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Clinical Policy: aflibercept (Eylea), ranibizumab (Lucentis), pegaptanib (Macugen), verteporfin (Visudyne) Reference Number: ERX.XXXX.## Effective Date: 05.17.17 Last Review Date: Line of Business: Commercial Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description The following are injectable agents for ocular conditions requiring prior authorization: aflibercept (Eylea®), ranibizumab (Lucentis®), pegaptanib (Macugen®), verteporfin (Visudyne®) FDA approved indication Indication Eylea Lucentis Macugen Neovascular (Wet) Age-Related Macular Degeneration (AMD) Macular Edema Following Retinal Vein Occlusion (RVO) Diabetic Macular Edema (DME) Diabetic Retinopathy in patients with DME Predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis Myopic Choroidal Neovascularization (mCNV) X = FDA indication X X X X X X X X X Visudyne X X Policy/Criteria Provider must submit documentation (including office chart notes and lab results) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Envolve Pharmacy Solutions™ that Eylea, Lucentis, Macugen, and Visudyne are medically necessary when the following criteria are met: I. Initial Approval Criteria A. Neovascular (Wet) Age-Related Macular Degeneration (must meet all): 1. Diagnosis of neovascular (wet) age-related macular degeneration (AMD); 2. Prescribed by or in consultation with an ophthalmologist; 3. Request is for Eylea, Lucentis, Macugen, or Visudyne; Page 1 of 9 CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin 4. For Lucentis or Eylea only: failure or clinically significant adverse effects to Avastin unless contraindicated or clinically significant adverse effects are experienced; 5. For Macugen or Visudyne only: failure or clinically significant adverse effects to two of the following drugs: Avastin, Lucentis, or Eylea; 6. Dose does not exceed: a. Eylea: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks for the first 3 months, then 2 mg (0.05 mL) via intravitreal injection once every 8 weeks; b. Lucentis: 0.5 mg (0.05 mL) via intravitreal injection once every month; c. Macugen: 0.3 mg (0.09 mL) via intravitreal injection once every 6 weeks; d. Visudyne: 6 mg/m2 body surface area via intravenous injection once every 3 months. Approval duration: Length of Benefit B. Macular Edema Following Retinal Vein Occlusion (must meet all): 1. Diagnosis of macular edema following retinal vein occlusion; 2. Prescribed by or in consultation with an ophthalmologist; 3. Request is for Eylea or Lucentis; 4. Dose does not exceed: a. Eylea: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks; b. Lucentis: 0.5 mg (0.05 mL) via intravitreal injection once every month. Approval duration: Length of Benefit C. Diabetic Macular Edema (must meet all): 1. Diagnosis of diabetic macular edema; 2. Prescribed by or in consultation with an ophthalmologist; 3. Request is for Eylea, Lucentis, or Macugen; 4. For Eylea and Lucentis only: failure or clinically significant adverse effects to Avastin unless contraindicated or clinically significant adverse effects are experienced 5. For Macugen only: failure or clinically significant adverse effects to Avastin, Lucentis, and Eylea unless contraindicated or clinically significant adverse effects are experienced 6. For Eylea only: patient’s baseline visual acuity is 20/50 or worse; 7. Dose does not exceed: a. Eylea: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks for the first 5 injections followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks; b. Lucentis: 0.3 mg (0.05 mL) per intravitreal injection once a month; c. Macugen: 0.3 mg (0.09 mL) via intravitreal injection once every 6 weeks; Approval duration: Length of Benefit D. Diabetic Retinopathy in Patients with Diabetic Macular Edema (must meet all): 1. Diagnosis of diabetic retinopathy with diabetic macular edema; Page 2 of 9 CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin 2. Prescribed by or in consultation with an ophthalmologist; 3. Request is for Eylea or Lucentis; 4. Dose does not exceed: a. Eylea: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks for the first 5 injections followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks; b. Lucentis: 0.3 mg (0.05 mL) per intravitreal injection once a month. Approval duration: Length of Benefit E. Predominantly Classic Subfoveal Choroidal Neovascularization due to Presumed Ocular Histoplasmosis (must meet all): 1. Diagnosis of predominantly classic Subfoveal Choroidal Neovascularization due to presumed ocular histoplasmosis; 2. Prescribed by or in consultation with an ophthalmologist; 3. Request is for Visudyne; 4. Dose does not exceed 6 mg/m2 body surface area via intravenous injection once every 3 months. Approval duration: Length of Benefit F. Myopic Choroidal Neovascularization (must meet all): 1. Diagnosis of myopic choroidal neovascularization; 2. Prescribed by or in consultation with an ophthalmologist; 3. Request is for Lucentis or Visudyne; 4. Dose does not exceed: a. Lucentis: 0.5 mg (0.05 mL) via intravitreal injection once a month for up to three months b. Visudyne: 6 mg/m2 body surface area via intravenous injection once every 3 months Approval duration: Length of Benefit G. Other diagnoses/indications 1. Refer to ERX.XXXX.## if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) II. Continued Therapy A. All Indications (must meet all): 1. Currently receiving medication via a health plan affiliated with Envolve Pharmacy Solutions or member has previously met initial approval criteria; 2. Documentation of positive response to therapy per one of the following: a. Detained neovascularization; b. Improvement in visual acuity; c. Maintenance of corrected visual acuity from prior treatment; d. Optical coherence tomography; 3. If request is for a dose increase, new dose does not exceed: a. Eylea: Page 3 of 9 CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin i. AMD: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks; ii. ME following RVO: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks; iii. DME and DR in Patients with DME: 2 mg (0.05 mL) via intravitreal injection once every 4 weeks for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks; b. Lucentis: i. AMD, RVO, and mCNV: 0.5 mg (0.05 mL) via intravitreal injection once every month; ii. DME and DR in Patients with DME: 0.3 mg (0.05 mL) via intravitreal injection once every month; c. Macugen: 0.3 mg (0.9 mL) via intravitreal injection every 6 weeks; d. Visudyne: 6 mg/m2 body surface area via intravenous injection once every 3 months. Approval duration: Length of Benefit B. Other diagnoses/indications (must meet 1 or 2): 1. Currently receiving medication via a health plan affiliated with Envolve Pharmacy Solutions and documentation supports positive response to therapy. Approval duration: Duration of request or 12 months (whichever is less); or 2. Refer to ERX.XXXX.