Ranibizumab Products Clinical Policy Form

PART B DRUG MEDICAL/PHARMACY Effective Date May 15, 2025 Policy # RANIBIZUMAB PRODUCTS BYOOVIZ; CIMERLI; LUCENTIS; SUSVIMO (IMPLANT) Ranibizumab Products Review Date Applicable to: 02/25/2025 Medicare Advantage Commercial Elevance Health HMO Blue Shield Trio Approver’s Name & Title QI & UM Drug Subcommittee Aspire Health Plan applies medical drug clinical criteria as a reference for medical policy information only. Federal and state laws or requirements, contract language, and Plan benefit may take precedence over the application of these clinical criteria. Please consult the applicable certificate or contract for benefit details. This policy is subject to revision at the discretion of the Plan and is therefore subject to change. Refer to the disclaimer section below for more information. POLICY This policy outlines the coverage of intravitreal ranibizumab for ophthalmic use. NOTE: Any U.S. Food and Drug Administration approved and launched ranibizumab biosimilar product not listed by name in this policy will be considered non-preferred until reviewed by Aspire Health APPLICABLE HCPCS Lucentis (ranibizumab) • J2778: Injection, ranibizumab, 0.1 mg; 1 billable unit = 0.1 mg (Lucentis Only) • Available as: 0.3 mg/0.05 mL and 0.5 mg/0.05 mL single-use vials/prefilled syringe Byooviz (ranibizumab-nuna) • Q5124: Injection, ranibizumab-nuna, biosimilar, (Byooviz), 0.1 mg; 1 billable unit = 0.1 mg (Byooviz Only) • Available as: 0.5 mg/0.05 mL single-use vial. Cimerli (ranibizumab-eqrn) • Q5128: Injection, ranibizumab-eqrn, biosimilar (cimerli), 0.1 mg; 1 billable unit = 0.1 mg (Cimerli Only) • Available as: 0.3 mg/0.05 mL and 0.5 mg/0.05 mL single-use vials. Susvimo (ranibizumab intravitreal implant) • J2779: Injection, ranibizumab, via intravitreal implant (Susvimo), 0.1 mg; 1 billable unit = 0.1 mg

• C1889: Implantable/insertable device, not otherwise classified (Used for Susvimo Ocular Implant Device) • Available as: 100 mg/mL single-dose glass vial. Interchangeability Status Cimerli (ranibizumab-eqrn) is FDA-approved as interchangeable with Lucentis for all five FDA-approved indications (as of August 2022). This designation allows for pharmacy-level substitution without prescriber intervention, subject to state laws. CLINICAL CRITERIA I. INITIAL CRITERIA Ranibizumab (Lucentis or biosimilar) may be authorized when ALL of the following are met with documentation: 1. Request for ranibizumab treatment, as indicated by ONE of the following (1 OR 2): a. For Lucentis and ranibizumab biosimilars requests: Member must meet ONE of the following diagnosis • Diabetic macular edema (DME) • Diabetic retinopathy with macular edema • Macular edema following retinal vein occlusion (RVO) • Myopic choroidal neovascularization (mCNV) • Neovascular (wet, or exudative) age-related macular degeneration (nAMD) OR b. For Susvimo requests: Member has previously responded to at least two intravitreal injections of a vascular endothelial growth factor (VEGF) inhibitor medication (e.g., aflibercept, pegaptanib, brolucizumab, bevacizumab, ranibizumab). AND 2. Exclusion Criteria: a. Active intraocular or periocular infection b. Known hypersensitivity to ranibizumab or any of its components. c. Other ocular conditions that, in the clinical judgment of the treating physician, would preclude ranibizumab treatment or confound assessment of its effectiveness. AND 3. Ranibizumab is prescribed as monotherapy, or in combination with other ocular treatments (e.g., laser photocoagulation) as deemed medically necessary by the treating physician. NOTE: If used in combination with another VEGF inhibitor (i.e., aflibercept, ranibizumab, pegaptanib, bevacizumab) documentation supporting the medical necessity of the combined therapy must be provided; AND 4. For Susvimo requests: Member has not required removal of a Susvimo implant in the past; AND 5. Baseline best corrected visual acuity (BCVA) is assessed and documented prior to initiating treatment.

