Coverage Policy Manual
Policy #: 2024066
Category: Pharmacy
Initiated: January 2025
Last Review: October 2024
  Non-Bevacizumab Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive)
Description:
For use of bevacizumab as a VEGF inhibitor, see Coverage Policy 2024021, Bevacizumab (e.g., Avastin) and Biosimilars for Ophthalmic Use.
 
Vascular Epithelial Growth Factor, or VEGF, is a biochemical signal protein that promotes angiogenesis throughout the body and in the eye. Medications targeting VEGF bind to and block major isoforms of vascular endothelial growth factor-A. VEGF-A is a member of the VEGF family of angiogenic factors that acts as a mitogenic, chemotactic, and vascular permeability factor for endothelial cells. VEGF-A interacts with 2 receptors, VEGFR-1 and VEGFR-2, on the surface of endothelial cells. Activation of VEGFR-1 and VEGFR-2 can result in neovascularization and vascular permeability. By blocking VEGF-A, these drugs suppress endothelial cell proliferation, neovascularization, and vascular permeability.
 
Ophthalmic VEFG drugs are approved to treat neovascular (wet) age-related macular degeneration (AMD), macular edema after central retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy, and retinopathy of prematurity (ROP). Guidelines often recommend those as a first-line therapy for the management of eyes with central-involved diabetic macular edema (CIDME).
 
Regulatory Status
 
Ranibizumab (e.g., Lucentis) was approved by the U.S. Food and Drug Administration (FDA) on June 30, 2006, for the treatment of wet age-related macular degeneration.
 
Ranibizumab (e.g., Lucentis) was approved by the U.S. Food and Drug Administration (FDA) on June 23, 2010, for the treatment of macular edema following retinal vein occlusion.
 
Ranibizumab (e.g., Lucentis) was approved by the U.S. Food and Drug Administration (FDA) on August 10, 2012, for the treatment of diabetic macular edema.
 
Ranibizumab (e.g., Lucentis) was approved by the U.S. Food and Drug Administration (FDA) on February 6, 2015, for the treatment of diabetic retinopathy.
 
Ranibizumab (e.g., Lucentis) was approved by the U.S. Food and Drug Administration (FDA) on January 5, 2017, for the treatment of myopic choroidal neovascularization.
 
Ranibizumab (e.g., Lucentis) was approved by the U.S. Food and Drug Administration (FDA) on April 17, 2017, for the treatment of all forms of diabetic retinopathy.
 
Ranibizumab-nuna (e.g., Byooviz) was approved by the U.S. Food and Drug Administration (FDA) on September 20, 2021, as a biosimilar to ranibizumab (e.g., Lucentis).
 
Ranibizumab-eqrn (e.g., Cimerli) was approved by the U.S. Food and Drug Administration (FDA) on August 2, 2021, as an interchangeable biosimilar to ranibizumab (e.g., Lucentis). =
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on November 11, 2011, for the treatment of wet age-related macular degeneration.
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on July 29, 2014, for the treatment of diabetic macular edema.
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on October 6, 2014, for the treatment of macular edema following retinal vein occlusion.
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on July 29, 2014, for the treatment of diabetic macular edema.
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on March 25, 2015, for the treatment of diabetic macular edema.
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on May 13, 2019, for the treatment of diabetic retinopathy.
 
Aflibercept (e.g., Eylea) was approved by the U.S. Food and Drug Administration (FDA) on February 8, 2023, for the treatment of preterm infants with retinopathy of prematurity.
 
Afilbercept-ayyh (e.g., Pavblu) was approved by the U.S. Food and Drug Administration (FDA) on August 23, 2024, for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RNO), diabetic macular edema (DME), and diabetic retinopathy (DR).
 
Brolucizumab-dbll (e.g., Beovu) was approved by the U.S. Food and Drug Administration (FDA) on October 8, 2019, for the treatment of wet age-related macular degeneration.
 
Brolucizumab-dbll (e.g., Beovu) was approved by the U.S. Food and Drug Administration (FDA) on June 1, 2022, for the treatment of diabetic macular edema.
 
Faricimab-svoa (e.g., Vabysmo) was approved by the U.S. Food and Drug Administration (FDA) on January 28, 2022, for the treatment of wet age-related macular degeneration and diabetic macular edema.
 
Faricimab-svoa (e.g., Vabysmo) was approved by the U.S. Food and Drug Administration (FDA) on October 26, 2023, for the treatment of retinal vein occlusion.
 
