative chronic macular edema who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Among the multiple observational studies, a large retrospective analysis of 100 patients showed that 2 of every 5 patients experienced clinically meaningful improvements in the vision at 1-year follow-up. An RCT is needed to confirm the efficacy of corticosteroid implants in patients with postoperative chronic macular edema. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with circumscribed choroidal hemangiomas who receive an intravitreal dexamethasone implant (0.7 mg) plus photodynamic therapy, the evidence includes a case report. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of the case report do not permit conclusions about the efficacy or safety of adding dexamethasone implants for circumscribed choroidal hemangiomas to photodynamic therapy. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with proliferative vitreoretinopathy who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes a case series and a case report. Relevant outcomes are symptoms, change in reported multiple interventions, including dexamethasone implants in conjunction with surgery and laser for preventing proliferative retinopathy after retinal detachment surgery. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with proliferative retinopathy. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with radiation retinopathy who receive an intravitreal dexamethasone implant (0.7 mg), the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Multiple observational studies have noted improvements in anatomic and visual acuity outcomes. Long-term follow-up for efficacy and safety is limited. RCTs are needed to permit conclusions on the efficacy of corticosteroid implants in patients with radiation retinopathy. The evidence is insufficient to determine the effects of the technology on health outcomes.
Clinical Input Received Through Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 1 physician specialty society and 1 academic medical center while this policy was under review in 2011. Input supported use of intravitreal corticosteroid implants, confined to the FDA-labeled indications. It was noted that Ozurdex is used for short-term uveitis control while the Retisert implant is used for more long-term control of uveitis.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American Academy of Ophthalmology
In 2019, the American Academy of Ophthalmology published its preferred Practice Pattern® for retinal vein occlusions. These stated: “Macular edema may complicate both central retinal vein occlusions and branch retinal vein occlusions. The first line of treatment for associated macular edema is anti-vascular endothelial growth factors. Intravitreal corticosteroids, with the associated risk of glaucoma and cataract formation, have demonstrated efficacy. Also, laser photocoagulation surgery in branch retinal vein occlusion
National Institute for Health and Care Excellence
In 2019, the National Institute for Health and Care Excellence (NICE) released guidance on the use of fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien) for treating chronic diabetic macular edema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).
The NICE guidance states, “Fluocinolone acetonide intravitreal implant is not recommended as an option for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies in an eye with a natural lens (phakic eye).” The NICE committee reached this conclusion based on their interpretation that “results from[Fluocinolone Acetonide in Diabetic Macular Edema] FAME may not be generalisable to people with chronic diabetic macular oedema in phakic eyes with symptomatic cataract seen in the NHS” because “in FAME, very few people had symptomatic cataract at baseline” and that the type of rescue therapy used in FAME is not used in NHS clinical practice.
In 2019, the NICE released guidance on the use of fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis. NICE's guidance stated, "Fluocinolone acetonide intravitreal implant is recommended, within its marketing authorisation, as an option for preventing relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye."
In 2017, the National Institute for Health and Care Excellence (NICE) released guidance on the use of dexamethasone intravitreal implant (with adalimumab) for the treatment of noninfectious uveitis.64 NICE recommended the implant only in cases of “active disease” with “worsening vision” and the “risk of blindness.”
In 2011, NICE provided guidance on the use of the dexamethasone intravitreal implant for macular edema secondary to retinal vein occlusion. The dexamethasone implant is recommended as an option for the treatment of macular edema following central retinal vein occlusion. It is recommended as an option for the treatment of macular edema following branch retinal vein occlusion when treatment with laser photocoagulation has not been beneficial, or if laser photocoagulation is not considered suitable because of the extent of macular hemorrhage.
In 2015, NICE provided guidance on the dexamethasone intravitreal implant for treating diabetic macular edema (NICE, 2015). Ozurdex is recommended as a possible treatment for diabetic macular edema if there is an artificial lens and the edema either has not improved with non-corticosteroid treatment or non-corticosteroid treatment is not considered suitable.