II. REAUTHORIZATION / CONTINUATION OF THERAPY CRITERIA Ranibizumab may be authorized for continuation of therapy when ALL of the following are met: 1. Member continues to meet the initial authorization criteria (as stated above); AND 2. Member has not experienced unacceptable adverse events from intravitreal injections of Ranibizumab (e.g., endophthalmitis and retinal detachments, increase in intraocular pressure, arterial thromboembolic events); AND 3. Positive response to therapy documented by ONE or more of the following: a. Improvement or stabilization in best corrected visual acuity (BCVA) b. Reduction in central retinal thickness (as measured by OCT) c. Other objective measures of disease activity as determined by the treating physician. OR Requests for supplemental treatment with Susvimo ONLY: Member has had an insufficient response during initial or maintenance therapy with Susvimo administered every 24 weeks and requires supplemental treatment with intravitreal ranibizumab (refer to ‘Appendix’ for Suvimo dosing and administration); AND 4. Documentation of administration records showing dates and eye(s) administered, along with documentation of member compliance with treatment plan. STEP THERAPY Step Therapy Does NOT Apply if: • The member is currently being treated with the requested medication. • The member has received the requested drug within the last 365 days. Step Therapy Applies if: • The member is new to therapy (i.e., has not received the requested drug in the last 365 days). A. PREFERRED PRODUCT(S): AVASTIN (no step therapy required) B. NON-PREFERRED PRODUCTS: Ranibizumab may be authorized when all of the clinical criteria above are met AND the member meets the following criteria for a non-preferred intravitreal VEGF antagonist: 1. Inadequate response to a trial of the preferred agent: bevacizumab (Avastin); or 2. History of contraindication or adverse event(s) to Avastin (bevacizumab); or 3. Member has been on the requested agent within the past 365 days; or 4. Member currently has a Susvimo ocular implant and requests supplemental injections with ranibizumab.

AHP-Ranibizumab Products DOSAGE AND AUTHORIZATION TIMEFRAMES 1. Recommended / Maximum Dose Indication Initial / Maintenance Dosing (per eye) Maximum Dosing Diabetic Macular Edema (DME);
Diabetic Retinopathy Lucentis (ranibizumab) and Cimerli (ranibizumab biosimilar) only Initial: 0.3 mg once a month Maintenance: After 3 consecutive monthly doses (if using the 0.5 mg dose), dosing interval may be extended. Lucentis and Cimerli only 0.3 mg per eye every month. Macular Edema following Retinal Vein Occlusion (RVO); Myopic Choroidal Neovascularization (mCNV) Lucentis and ranibizumab biosimilars Initial: 0.5 mg once a month for up to 3 months Maintenance: May be retreated if needed. Lucentis and ranibizumab biosimilars 0.5 mg per eye every month. Neovascular (Wet) Age-Related Macular Degeneration (AMD) Lucentis and ranibizumab biosimilars Initial: 0.5 mg per eye once a month for 3-4 months Maintenance: 0.5 mg per eye once every 1-3 months based on clinical response. Lucentis and ranibizumab biosimilars 0.5 mg per eye every month. Neovascular (Wet) AMD (Susvimo) Susvimo (ranibizumab intravitreal implant) Initial: 2 mg per eye via ocular implant every 24 weeks Maintenance: 0.5 mg per eye every 24 weeks while implant is in place, if needed. Note: Supplemental intravitreal injections (Lucentis) of 0.5 mg may be administered to the affected eye while the implant is in place, if needed. Susvimo 2 mg per eye via ocular implant every 24 weeks. 2. Authorization Period a. Authorization may be granted for up to 12 months and reauthorized based on continuation of therapy criteria. b. Frequency is considered excessive when services are performed more frequently than indicated in the FDA-approved labeling or generally accepted by guidelines. A documented rationale for additional services is required. c. Dosage and frequency must align with the FDA label or CMS-recognized compendia (for off-label use). Services exceeding the standard of care may be subjected to review. 3. Limitations Anti-VEGF Medication Use: a. It is not reasonable and necessary to inject more than one anti-VEGF medication (e.g., aflibercept, pegaptanib, brolucizumab, bevacizumab, ranibizumab, faricimab-svoa, etc.) in the same eye during the same treatment session. b. If different anti-VEGF medications are injected into each eye during the same date of

