EYLEA, Aflibercept Form

Aflibercept (Eylea®, Eylea® HD) is a vascular endothelial growth factor (VEGF) inhibitor. FDA Approved Indication(s) Eylea is indicated for the treatment of patients with: • Neovascular (wet) age-related macular degeneration (nAMD) • Macular edema following retinal vein occlusion (RVO) • Diabetic macular edema (DME) • Diabetic retinopathy (DR)
• Retinopathy of prematurity (ROP) Eylea HD is indicated for the treatment of patients with: • nAMD • DME • DR Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Eylea and Eylea HD are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Adult Ophthalmic Diseases (must meet all):

1. Diagnosis of one of the following (a, b, c, or d): a. nAMD; b. Macular edema following RVO and request is for Eylea®; c. DME; d. DR;

2. Prescribed by or in consultation with an ophthalmologist;

   3. Age ≥ 18 years;
   4. For all indications, except for DME in members with baseline best corrected visual acuity (BCVA) 20/50 or worse: Failure of bevacizumab intravitreal solution, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for bevacizumab intravitreal solution. Requests for IV formulations of Avastin, Mvasi, and Zirabev will not be approved. Page 1 of 10

   CLINICAL POLICY Aflibercept

3. Dose does not exceed one of the following (a or b): a. For Eylea, one of the following (i, ii, or iii): i. nAMD: 2 mg (1 vial) every 4 weeks for the first 3 months, then every 8 weeks thereafter; ii. DME and DR: 2 mg (1 vial) every 4 weeks for the first 5 injections, then every 8 weeks thereafter;
   iii. RVO: 2 mg (1 vial) every 4 weeks; b. For Eylea HD, one of the following (i or ii): i. nAMD and DME: 8 mg (1 vial) every 4 weeks for the first 3 doses, followed by 8 mg (1 vial) every 8-16 weeks thereafter; ii. DR: 8 mg (1 vial) every 4 weeks for the first 3 doses, followed by 8 mg (1 vial) every 8-12 weeks thereafter. Approval duration: 6 months B. Retinopathy of Prematurity (must meet all):
4. Request is for Eylea;
   2. Diagnosis of ROP with one of the following retinal findings (a, b, or c):
      a. Zone I stage 1+, 2+, 3, or 3+;
      b. Zone II stage 2+ or 3+;
      c. Aggressive posterior ROP (AP-ROP);
5. Prescribed by or in consultation with an ophthalmologist;
   
   4. Member meets all of the following (a and b): a. Gestational age at birth ≤ 32 weeks OR birth weight ≤ 1,500 g;
      b. Body weight > 800 g on day of treatment initiation;
6. Failure of bevacizumab intravitreal solution, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for bevacizumab intravitreal solution. Requests for IV formulations of Avastin, Mvasi, and Zirabev will not be approved.
7. Dose does not exceed 0.4 mg one time, followed by an optional second and third dose of 0.4 mg at least 10 days apart for the same eye.
   Approval duration: 6 months (up to 3 doses per eye per lifetime) C. Other diagnoses/indications (must meet 1 or 2):
8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

9. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line Page 2 of 10

   CLINICAL POLICY Aflibercept of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Adult Ophthalmic Diseases (must meet all):

10. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
11. Member is responding positively to therapy as evidenced by one of the following (a, b, c, or d): a. Detained neovascularization;
    b. Improvement/stabilization in visual acuity;
    c. Maintenance of corrected visual acuity from prior treatment; d. Supportive findings from optical coherence tomography or fluorescein angiography;

12. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. For Eylea, one of the following (i or ii): i. nAMD, DME and DR: One of the following (1 or 2): 1) Dose does not exceed 2 mg (1 vial) every 8 weeks; 2) Member meets both of the following (a and b): a) Documentation supports evidence of continued disease activity; b) New dose does not exceed 2 mg (1 vial) every 4 weeks; ii. RVO: 2 mg (1 vial) every 4 weeks; b. For Eylea HD, one of the following (i or ii): i. nAMD and DME: One of the following (1 or 2): 1) Dose does not exceed 8 mg (1 vial) every 16 weeks; 2) Member meets both of the following (a and b): a) Documentation supports evidence of continued disease activity; b) New dose does not exceed 8 mg (1 vial) every 8 weeks; ii. DR: One of the following (1 or 2): 1) Dose does not exceed 8 mg (1 vial) every 12 weeks; 2) Member meets both of the following (a and b): a) Documentation supports evidence of continued disease activity; b) New dose does not exceed 8 mg (1 vial) every 8 weeks. Approval duration: 6 months Page 3 of 10

    CLINICAL POLICY Aflibercept B. Retinopathy of Prematurity

13. Reauthorization beyond the first three doses is not permitted. Member must meet initial approval criteria.
    Approval duration: Not applicable C. Other diagnoses/indications (must meet 1 or 2):
14. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

15. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AP: aggressive posterior BCVA: best corrected visual acuity DME: diabetic macular edema DR: diabetic retinopathy
    FDA: Food and Drug Administration nAMD: neovascular (wet) age-related macular degeneration ROP: retinopathy of prematurity RVO: retinal vein occlusion VEGF: vascular endothelial growth factor Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose 2.5 mg/month bevacizumab (Avastin) nAMD: 1.25 to 2.5 mg administered by intravitreal injection every 4 weeks. Page 4 of 10

    CLINICAL POLICY Aflibercept Drug Name Dosing Regimen Macular edema secondary to RVO: 1 mg to 2.5 mg administered by intravitreal injection every 4 weeks DR: 1.25 mg administered by intravitreal injection every 6 weeks DME: 1.25 mg administered by intravitreal injection every 6 weeks ROP:
    Varies depending treatment regimen (i.e., followed by vitrectomy, laser therapy) Dose Limit/ Maximum Dose 2.5 mg/month 1.25 mg/6 weeks 1.25 mg/6 weeks Varies Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Ocular or periocular infection o Active intraocular inflammation o Hypersensitivity • Boxed warning(s): none reported Appendix D: General Information • In the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW)-1 trial, the difference in the number of patients who lost fewer than 15 letters at 52 weeks between Eylea every 8 weeks compared to Lucentis was 0.6% (95.1% CI -0.32, 4.4). In terms of the number of patients who gained at least 15 letters, the mean difference between Eylea every 8 weeks was 6.6% (95.1% CI -1.0, 14.1). There were no adverse events that were found to be significant from the Lucentis arm.
    In a trial comparing Eylea, Avastin and Lucentis, the Diabetic Retinopathy Clinical Research Network found in patients with diabetic macular edema that when the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with Eylea, 7.5 with Avastin, and 8.3 with Lucentis (p > 0.50 for each pair wise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with Eylea, 11.8 with Avastin, and 14.2 with Lucentis (p < 0.001 for Eylea vs. Avastin, p = 0.003 for Eylea vs. Lucentis, and p = 0.21 for Lucentis vs. Avastin). In clinical trials for the treatment of nAMD, DME, and DR, additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks as a maintenance dose, compared to every 8 weeks. Maintenance dosing at every 8 weeks should be attempted before increasing the intravitreal injection frequency to every 4 weeks. In Eylea HD PULSAR and PHOTON studies of patients with nAMD and DME, patients could be treated as frequently as every 8 weeks based on protocol-defined visual and anatomic criteria, starting at week 16. For both the every 12 week- and every 16 week- • • • Page 5 of 10

    CLINICAL POLICY Aflibercept Eylea HD treated groups, treatments were shown to be non-inferior and clinically equivalent to Eylea 2mg every 8 week treatment with respect to the change in BCVA score at week 48 using the pre-specified non-inferiority margin of 4 letters. • From the Eylea HD PHOTON study, DR data was derived to support FDA approval for continued dosing every 8 to 12 weeks following the first 3 doses. For this measure, the group that received Eylea HD every 12 weeks met the noninferiority margin of 10% in comparison to Eylea 2 mg every 8 weeks; however, the group that received Eylea HD every 16 weeks did not. V. Dosage and Administration
    Drug Name Indication Dosing Regimen aflibercept (Eylea) nAMD 2 mg (1 vial) administered by intravitreal injection once a month for 3 months then 2 mg every 2 months Maximum Dose 2 mg/month Although Eylea may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). 2 mg (1 vial) administered by intravitreal injection once every 4 weeks (monthly) 2 mg (1 vial) administered by intravitreal injection once a month for the first 5 injections, followed by 2 mg via intravitreal injection once every 2 months Although Eylea may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). 0.4 mg administered by intravitreal injection once, followed by an optional Page 6 of 10 2 mg/month 2 mg/month 0.4 mg/dose aflibercept (Eylea) aflibercept (Eylea) Macular edema following RVO
    DME, DR
    aflibercept (Eylea) ROP

    CLINICAL POLICY Aflibercept Drug Name Indication Dosing Regimen aflibercept (Eylea HD) nAMD, DME aflibercept (Eylea HD) DR two additional doses spaced at least 10 days apart for the same eye. 8 mg administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg via intravitreal injection once every 8 to 16 weeks, +/- 1 week 8 mg administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg via intravitreal injection once every 8 to 12 weeks, +/- 1 week Maximum Dose 0.8 mg/dose 0.8 mg/dose VI. Product Availability
    Drug Name aflibercept (Eylea) Availability Single-dose vial and pre-filled syringe for intravitreal injection:
    2 mg/0.05 mL solution
    aflibercept (Eylea HD) Single-dose vial for intravitreal injection: 8 mg/0.07 mL solution VII.