Faricimab-svoa (e.g., Vabysmo) prefilled syringe formulation was approved by the U.S. Food and Drug Administration (FDA) on July 4, 2024.
 
Afilbercept-abzv (e.g., Enzeevu) was approved by the U.S. Food and Drug Administration (FDA) on August 12, 2024, for the treatment of Neovascular (wet) Age-Related Macular Degeneration (AMD).
 
Afilbercept-mrbb (e.g., Ahzantive) was approved by the U.S. Food and Drug Administration (FDA) on June 28, 2024, for the treatment of Neovascular (wet) Age-Related Macular Degeneration (AMD), Macular Edema Following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR).
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
For use of bevacizumab as a VEGF inhibitor, see Coverage Policy 2024021, Bevacizumab (e.g., Avastin) and Biosimilars for Ophthalmic Use.
 
Prior Approval is required for brolucizumab (e.g., Beovu), afilbercept-abzv (e.g., Enzeevu), and afilbercept-mrbb (e.g., Ahzantive).
 
Effective January 1, 2026, Prior Approval is required for a Aflibercept (e.g., Eylea), Aflibercept (e.g., Eylea HD), and Afibercept-jbvf (e.g., Yesafili).
 
This policy does not address use of ophthalmic bevacizumab. Please see policy 2024021.
 
Approval timeframes may differ for members/participants of Self-Insured plans.
 
Effective January 1, 2026
 
Select products (e.g., Byooviz, Cimerli, Lucentis, Pavblu, Vabysmo) are preferred.
 
Preferred Products:
 
HCPCS         Brand Name         Generic Name
 
Q5124          Byooviz                  Ranibizumab-nuna
J2778           Lucentis                 Ranibizumab
Q5147          Pavblu                    Afilbercept-ayyh
J2777           Vabysmo                Faricimab-svoa
 
Non-Preferred Products:
 
HCPCS        Brand Name          Generic Name
 
Q5150          Ahzantive               Aflibercept-mrbb
J0179           Beovu                    Brolucizumab-dbll
Q5128          Cimerli                   Ranibizumab-eqrn
Q5149          Enzeevu                 Afilbercept-abzv
J0178           Eylea                     Aflibercept
J0177           Eylea HD               Aflibercept
Q5153          Opuviz                   Aflibercept-yszy
Q5155          Yesafili                  Afibercept-jbvf
 
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
 
1. The individual has a documented serious adverse event to all preferred products that required medical intervention AND the prescriber has completed and submitted an FDA MedWatch Adverse Event Reporting Form for each event (the prescriber must provide a copy of the completed MedWatch form. Authorizations will not be considered unless the form is completed and submitted to the FDA); OR
2. None of the preferred products have an FDA approved indication that is requested, and the requested non-preferred product has the FDA approved indication that is requested.
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive, Yesafili) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
For FDA labeled indications, Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
 
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Individual is using vascular epithelial growth factors for ophthalmologic indication including but not limited to:
a. Macular edema:
i. Diabetic macular edema which may include diabetic retinopathy [AAO 2019]; OR
ii. Branch retinal vein occlusion macular edema [AAO 2019]; OR
iii. Central retinal vein occlusion macular edema [AAO 2019]; OR
b. Age-related wet (neovascular) macular degeneration [AHFS); OR
c. Diabetic retinopathy with or without macular edema [AOO 2019]:
i. Proliferative retinopathy; OR
ii. Non-proliferative retinopathy moderate-severe; OR
d. Choroidal neovascularization with:
i. Myopic degeneration [AAO Consensus 2017]; OR
ii. Choroiditis (e.g., associated with histoplasmosis); OR
e. Retinopathy of prematurity; OR
2. Individual is NOT using vascular epithelial growth factors for sickle cell retinopathy.
 
CONTINUED APPROVAL for up to 12 months:
 
1. Individual continues to meet initial approval criteria; AND
2. Individual is NOT using vascular epithelial growth factors for sickle cell retinopathy.
 
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
 
In ophthalmology, vascular epithelial growth factors are typically given by transconjunctival intravitreal injections into the posterior segment of an eye. Intravitreal injections for retinal pathologies are typically administered at 4–6-week intervals, although this varies widely based on disease and response.
 
