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Formation of new blood vessels through neovascularization or angiogenesis in the posterior segment of the eye, particularly in the region of the retina, can result in a number of conditions that may severely impair vision. Conditions related to neovascularization of the eye include the "wet" form of age-related macular degeneration (AMD) and macular edema. The proliferation of blood vessels behind the retina is due, in part, to the activity of vascular endothelial growth factor (VEGF) family members, which induce angiogenesis and increase vascular permeability and inflammation of the choroid, retina, and macula. Inhibition of the angiopoietin-2 (Ang-2) pathway has also been paired with vascular endothelial growth factor (VEGF) inhibition in drug development. Several VEGF inhibitors can be administered by intravitreal injection for treatment of ophthalmic disorders characterized by retinal and choroidal neovascularization.

• Pegaptanib sodium (Macugen^®) is a pegylated modified oligonucleotide, or aptamer, that binds and inhibits an isomer of VEGF-A. Pegaptanib sodium is FDA-approved for treatment of neovascular (wet) AMD.
• Aflibercept (Eylea^®) is a recombinant fusion protein, consisting of components of human VEGF receptors and human IgG, which binds and inhibits multiple VEGF family members. Aflibercept is FDA-approved for treatment of neovascular (wet) AMD, macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy. Another aflibercept product, ziv-aflibercept (Zaltrap^®), is FDA-approved for cancer indications.
• Ranibizumab (Lucentis^®) is a recombinant humanized anti-VEGF antibody fragment that binds and inhibits all isoforms of VEGF-A. Ranibizumab is FDA-approved for treatment of neovascular (wet) AMD, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization.
• Ranibizumab (Byooviz™) is a biosimilar to Lucentis®. Byooviz™ is FDA approved for neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV). 
• Ranibizumab injection (Susvimo™) is a vascular endothelial growth factor (VEGF) inhibitor indicated for intravitreal use via an ocular implant. Susvimo™ is FDA-approved for the treatment of patients with neovascular (wet) age-related macular degeneration (AMD) who have previously responded to at least two intravitreal injections of a VEGF inhibitor.
• Bevacizumab (Avastin^®) is a recombinant humanized anti-VEGF antibody derived from the same monoclonal antibody as ranibizumab that also binds and inhibits all isoforms of VEGF-A. Bevacizumab is FDA-approved for a number of cancer indications and is used off-label for treatment of neovascular conditions of the choroid and retina.
• Brolucizumab (Beovu®) is a humanized single-chain antibody fragment that binds and inhibits all isoforms of vascular endothelial growth factor-A (VEGF-A). Brolucizumab is FDA-approved for the treatment of neovascular (wet) age-related macular degeneration (AMD). Serious adverse reactions have occurred with treatment of Beovu®, including endophthalmitis and retinal detachment, retinal vasculitis and/or retinal vascular occlusion, increases in intraocular pressure, and a potential risk for arterial thromboembolic events.
• Faricimab (Vabysmo™) a is a humanized bispecific immunoglobulin G1 (IgG1) antibody that binds both vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2). Faricimab is FDA-approved for the treatment of neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME). Serious adverse reactions have occurred with treatment of Vabysmo™ including conjunctival hemorrhage, endophthalmitis, retinal detachment, increases in intraocular pressure, and a potential risk for arterial thromboembolic events.

Definitions

Age-related macular degeneration (AMD): A painless, progressive deterioration of the macula, the central portion of the retina, that results in loss of central vision needed for "straight ahead" tasks such as reading, sewing, and driving. Late-stage AMD is classified as dry or wet. The neovascular, exudative, wet form is due to choroidal neovascularization, which leads to leakage of fluid, scarring, and vision loss.

Choroidal neovascularization: The ingrowth of new vessels in the sponge-like membrane in the eye located between the white outer layer of the eye (sclera) and the retina.

Macular edema: Thickening and swelling of the macula due to leakage of fluid into the retina that is caused by damage to the blood vessels.

Retinal vein occlusion: Blockage of central or branch retinal veins due to  a number of conditions including diabetic retinopathy, hypertension, atherosclerosis, and some blood coagulation disorders. Occlusion can cause leakage of fluid from the retinal veins resulting in macular edema.

Retinopathy: Damage to the blood vessels in the retina.

I.   Initial Review for Bevacizumab (Avastin®)

Intravitreal injection of bevacizumab may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Diagnosis of ONE of the following:
  • Diabetic macular edema; OR
  • Diabetic retinopathy; OR
  • Neovascular (wet) age-related macular degeneration or choroidal neovascularization; OR
  • Macular edema (e.g. cystoid) following retinal vein occlusion; OR
  • Neovascular glaucoma; OR
  • Rubeosis (i.e., neovascularization of the iris); OR
  • Retinopathy of prematurity; AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to bevacizumab (see table 1 below).