In November 2013, NICE replaced technology appraisal (TA) guidance 271 (January 2013) with TA 301, concluding that the fluocinolone acetonide intravitreal implant (Iluvien) is recommended as an option for treating chronic diabetic macular edema 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.
April 2020 Update
A multicenter randomized double-masked clinical trial was conducted to evaluate the safety and efficacy of dexamethasone as a sustained-release drug depot when placed in the canaliculus for the treatment of ocular inflammation and pain in cataract surgery patients.
Patients were randomized (1:1) to receive either the sustained-release dexamethasone or a placebo vehicle punctum plug inserted into the inferior distal canaliculus of the operated eye intraoperatively during cataract surgery. The primary endpoints were the proportions of patients with absence of cells or pain in the anterior chamber at 8 days. Secondary endpoints included cells, flare, pain, and the presence of the device at various timepoints through 30 days.
Approximately one fifth (20.7%) of patients in the sustained-release dexamethasone group had an absence of anterior chamber cells at 8 days compared with 10.0% in the placebo group (P = .1495). A higher proportion of patients in the sustained-release dexamethasone group (79.3%) than in the placebo group (30.0%) had an absence of ocular pain at 8 days (P < .0001) and at all other timepoints (P < .0002). There were significantly higher proportions of patients in the sustained-release dexamethasone group than in the placebo group with an absence of anterior chamber cells, anterior chamber flare, and pain at several timepoints through 30 days (P ≤ .0251).
Sustained-release dexamethasone provided elution of drug for up to 1 month after cataract surgery, providing clinically significant reductions in inflammation and pain. (Walters T, Bafna S, Vold S, Wortz G, Harton P, et al., 2016).
A randomized, parallel design, and clinical trial was conducted to determine the utility of the dexamethasone implant (IVD) as an alternative to systemic steroids as prophylaxis against cystoid macular edema (CMO) in patients with chronic, recurrent CMO associated intermediate or posterior uveitis (IU/PU), and cataract undergoing cataract surgery.
Patients with IU/PU and cataract scheduled for cataract surgery were randomly assigned to receive the IVD concurrently with cataract surgery (Group 1: 20 patients) or systemic steroids (Group 2: 23 patients) tapered over 4-6 weeks along with uneventful cataract surgery and routine postoperative care. Patients with glaucoma/contraindications to steroids were excluded. All patients were followed up for 6 months. Primary-incidence of postoperative CMO. Secondary-the change in BCVA (corrected distance visual acuity) and Central Subfield thickness (CST) and complications. Appropriate statistical analysis was done. The median age was 47.3 ± 4.23 years (group 1) and 49.12 ± 5.32 years (Group 2). One patient (Group 1) and two (Group 2) developed CMO. The BCVA improved significantly in both groups (p = 0.013). The CST change was insignificant. Four patients (Group 1) required intraocular pressure (IOP) lowering medications. Three patients (Group 2) required early steroid taper. ( Sudhalkar A, Vasavada A, Bhojwani D, et al., 2019).
A multicenter, randomized, prospective, doubled-masked, sham-controlled, 3-year phase 3 clinical trial was conducted to assess the safety and efficacy of an intravitreal fluocinolone acetonide (FA) insert to manage inflammation associated with chronic non-infectious posterior uveitis.
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 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. The FA insert group showed higher rates of cataract. Intraocular pressure-lowering treatment use was similar between groups. No deaths, treatment-related study discontinuations, or unanticipated safety signals were observed through 12 months.
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.
The data represent the early results of a pivotal trial. Analysis of the study data through 36 months, as well as additional randomized well-controlled studies, are needed to confirm the 12-month results and to quantify the benefits of continuous long-term control of intraocular inflammation. (Jaffe GJ, Foster CS, Pavesio CE, et al., 2019).