The recommended dose of ranibizumab (e.g., Byooviz, Cimerli, Lucentis) for age-related macular degeneration, diabetic macular edema, diabetic retinopathy, macular edema following retinal vein occlusion and myopic choroidal neovascularization is 0.5 milligram per eye once monthly for the first 4 doses followed by maintenance of 0.5 mg injection every 8 to 12 weeks on average with some individuals requiring every 4 weeks maintenance treatment.
 
Ranibizumab (e.g., Byooviz, Cimerli, Lucentis) is available as a 0.5 mg/ 0.05 mL pre-filled syringe of solution for injection.
 
Ranibizumab (e.g., Cimerli, Lucentis) is also available as a 0.3 mg/ 0.05 mL pre-filled syringe of solution for injection.
 
The recommended dose of faricimab (e.g., Vabysmo) for age-related macular degeneration, diabetic macular edema, and macular edema following retinal vein occlusion is 6 milligram per eye once monthly for the first 4 doses followed by maintenance of 6 mg injection every 8 to 12 weeks on average with some individuals requiring every 4 weeks maintenance treatment.
 
Faricimab (e.g., Vabysmo) is available as a 120 mg/ mL solution for injection.
 
The recommended dose of brolucizumab (e.g., Beovu) for age-related macular degeneration, diabetic macular edema is induction of 6 milligram per eye once monthly for the first 3 doses followed by maintenance of 6 mg injection every 8 to 12 weeks.
 
Brolucizumab (e.g., Beovu) is available as a 6 mg/0.05 mL pre-filled syringe of solution for injection.
 
The recommended dose of aflibercept (e.g., Eylea) for age-related macular degeneration, diabetic macular edema, diabetic retinopathy, macular edema following retinal vein occlusion and choroidal neovascularization due to presumed ocular histoplasmosis syndrome is 2 milligram per eye based on central subfield thickness and visual acuity evaluations.
 
The recommended dose of aflibercept (e.g., Eylea) for retinopathy of prematurity is 0.4 milligram per eye via intravitreal injection which can be repeated with at least 10-day interval between treatments in the same eye.
 
The recommended dose of aflibercept (e.g., Eylea HD) for age-related macular degeneration, diabetic macular edema, diabetic retinopathy is induction of 8 milligram per eye every 4 weeks for 3 doses, followed by maintenance of 8 mg injection every 8 to 12 weeks.
 
Aflibercept (e.g., Eylea) is available as a 2 mg/0.05 mL pre-filled syringe of solution for injection. Aflibercept (e.g., Eylea HD) is available as an 8 mg/0.07 mL vial of solution for injection.
 
The recommended dose of aflibercept (e.g., Pavblu) for neovascular (wet) Age-Related Macular Degeneration is 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg via intravitreal injection once every 8 weeks.
 
The recommended dose of aflibercept (e.g., Pavblu) for macular edema following retinal vein occlusion is 2 mg administered by intravitreal injection once every 4 weeks.
 
The recommended dose of aflibercept (e.g., Pavblu) for diabetic macular edema and diabetic retinopathy is 2 mg administered by intravitreal injection every 4 weeks.
 
Aflibercept (e.g., Pavblu) is available as a 2 mg (0.05 mL of 40 mg/mL) solution in a single-dose prefilled syringe or single-dose vial.
 
The recommended dose of afilbercetp-abzv (e.g., Enzeevu) for neovascular (wet) Age-Related Macular Degeneration is 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg via intravitreal injection once every 8 weeks.
 
Afilbercetp-abzv (e.g., Enzeevu) is available as a 2 mg (0.05 mL of 40 mg/mL) solution in a single-dose prefilled syringe or single-dose vial.
 
The recommended dose of afilbercept-mrbb (e.g., Ahzantive) for neovascular (wet) Age-Related Macular Degeneration is 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg via intravitreal injection once every 8 weeks.
 
The recommended dose of afilbercept-mrbb (e.g., Ahzantive) for macular edema following Retinal Vein Occlusion is 2 mg administered by intravitreal injection once every 4 weeks.
 
The recommended dose of afilbercept-mrbb (e.g., Ahzantive) for diabetic macular edema and diabetic retinopathy is 2 mg administered by intravitreal injection every 4 weeks for the first 5 injections followed by 2 mg via intravitreal injection one every 8 weeks.
 
Afilbercept-mrbb (e.g., Ahzantive) is available as 2 mg (0.05 mL of 40 mg/mL) solution in a single-dose vial.
 
Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive) should be administered as an intravitreal injection by a healthcare professional.
 