II.  Initial Review for Ranibizumab (Lucentis®, Byooviz™)

Intravitreal injection of ranibizumab (Lucentis®, Byooviz™) may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• ONE of the following:
  • Diagnosis of diabetic macular edema, with or without diabetic retinopathy; OR
  • BOTH of the following:
    1. Diagnosis of ONE of the following:
       • Diabetic retinopathy without diabetic macular edema; OR
       • Neovascular (wet) age-related macular degeneration or choroidal neovascularization; OR
       • Macular edema (e.g. cystoid) following retinal vein occlusion; AND
    2. ONE of the following:
       • Previously tried and failed intravitreal bevacizumab; OR
       • Documented intolerance, FDA labeled contraindication, or hypersensitivity to intravitreal bevacizumab;
• AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to ranibizumab (see table 1 below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

III.  Initial Review for Ranibizumab (Susvimo™)

Intravitreal injection of ranibizumab (Susvimo™) via ocular implant may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Diagnosis of neovascular (wet) age-related macular degeneration or choroidal neovascularization; AND
• ONE of the following:
  • Previously tried and failed intravitreal bevacizumab; OR
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to intravitreal bevacizumab;
• AND
• Previously responded to at least two intravitreal injections of ranibizumab (Lucentis®, Byooviz™);
• AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to ranibizumab (see table 1 below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).

IV.   Initial Review for Aflibercept (Eylea®)

Intravitreal injection of aflibercept may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• ONE of the following:
  • Diagnosis of diabetic macular edema, with or without diabetic retinopathy; OR
  • BOTH of the following:
    1. Diagnosis of ONE of the following:
       • Diabetic retinopathy without diabetic macular edema; OR
         
       • Neovascular (wet) age-related macular degeneration or choroidal neovascularization; OR
       • Macular edema (e.g. cystoid) following retinal vein occlusion; AND
    2. ONE of the following:
       • Previously tried and failed intravitreal bevacizumab; OR
       • Documented intolerance, FDA labeled contraindication, or hypersensitivity to intravitreal bevacizumab;
• AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to aflibercept (see table 1 below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

V.    Initial Review for Pegaptanib (Macugen®)

Intravitreal injection of pegaptanib may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Diagnosis of neovascular (wet) age-related macular degeneration or choroidal neovascularization; AND
• ONE of the following:
  • Previously tried and failed intravitreal bevacizumab; OR
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to intravitreal bevacizumab; AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to pegaptanib (see table 1 below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

VI.  Initial Review for Brolucizumab (Beovu®) 

Intravitreal injection of brolucizumab may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Diagnosis of neovascular (wet) age-related macular degeneration or choroidal neovascularization; AND
• ONE of the following:
  • Previously tried and failed intravitreal bevacizumab; OR
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to intravitreal bevacizumab;
• AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to brolucizumab (see table 1 below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

VII.   Initial Review for Faricimab (Vabysmo™)

Intravitreal injection of faricimab may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• ONE of the following:
  • Diagnosis of diabetic macular edema; OR
  • BOTH of the following:
    • Diagnosis of neovascular (wet) age-related macular degeneration; AND
    • ONE of the following:
      • Previously tried and failed intravitreal bevacizumab; OR
      • Documented intolerance, FDA labeled contraindication, or hypersensitivity to intravitreal bevacizumab;
• AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to faricimab (see table 1 below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).

VIII.   Renewal Review for Bevacizumab (Avastin®), Ranibizumab (Lucentis® Byooviz™), Ranibizumab (Susvimo™), Aflibercept (Eylea®), Pegaptanib (Macugen®), Brolucizumab (Beovu®), or Faricimab (Vabysmo™)

Intravitreal injection of bevacizumab, ranibizumab, aflibercept, pegaptanib, brolucizumab, or faricima may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Previously approved for the requested agent through the initial review process; AND
• Demonstrated positive clinical response to the requested therapy (e.g., improvement or stabilization of visual acuity, macular thickness, subretinal/intraretinal cystic fluid, or subretinal hemorrhage, stabilization and/or slowing of disease progression); AND
• Prescribed by or in consultation with an ophthalmologist; AND
• Not used in combination with intravitreal corticosteroid injection or verteporfin photodynamic therapy; AND
• No FDA labeled contraindications to the requested agent (see table 1 below).

IX.   Experimental/Investigative Uses

All other uses of ranibizumab, pegaptanib, brolucizumab, or faricima are considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

All other non-oncologic uses of bevacizumab and aflibercept are considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

Table 1. FDA Labeled Contraindications

.*Bevacizumab is not FDA-approved for treatment of ocular conditions; therefore, there are no FDA labeled contraindications related to intravitreal administration.

Documentation Submission:

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization, when prior authorization is required. In addition, the following documentation must also be submitted:

Initial Review

1. Clinical notes describing the diagnosis and clinical features of the diagnosis.
2. Clinical notes describing current and past medications for the diagnosis, including response to the medications.
3. Clinical notes documenting absence of active ocular or periocular infection.
4. For commercial health plan members only, when step therapy requirements apply for the requested indication, documentation for one or more of the step therapy supplement criteria MUST be provided (see policy II-242).

Renewal Review 

1. Documentation of prior approval through the initial review process.
2. Documentation since most recent approval supporting continued positive clinical response (e.g., improvement or stabilization of visual acuity, macular thickness, subretinal/intraretinal cystic fluid).