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Rittiphairoj et al published a Cochrane review that evaluated the efficacy of intravitreal steroids for macular edema in diabetes (Rittiphairoj, 2020). It is an update of the previously published Cochrane review by Grover et al (Grover, 2008). Ten trials were included, involving 4,505 eyes with diabetic macular edema. Among those, 4 trials examined the effectiveness of intravitreal steroid implantation with fluocinolone acetonide (Retisert) or the dexamethasone drug delivery system compared with sham or an anti-vascular endothelial growth factor agent (all discussed below) and 6 examined triamcinolone. Cochrane reviewers concluded that, compared to sham or control, intravitreal steroids may improve visual outcomes in people with diabetic macular edema, but that these benefits should be weighed against risk of intraocular pressure elevation.
Subsequent to the 2014 pivotal trials and FDA approval, several small and/or short-term trials and retrospective studies were published that evaluated the comparative effects of intravitreal dexamethasone implant (0.7 mg) versus other treatments. One of these was a random control trial by Callanan et al that evaluated 363 patients with diabetic macular edema, and concluded that dexamethasone was noninferior to ranibizumab in mean average BCVA change based on the prespecified noninferiority margin of 5 letters, similar in retinal thickness reduction, but ocular adverse events were more frequent for dexamethasone (Callanan, 2017).
Various drugs and therapeutic strategies are used to treat cystoid macular edema, with no consensus on the optimal approach or combination of drugs (Donati, 2018). Intravitreally administered vascular endothelial growth factor antagonists (anti-VEGF) are an established treatment option (Laine, 2017). Other treatment options may include carbonic anhydrase inhibitors and/or nonsteroidal anti-inflammatory drugs (Spaide, 2016). In those that do not respond to anti-VEGF agents, intravitreal corticosteroids are typically used (Ozkok, 2015).
The beneficial outcomes of general interest are symptom improvement, change in disease status, functional status and quality of life. Harmful outcomes of interest are treatment-related morbidity. Follow-up over the first few weeks following surgery is of interest for relevant outcomes. For visual acuity, the FDA considers a 3-line or 15-or-more letter improvement from baseline in best-corrected visual acuity as a clinically significant change (Csaky, 2008).
Three observational studies have compared intravitreal dexamethasone to other treatments in patients with cystoid macular edema (Ozkok, 2015; Laine, 2017; Veritti, 2020). These studies are heterogenous in the type of cystoid macular edema treated, the comparator treatment, and outcome assessment approaches. The strength and relevancy of their findings is limited as they have included only small numbers of patients and lack responder analysis of the proportion of patients with a 15-or-more letter improvement from baseline in best-corrected visual acuity.
Ozkok et al did a prospective study in the US between 2009-2013. Participants had refractory cystoid macular edema due to retinal vein occlusion, initially treated with bevacizumab. 35 participants received intravitreal dexamethasone and 39 participants received triamcinolone. Results include BCVA Final: 0.36 vs. 0.36 (P=.920); Central Retinal Thickness Final: 310.3 vs. 311.6 (P=.962), and Intraocular Pressure (mmHg) IOP increase >6 mmHg or needed IOP decreasing drops: 20% vs. 25.6% (P=.462) (Ozkok, 2015).
Laine et al did a retrospective study in Finland between 2011-2015. Participants had treatment-naive cystoid macular edema due to retinal vein occlusion. 14 participants received intravitreal dexamethasone and 121 participants received bevacizumab. Results include BCVA 3-month mean gain estimated from graph: 0.33 vs. 0.37 (P NR, but described as not significantly different); Central Retinal Thickness 3-month reduction estimated from graph: -150 vs. -200 (P NR, but described as not significantly different), and Intraocular Pressure (mmHg) IOP ≥ 25 mmHg and elevation ≥ 5 mmHg from baseline: 2 (14%) vs. 0 (P=.010) (Laine, 2017).
Veritti et al did a prospective study in Italy between 2015-2016. Participants had cystoid macular edema secondary to retinitis pigmentosa. 30 participants received intravitreal dexamethasone and 30 participants received oral acetazolamide. Results include BCVA +4.2 letters vs. +1.6 letters (P <.05); Central Retinal Thickness -327 µm vs. -180 µm (P=.001), and Intraocular Pressure (mmHg) Elevated IOP requiring topical treatment: 4 (13%) vs. 0 (P=.11) (Veritti, 2020).