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
 
Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective March 12, 2025 to December 31, 2025
 
Select products (e.g., Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo) are preferred.
 
Preferred Products:
 
HCPCS     Brand Name         Generic Name
J2777        Vabysmo             Faricimab-svoa
J2778        Lucentis              Ranibizumab
Q5124       Byooviz               Ranibizumab-nuna
Q5128       Cimerli                Ranibizumab-eqrn
J0177        Eylea HD            Aflibercept
J0178        Eylea                 Aflibercept
J3590        Pavblu                Afilbercept-ayyh
 
Non-Preferred Products:
 
HCPCS     Brand Name        Generic Name
J0179        Beovu                 Brolucizumab-dbll
Q5149       Enzeevu             Afilbercept-abzv
Q5150       Ahzantive           Aflibercept-mrbb
Q5153       Opuviz               Aflibercept-yszy
 
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
1. The individual has a documented serious adverse event to all preferred products that required medical intervention AND the prescriber has completed and submitted an FDA MedWatch Adverse Event Reporting Form for each event (the prescriber must provide a copy of the completed MedWatch form. Authorizations will not be considered unless the form is completed and submitted to the FDA); OR
2. None of the preferred products have an FDA approved indication that is requested, and the requested non-preferred product has the FDA approved indication that is requested.
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
For FDA labeled indications, Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
 
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Individual is using vascular epithelial growth factors for ophthalmologic indication including but not limited to:
a. Macular edema:
i. Diabetic macular edema which may include diabetic retinopathy [AAO 2019]; OR
ii. Branch retinal vein occlusion macular edema [AAO 2019]; OR
iii. Central retinal vein occlusion macular edema [AAO 2019]; OR
b. Age-related wet (neovascular) macular degeneration [AHFS); OR
c. Diabetic retinopathy with or without macular edema [AOO 2019]:
i. Proliferative retinopathy; OR
ii. Non-proliferative retinopathy moderate-severe; OR
d. Choroidal neovascularization with:
i. Myopic degeneration [AAO Consensus 2017]; OR
ii. Choroiditis (e.g., associated with histoplasmosis); OR
e. Retinopathy of prematurity; OR
2. Individual is NOT using vascular epithelial growth factors for sickle cell retinopathy.
 
CONTINUED APPROVAL for up to 12 months:
 
1. Individual continues to meet initial approval criteria; AND
2. Individual is NOT using vascular epithelial growth factors for sickle cell retinopathy.
 
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
 
In ophthalmology, vascular epithelial growth factors are typically given by transconjunctival intravitreal injections into the posterior segment of an eye. Intravitreal injections for retinal pathologies are typically administered at 4–6-week intervals, although this varies widely based on disease and response.
 
The recommended dose of ranibizumab (e.g., Byooviz, Cimerli, Lucentis) for age-related macular degeneration, diabetic macular edema, diabetic retinopathy, macular edema following retinal vein occlusion and myopic choroidal neovascularization is 0.5 milligram per eye once monthly for the first 4 doses followed by maintenance of 0.5 mg injection every 8 to 12 weeks on average with some individuals requiring every 4 weeks maintenance treatment.
 
Ranibizumab (e.g., Byooviz, Cimerli, Lucentis) is available as a 0.5 mg/ 0.05 mL pre-filled syringe of solution for injection.
 
Ranibizumab (e.g., Cimerli, Lucentis) is also available as a 0.3 mg/ 0.05 mL pre-filled syringe of solution for injection.
 
The recommended dose of faricimab (e.g., Vabysmo) for age-related macular degeneration, diabetic macular edema, and macular edema following retinal vein occlusion is 6 milligram per eye once monthly for the first 4 doses followed by maintenance of 6 mg injection every 8 to 12 weeks on average with some individuals requiring every 4 weeks maintenance treatment.
 
Faricimab (e.g., Vabysmo) is available as a 120 mg/ mL solution for injection.
 
The recommended dose of brolucizumab (e.g., Beovu) for age-related macular degeneration, diabetic macular edema is induction of 6 milligram per eye once monthly for the first 3 doses followed by maintenance of 6 mg injection every 8 to 12 weeks.
 
Brolucizumab (e.g., Beovu) is available as a 6 mg/0.05 mL pre-filled syringe of solution for injection.
 