AHP-Ranibizumab Products service, the rationale must be documented in the medical record, and the appropriate billing modifier (RT for right eye and LT for left eye) must be appended to the correct drug. c. Intravitreal injections for macular edema more frequently than every 4 weeks (regardless of which drug is used) will not be covered. Concurrent Use of VEGF Inhibitors: The safety and effectiveness of combinational using more than one VEGF inhibitor in the same eye has not been established. This practice is not supported by clinical evidence or guidelines and is not considered the standard of care. DRUG INFORMATION PHARMACOLOGIC CATEGORY: Ophthalmic Agent; Vascular Endothelial Growth Factor (VEGF) Inhibitor
ROUTE OF ADMINISTRATION: Intravitreal Injection FDA-APPROVED INDICATIONS 1. Neovascular (wet) Age-related Macular Degeneration (AMD) • Approved for Lucentis, ranibizumab biosimilars, and Susvimo 2. Diabetic Macular Edema (DME) • Approved for Lucentis and Cimerli only 3. Diabetic Retinopathy (DR) • Approved for Lucentis and Cimerli only 4. Macular edema following retinal vein occlusion (RVO) • Approved for Lucentis and ranibizumab biosimilars 5. Myopic Choroidal Neovascularization (mCNV) • Approved for Lucentis and ranibizumab biosimilars) COMPENDIAL APPROVED (OFF-LABEL) USES: Retinopathy of prematurity (ROP), Type 1 CONTRAINDICATIONS: • Hypersensitivity to ranibizumab or any component of the formulation • Ocular or periocular infections • Active intraocular inflammation (implant only). BOXED WARNING: Susvimo (Implant) Endophthalmitis: The implant has been associated with a 3-fold higher rate of endophthalmitis compared to monthly intravitreal injections of ranibizumab. Many of these events were associated with conjunctival retractions or erosions. Appropriate conjunctival management and early detection with surgical repair of conjunctival retractions or erosions may reduce the risk of endophthalmitis. OTHER CONSIDERATIONS: Monitoring Parameters Prior to and during treatment: • Intraocular pressure (prior to and 30 minutes following injection via tonometry) • Optic nerve head perfusion assessment immediately following injection (recommended) • Signs of infection/inflammation (particularly during first week post-injection)

AHP-Ranibizumab Products • Retinal perfusion • Visual acuity For implant (Susvimo): • Dilated slit lamp examination and/or dilated indirect ophthalmoscopy before and after refill- exchange procedure to check for implant dislodgement • Routine monitoring of implant and overlying tissue for: ― Conjunctival blebs ― Conjunctival erosion ― Conjunctival retraction ― Endophthalmitis ― Implant dislocation ― Rhegmatogenous retinal detachment ― Vitreous hemorrhage CLINICAL SUMMARY / APPENDIX This clinical policy outlines the appropriate use of ranibizumab (including its biosimilars) for the treatment of retinal conditions, in alignment with the standard of care and guidelines from professional societies such as the American Academy of Ophthalmology (AAO) and the American Society of Retina Specialists (ASRS). The policy ensures that ranibizumab is used safely, effectively, and in accordance with evidence-based practices.
American Academy of Ophthalmology (AAO) Preferred Practice Patterns • Wet AMD: Ranibizumab is recommended as a first-line anti-VEGF therapy. Treatment typically involves an initial phase of monthly injections (0.5 mg) for 3-4 months, followed by a maintenance phase with individualized dosing intervals (e.g., treat-and-extend or as- needed regimens). • DME and DR: Ranibizumab (0.3 mg) is recommended for the treatment of DME and DR. Initial monthly injections are followed by individualized maintenance dosing based on clinical response. • RVO: Ranibizumab (0.5 mg) is effective for macular edema secondary to RVO. Treatment involves monthly injections until visual and anatomic stability is achieved, followed by as- needed dosing. American Society of Retina Specialists (ASRS) Guidelines • Anti-VEGF Therapy: Ranibizumab is a cornerstone of anti-VEGF therapy for retinal vascular diseases. The ASRS emphasizes individualized treatment plans, including treat- and-extend protocols, to optimize outcomes and reduce treatment burden. • Biosimilars: The use of ranibizumab biosimilars (e.g., Cimerli) is supported when they meet FDA approval standards for safety, efficacy, and interchangeability. FDA Labeling Ranibizumab dosing and administration must adhere to FDA-approved labeling: • Wet AMD: 0.5 mg monthly for 3-4 months, followed by individualized maintenance dosing. • DME and DR: 0.3 mg monthly, with potential for extended dosing intervals after initial treatment. • RVO and mCNV: 0.5 mg monthly, with retreatment as needed based on clinical response.