Multiple case series have assessed improvements in visual acuity and anatomic changes following intravitreal dexamethasone implant (0.7 mg) in patients with cystoid macular edema of various etiologies (Donati, 2018; Novais, 2016; Bansal, 2015; Fortoul, 2015; Bezatis, 2013). However, these studies have generally included only small numbers of patients (n range of 26 to 112) and lacked responder analysis of clinically meaningful changes in outcomes. One exception is the case series by Fortoul et al, that evaluated the efficacy of the first intravitreal injection of dexamethasone implant in 26 eyes with cystoid macular edema secondary to retinal vein occlusion over 6 months in a single center in France (Fortoul, 2015). Fortoul et al reported that although 88% of patients achieved at least a 3-line improvement in best-corrected visual acuity 2 months, this was not sustained and only 27.8% of eyes still achieved clinically significant response at 6 months.
There are no FDA approved treatments specifically for postoperative chronic macular edema. Also, there are no guidelines or position statements that provide definitive guidance on standard of care for postoperative chronic macular edema. However, first-line treatment typically involves topical corticosteroids and nonsteroidal anti-inflammatory drugs, either as monotherapy or combined therapy (Hollo, 2020; Grzybowski, 2016). When postoperative chronic macular edema persists following topical treatments, then intravitreal corticosteroids and anti-vascular endothelial growth factor agents may be an option.
Mylonas et al published an RCT that compared dexamethasone intravitreal implant to triamcinolone intravitreal injection in 29 patients with refractory postoperative cystoid macular edema (Mylonas, 2017). Participants were mostly female (72%) and the mean age was 73 years in the dexamethasone group and 71 years in the triamcinolone group. No primary outcome was specified. There were no significant differences between the groups in improvement in mean best corrected visual acuity, but central millimeter retinal thickness reduction was significantly greater for triamcinolone at 1 week and 6 months. Minimal information on adverse events was reported.
Two observational studies have compared intravitreal dexamethasone to other treatments in patients with postoperative macular edema (Dang, 2014; Guclu, 2019). However, these studies have included only small numbers of patients and lack responder analysis of the proportion of patients with a 15-or-more letter improvement from baseline in best-corrected visual acuity.
Multiple case series have assessed improvements in visual acuity and anatomic changes (Klamann, 2016; Sudhalkar, 2016; Keilani, 2016; Mayer, 2015; Landre, 2016; Degoumois, 2015; Dutra Medeiros, 2013; and Freissinger, 2020). However, these studies have included only small numbers of patients and reported mean pre-post changes in visual acuity and eye anatomy that lack responder analysis using clinically meaningful changes in outcomes. Effectiveness and safety of dexamethasone implants for postsurgical macular edema including Irvine-Glass syndrome (EPISODIC), a 2017 observational retrospective study conducted in France, included 100 patients with postsurgical macular edema who received dexamethasone implants between 2011 and 2014 and who had a minimum of 1-year follow-up (Bellocq, 2017). Mean improvement in best-corrected visual acuity was 9.6 Early Treatment Diabetic Retinopathy Study letters at month 6 and 10.3 at month 12. The proportions of eyes with gains in best-corrected visual acuity of 15 or more letters were 32.5% and 37.5% at months 6 and 12, respectively. The average reduction in central subfield macular thickness was 135.2 and 160.9 μm at months 6 and 12.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.
A phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial was conducted to evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD).
Inclusion criteria included patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy.
Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab).
Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin, -4.5 letters: equivalence margin, ±4.5 letters).
Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation.
Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval. (Holekamp NM, Campochiaro PA, Chang MA, et.al., 2021)
Madison, NJ: Allergan USA, Inc.; 2022
2023 Update
In three randomized, multicenter, double-masked, parallel group, vehicle-controlled efficacy trials, patients received DEXTENZA or its vehicle immediately upon completion of cataract surgery (NCT02034019, NCT02089113, NCT02736175). 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 postoperative
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. (FDA, 2021)
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