The recommended dose of aflibercept (e.g., Eylea) for age-related macular degeneration, diabetic macular edema, diabetic retinopathy, macular edema following retinal vein occlusion and choroidal neovascularization due to presumed ocular histoplasmosis syndrome is 2 milligram per eye based on central subfield thickness and visual acuity evaluations.
 
The recommended dose of aflibercept (e.g., Eylea) for retinopathy of prematurity is 0.4 milligram per eye via intravitreal injection which can be repeated with at least 10-day interval between treatments in the same eye.
 
The recommended dose of aflibercept (e.g., Eylea HD) for age-related macular degeneration, diabetic macular edema, diabetic retinopathy is induction of 8 milligram per eye every 4 weeks for 3 doses, followed by maintenance of 8 mg injection every 8 to 12 weeks.
 
Aflibercept (e.g., Eylea) is available as a 2 mg/0.05 mL pre-filled syringe of solution for injection. Aflibercept (e.g., Eylea HD) is available as an 8 mg/0.07 mL vial of solution for injection.
 
The recommended dose of aflibercept (e.g., Pavblu) for neovascular (wet) Age-Related Macular Degeneration is 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg via intravitreal injection once every 8 weeks.
 
The recommended dose of aflibercept (e.g., Pavblu) for macular edema following retinal vein occlusion is 2 mg administered by intravitreal injection once every 4 weeks.
 
The recommended dose of aflibercept (e.g., Pavblu) for diabetic macular edema and diabetic retinopathy is 2 mg administered by intravitreal injection every 4 weeks.
 
Aflibercept (e.g., Pavblu) is available as a 2 mg (0.05 mL of 40 mg/mL) solution in a single-dose prefilled syringe or single-dose vial.
 
The recommended dose of afilbercetp-abzv (e.g., Enzeevu) for neovascular (wet) Age-Related Macular Degeneration is 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg via intravitreal injection once every 8 weeks.
 
Afilbercetp-abzv (e.g., Enzeevu) is available as a 2 mg (0.05 mL of 40 mg/mL) solution in a single-dose prefilled syringe or single-dose vial.
 
The recommended dose of  afilbercept-mrbb (e.g., Ahzantive) for neovascular (wet) Age-Related Macular Degeneration is 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg via intravitreal injection once every 8 weeks.
 
The recommended dose of  afilbercept-mrbb (e.g., Ahzantive) for macular edema following Retinal Vein Occlusion is 2 mg administered by intravitreal injection once every 4 weeks.
 
The recommended dose of  afilbercept-mrbb (e.g., Ahzantive) for diabetic macular edema and diabetic retinopathy is 2 mg administered by intravitreal injection every 4 weeks for the first 5 injections followed by 2 mg via intravitreal injection one every 8 weeks.
 
Afilbercept-mrbb (e.g., Ahzantive) is available as 2 mg (0.05 mL of 40 mg/mL) solution in a single-dose vial.
 
Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive) should be administered as an intravitreal injection by a healthcare professional.
 
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
 
Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Vascular Epithelial Growth Factors for Ophthalmic use (e.g., Beovu, Byooviz, Cimerli, Eylea, Eylea HD, Lucentis, Pavblu, Vabysmo, Enzeevu, Ahzantive), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to March 12, 2025 is not online. If you would like a hardcopy print, please email:    codespecificinquiry@arkbluecross.com
Rationale:
Solomon et al evaluated the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.10 A database search identified 12 randomized controlled trials which included 5496 patients with neovascular AMD. Patients treated with any of the three anti-VEGF agents more often experienced improved vision, less often lost vision, and were less likely to be legally blind than patients treated with control interventions after one year of treatment. Additionally, these patients also showed improvements in structural areas of the eye that doctors use to monitor disease progression and treatment response compared with untreated patients. Compared with control treatments, treatment with ranibizumab or bevacizumab yielded larger improvements than pegaptanib. No trial compared pegaptanib directly with other anti-VEGF agents. When bevacizumab and ranibizumab were compared with each other, there were no major differences with respect to vision-related outcomes; there was, however, a large difference in cost between the two agents. Inflammation and increased pressure in the eye were the most common vision-related adverse events with anti-VEGF agents. Endophthalmitis was reported in < 1% of anti-VEGF-treated patients and no cases were reported in control groups. The occurrence of serious adverse health effects, such as high blood pressure and internal bleeding, was comparable across anti-VEGF-treated groups and control groups; however, the number of events was small relative to the number of people in the studies making it difficult to detect any meaningful differences between groups. Few data were available for visual function (e.g., reading speed and critical print size), quality of life, and economic outcomes. The overall quality of the evidence was very good, with most trials having an overall low risk of bias. The results of the review indicated the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes.
 
