LUCENTIS, Ranibizumab Form

Ranibizumab (Lucentis®, Susvimo™), ranibizumab-nuna (Byooviz®), and ranibizumab-eqrn (Cimerli™) are vascular endothelial growth factor (VEGF) inhibitors. FDA Approved Indication(s) Byooviz is indicated for the treatment of: • Neovascular (wet) age-related macular degeneration (AMD) • Macular edema following retinal vein occlusion (RVO) • Myopic choroidal neovascularization (mCNV) Lucentis and Cimerli are indicated for the treatment of: • Neovascular (wet) AMD • Macular edema following RVO • Diabetic macular edema (DME) • Diabetic retinopathy (DR)
• mCNV Susvimo is indicated for the treatment of patients with neovascular (wet) AMD who have previously responded to at least two intravitreal injections of a VEGF inhibitor. 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 Byooviz, Cimerli, Lucentis, and Susvimo are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Ophthalmic Disease (must meet all):

1. Diagnosis of one of the following (a, b, c, d, or e): a. Neovascular (wet) AMD; b. Macular edema following RVO; c. DME; d. DR; e. mCNV;

2. Prescribed by or in consultation with an ophthalmologist;

   3. Age ≥ 18 years;
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   CLINICAL POLICY Ranibizumab and Biosimilars

3. 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
4. If request is for Susvimo, member meets both of the following (a and b): a. Member has previously responded to at least 2 intravitreal injections of a VEGF inhibitor (e.g., intravitreal bevazicumab); b. Request is for the treatment of neovascular (wet) AMD;
5. Dose does not exceed one of the following (a, b, or c): a. For DME or DR: 0.3 mg per month; b. For RVO or mCNV: 0.5 mg per month; c. For AMD, either i or ii: If request is for Byooviz, Cimerli, or Lucentis: 0.5 mg per month; i. ii. If request is for Susvimo: 2 mg per 6 months. Approval duration:
   mCNV: 3 months All other indications: 6 months B. Other diagnoses/indications (must meet 1 or 2):
6. 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
7. 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.
   II. Continued Therapy A. Ophthalmic Disease (must meet all):
8. 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);

9. Member is responding positively to therapy as evidenced by one of the following (a, b, c, or d): a. Detained neovascularization; Page 2 of 9

   CLINICAL POLICY Ranibizumab and Biosimilars b. Improvement in visual acuity; c. Maintenance of corrected visual acuity from prior treatment; d. Supportive findings from optical coherence tomography or fluorescein angiography;

10. If request is for a dose increase, new dose does not exceed one of the following (a, b, or c): a. For DME or DR: 0.3 mg per month; b. For RVO or mCNV: 0.5 mg per month; c. For AMD, either i or ii: If request is for Byooviz, Cimerli, or Lucentis: 0.5 mg per month; i. ii. If request is for Susvimo: 2 mg per 6 months. Approval duration:
    mCNV: 3 months All other indications: 6 months B. Other diagnoses/indications (must meet 1 or 2):
11. 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

12. 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 evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AMD: age-related macular degeneration DME: diabetic macular edema DR: diabetic retinopathy FDA: Food and Drug Administration mCNV: myopic choroidal neovascularization RVO: retinal vein occlusion VEGF: vascular endothelial growth factor
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    CLINICAL POLICY Ranibizumab and Biosimilars 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 Bevacizumab (Avastin) Neovascular (wet) AMD: 1.25 to 2.5 mg administered by intravitreal injection every 4 weeks Neovascular glaucoma: 1.25 mg administered by intravitreal injection every 4 weeks 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 mCNV: 0.05 mL initial intravitreal injection, followed by monthly evaluation for additional injections as needed Dose Limit/ Maximum Dose 2.5 mg/month 1.25 mg/month 2.5 mg/month 1.25 mg/6 weeks 1.25 mg/6 weeks 0.5 mL/month 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 Byooviz, Cimerli, Lucentis, Susvimo: ocular or periocular infections; hypersensitivity
    o Susvimo: active intraocular inflammation • Boxed warning(s): o Byooviz, Cimerli, Lucentis: none reported o Susvimo: associated with a 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab Appendix D: General Information • In the Comparison of AMD Treatments Trials study, the difference in mean visual acuity improvement for patients treated with Avastin compared to Lucentis was -1.4 letters (95% [CI],- 3.7 to 0.8) at two years. The proportion of patients with arteriothrombotic events was similar in the Lucentis-treated patients (4.7%) compared to the Avastin- treated patients (5.0%; p=0.89). The proportion of patients with one or more systemic serious adverse events was higher with Avastin (39.9%) than Lucentis (31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; p = 0.009). Serious systemic adverse events included Page 4 of 9

    CLINICAL POLICY Ranibizumab and Biosimilars • • • all-cause mortality, non-fatal stroke, non-fatal myocardial infarction, vascular death, venous thrombotic events and hypertension. In the ANti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularisation in AMD (ANCHOR) trial, the number of patients that lost fewer than 15 letters at 12 months was achieved by 96.4% of patients treated with Lucentis 0.5 mg compared to 64.3% of patients treated with Visudyne (p < 0.001). Rate of intraocular inflammation was higher for patients treated with Lucentis 0.5 mg at 15% compared to Visudyne at 2.8%. 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). V. Dosage and Administration
    Indication Dosing Regimen Neovascular (wet) AMD 0.5 mg (0.05 mL) administered by intravitreal injection once a month. Maximum Dose 0.5 mg/month Drug Name Ranibizumab (Lucentis), ranibizumab- nuna (Byooviz), ranibizumab- eqrn (Cimerli) Macular edema following RVO mCNV Ranibizumab (Lucentis), DME and DR with or Alternative dosing: Once monthly injections for three months followed by 4-5 doses dispersed among the following 9 months; or treatment may be reduced to one injection every 3 months after the first four injections if monthly injections are not feasible. 0.5 mg (0.05 mL) administered by intravitreal injection once a month. 0.5 mg (0.05 mL) administered by intravitreal injection once a month for up to 3 months. Patients may be retreated if needed. 0.3 mg (0.05 mL) administered by intravitreal injection once a month 0.5 mg/month 0.5 mg/month 0.3 mg/month Page 5 of 9

    CLINICAL POLICY Ranibizumab and Biosimilars Drug Name Ranibizumab- eqrn (Cimerli) Ranibizumab (Susvimo) Indication Dosing Regimen without DME Maximum Dose Neovascular (wet) AMD 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the Susvimo implant with refills every 24 weeks (approximately 6 months) 2 mg/6 months VI. Product Availability
    Drug Name Ranibizumab- nuna (Byooviz) Ranibizumab- eqrn (Cimerli) Ranibizumab (Lucentis) Ranibizumab (Susvimo) Availability Single-dose glass vial: 0.5 mg/0.05 mL Single-dose glass vials: 0.3 mg/0.05 mL, 0.5 mg/0.05 mL Single-use prefilled syringes: 0.3 mg/0.05 mL, 0.5 mg/0.05 mL Single-use glass vials: 0.3 mg/0.05 mL, 0.5 mg/0.05 mL Single-dose glass vial: 100 mg/mL VII.