AHP-Ranibizumab Products REFERENCES Government Agency Centers for Medicare and Medicaid Services (CMS). Medicare coverage database (no National Coverage Determination identified; no applicable LCD identified). Available from CMS. Prescribing Information 1. Lucentis [package insert]. South San Francisco, CA; Genentech, Inc; March 2018. 2. Byooviz [package insert]. Cambridge, MA; Biogen, Inc; June 2022. 3. Cimerli [package insert]. Redwood City, CA; Coherus BioSciences, Inc; August 2022. 4. Susvimo (ranibizumab) [prescribing information]. South San Francisco, CA: Genentech Inc; April 2022. Peer-reviewed Literature, Guidelines, and Consensus 1. Flaxel CJ, et al. Age-Related Macular Degeneration. Preferred Practice Pattern [Internet] American Academy of Ophthalmology. 2019 Accessed at: http://www.aao.org/. 2. Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.: CD005139. DOI: 10.1002/14651858.CD005139.pub4. 3. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Age-Related Macular Degeneration. San Francisco, CA: American Academy of Ophthalmology; 2019. Available at: https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp. 4. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2020. Available at: https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp. 5. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Retinal Vein Occlusions. San Francisco, CA: American Academy of Ophthalmology; 2019. Available at: https://www.aao.org/preferred-practice-pattern/retinal-vein-occlusions-ppp. 6. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Macular Edema. San Francisco, CA: American Academy of Ophthalmology; 2021. Available at: https://www.aao.org/preferred-practice-pattern/macular-edema-ppp. 7. American Society of Retina Specialists. Guidelines for the Use of Anti-VEGF Agents in Retinal Diseases.

2022. Available at: https://www.asrs.org/clinical/clinical-guidelines. 8. American Society of Retina Specialists. Diabetic Retinopathy Clinical Guidelines. 2021. Available at: https://www.asrs.org/clinical/clinical-guidelines. 9. American Society of Retina Specialists. AMD Clinical Guidelines. 2021. Available at: https://www.asrs.org/clinical/clinical-guidelines.
2023. American Society of Retina Specialists. Retinal Vein Occlusion Clinical Guidelines. 2021. Available at: https://www.asrs.org/clinical/clinical-guidelines. IMPORTANT REMINDER This Medicare Part B Step Therapy Medical Necessity Guideline is for informational purposes only and does not constitute or replace professional medical advice. Physicians, hospitals, and other providers are responsible for administering and using drugs/biologicals in the most effective and clinically appropriate manner and are solely responsible for all medical care decisions. This guideline is not a substitute for clinical judgment or individualized patient care. Coverage determinations are based on the member's Evidence of Coverage (EOC), which contains specific coverage provisions, limitations, and exclusions. In the event of a conflict between this guideline and the member's EOC, the EOC will govern. Aspire Health Plan (AHP) adheres to applicable Medicare guidelines, including National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs), Local Coverage Articles (LCAs), and other relevant Medicare manuals published by the Centers for Medicare & Medicaid Services (CMS). Compliance with these guidelines is required where applicable. For the most current Medicare policies

AHP-Ranibizumab Products and coverage information, please refer to the CMS website at cms.gov and search the Medicare Coverage Database. All LCDs are the same for each state within a Jurisdiction. The Medicare Administrative Contractor (MAC) for California (Jurisdiction E) is Noridian. Active LCDs for JE Part B can be found on the Noridian Medicare website (noridianmedicare.com). In the event of a discrepancy between this guideline and a Medicare NCD or LCD, the NCD/LCD will govern. This guideline is used by AHP to determine coverage in the absence of applicable CMS Medicare guidelines. The Medicare source materials used to develop this guideline are referenced below. This document does not replace the official Medicare source materials, which provide detailed information on Medicare coverage requirements. In the event of a conflict between this document and Medicare source materials, the Medicare source materials will prevail. The inclusion of a code in this guideline does not guarantee coverage or reimbursement. Benefit coverage is determined by the member's specific plan document, applicable state and federal laws, and CMS guidelines. Other policies and standards may also apply. Providers are expected to maintain documentation to support coverage decisions and make it available upon request. POLICY HISTORY Version Date Summary of Changes 1 9/27/2023 New Policy 2 02/25/2025 Annual Review. The policy has been revised and reformatted to enhance clarity with no alteration to the intent or clinical criteria. References reviewed and policy updated where applicable. Effective 05/15/2025.