Age-related Macular Degeneration (neovascular with CNV): The sham injection/untreated arm of the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) trial showed vision loss of 14.9 letters from baseline over 24 months, which is often quoted as the natural history of neovascular AMD (Rosenfeld et al, 2006). The Comparison of Age-related Macular Degeneration Treatments Trials (CATT) did not have an untreated arm, it was perhaps the most well-structured clinical trial involving bevacizumab and showed a 7.8 letter gain from baseline with monthly administration (Martin et al, 2012). The Inhibit VEGF in the Age-Related Choroidal Neovascularization (IVAN) trial has echoed this positive result (Chakravarty et al, 2013).
 
Diabetic Macular Edema (DME): The Pan-American Collaborative Retina Study Group (PACORES) trial compared monthly intravitreal bevacizumab with macular focal-grid laser photocoagulation (standard of care at that time) and showed an average of 11.86 letters gained with bevacizumab and 3.66 letters gained with focal grid laser over 24-months (Arevalo et al, 2013).
 
The incidence of serious systemic adverse effects is rare with both intravitreal bevacizumab and ranibizumab (Johnson et al, 2013). The large head-to-head clinical trials show no statistical difference in serious arteriothrombotic events or all-cause death between bevacizumab and ranibizumab (CATT, 2011; Chakravarty et al, 2013).
CPT/HCPCS:
J0177Injection, aflibercept hd, 1 mg
J0178Injection, aflibercept, 1 mg
J0179Injection, brolucizumab dbll, 1 mg
J2777Injection, faricimab-svoa, 0.1 mg
J2778Injection, ranibizumab, 0.1 mg
J3590Unclassified biologics
Q5124Injection, ranibizumab-nuna, biosimilar, (byooviz), 0.1 mg
Q5128Injection, ranibizumab-eqrn (cimerli), biosimilar, 0.1 mg
Q5147Injection, aflibercept ayyh (pavblu), biosimilar, 1 mg
Q5149Injection, aflibercept abzv (enzeevu), biosimilar, 1 mg
Q5150Injection, aflibercept mrbb (ahzantive), biosimilar, 1 mg
Q5153Injection, aflibercept yszy (opuviz), biosimilar, 1 mg
Q5155Injection, aflibercept jbvf (yesafili), biosimilar, 1 mg
References: Bakri SJ, Thorne JE, Ho AC, Ehlers JP, Schoenberger SD, Yeh S, Kim SJ.(2019) Safety and efficacy of anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2019 Jan 1;126(1):55-63.

Beovu(2024) Package Insert East Hanover, NJ: Novartis Pharmaceuticals Corporation;

Byoovi(2023) Package Insert Cambridge, MA: Biogen Inc.;

CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL et al.(2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-908. 

Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA et al.(2013) Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-67.

Cimerli(2024) Package Insert Redwood City, CA: Coherus BioSciences Inc.; 2024.

Eylea HD(2023) Package Insert Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2023.

Eylea(2023) Package Insert Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2023.

Johnson D, Sharma S.(2013) Ocular and systemic safety of bevacizumab and ranibizumab in patients with neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2013;24(3):205-12.

Lanzetta P, Loewenstein A, Vision Academy Steering Committee.(2017) Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti–vascular endothelial growth factor therapy of macular diseases. Graefe's Archive for Clinical and Experimental Ophthalmology. 2017 Jul;255:1259-73.

Lucentis(2024) Package Insert South San Francisco, CA: Genentech Inc.; 2024.

Martin D, Maguire M, Fine S, Ying G, Jaffe G, Grunwald J et al.(2012) Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology Jul. 2012;119(7):1388-98.

Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al.(2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-31. 

Solomon SD, Lindsley K, Vedula SS, et al.(2014) Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014 Aug 29;8:CD005139.

Vabysmo(2024) Package Insert South San Francisco, CA: Genentech Inc.; 2024.

Wykoff CC, Brown DM, Chen E, Major JC, Croft DE, Mariani A et al.(2013) SAVE (Super-dose anti-VEGF) trial: 2.0 mg ranibizumab for recalcitrant neovascular age-related macular degeneration: 1-year results. Ophthalmic surgery, lasers & imaging retina. 2013;44(2):121-6.
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