## if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) 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 policy – ERX.XXXX.## 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 mCNV: Myopic choroidal neovascularization ME: Macular edema RVO: Retinal vein occlusion Appendix B: General Information This section is reserved for information that would be useful in making a coverage determination, such as definitions of therapeutic failure not listed in the usage guideline section. Page 4 of 9 CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin • • • • • 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 allcause 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 AgeRelated 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 the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial, the proportion of patients who lost fewer than 15 letters at week 54 for patients treated with Macugen 0.3 mg was 70%, compared to 55% for placebo (p<0.001). There was a significant difference in adverse events between patients treated with Macugen compared to placebo for vitreous floaters (33% vs. 8%, p<0.001), vitreous opacities (18% vs. 10%, p<0.001), and anterior chamber inflammation (14% vs. 6%, p=0.001). 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). Appendix C: Therapeutic Alternatives Drug Dosing Regimen Page 5 of 9 Dose Limit/Maximu m Dose CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin Drug Avastin (bevacizumab) V. Dosing Regimen Neovascular (wet) macular degeneration: 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 retinal vein occlusion: 1 mg to 2.5 mg administered by intravitreal injection every 4 weeks Proliferative diabetic retinopathy: 1.25 mg administered by intravitreal injection 5 to 20 days before vitrectomy Diabetic macular edema: 1.25 mg administered by intravitreal injection Dosage and Administration Drug Name Indication Aflibercept (Eylea) Ranibizumab (Lucentis) Dose Limit/Maximu m Dose Dosing Regimen Neovascular (Wet) AgeRelated Macular Degeneration (AMD) 2 mg (0.05 mL) administered by intravitreal injection once a month for 3 months then 2mg every 2 months. Macular Edema Following Retinal Vein Occlusion 2 mg (0.05 mL) administered by intravitreal injection once a month Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in patients with Diabetic Macular Edema 2mg (0.05mL) administered by intravitreal injection once a month for the first 5 injections followed by 2 mg via intravitreal injection once every 2 months. (Some patients may need once monthly dosing after the first 5 doses) 0.5 mg (0.05 mL) administered by intravitreal injection once a month. Neovascular (Wet) AgeRelated Macular Degeneration (AMD) Alternative dosing: Once monthly injections for three months followed by 4-5 doses dispersed among the following 9 months Or Macular Edema Following Retinal Vein Occlusion Diabetic Macular Edema (DME) and Diabetic 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. 0.3 mg (0.05 mL) administered by intravitreal injection once a month Page 6 of 9 2.5 mg 1.25 mg 2.5 mg 1.25 mg 1.25 mg Maximum Dose CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin Retinopathy (DR) in patients with Diabetic Macular Myopic Choroidal Neovascularization (mCNV) Pegaptanib (Macugen) Verteporfin (Visudyne) VI. Neovascular (Wet) AgeRelated Macular Degeneration (AMD) Diabetic Macular Edema Predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis Product Availability Drug Aflibercept (Eylea) Ranibizumab (Lucentis) Pegaptanib (Macugen) Verteporfin (Visudyne) VII. 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 (0.09 mL) administered by intravitreal injection every 6 weeks 0.3 mg (0.09 mL) administered by intravitreal injection once every 6 weeks x 3 doses 2 6 mg/m Body Surface Area IV diluted with 5% dextrose to a final volume of 30 mL infused over 10 minutes Availability Single-use vial: 2 mg/0.05 mL Single-use glass vials: 0.3 mg/0.05 mL, 0.5 mg/0.05 mL Prefilled syringe: 0.3 mg/0.09 mL Vial for reconstitution: 15mg (2mg/mL after reconstitution) References 1. Lucentis [Prescribing Information] South San Francisco, CA: Genentech, Inc.; February 2015. 2. Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial. The IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, Reeves BC. Ophthalmology. 2012;7:1399-1411. Epub 2012 May 11. 3. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, et al. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results. Ophthalmology; 2012;7:1388-98. 4. Weigert G, Michels S, Sacu S, et al. Intravitreal bevacizumab (Avastin) therapy versus photodynamic therapy plus intravitreal triamcinolone for neovascular agerelated macular degeneration: 6-month results of a prospective, randomised, controlled clinical study. Br J Ophthalmol. 2008 Mar;92(3):356-360. 5. Bashshur Zf , Haddad Za, Schakal A, et al. Intravitreal Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: A One-year Prospective Study. Am J Ophthalmol. 2008;145:249–256. Page 7 of 9 CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin 6. Yazdani S, Hendi K, Pakravan M, et al. Intravitreal bevacizumab for neovascular glaucoma: a randomized controlled trial. J Glaucoma. OctoberNovember 2009;18(8):632-637. 7. Brouzas D, Charakidas A, Moschos M, et al. Bevacizumab (Avastin®) for the management of anterior chamber neovascularization and neovascular glaucoma. Clinical Ophthalmology. 2009;3:685-688. 8. Moraczewski AL, Lee RK, Palmberg PF, et al. Outcomes of treatment of neovascular glaucoma with intravitreal vevacizumab. Br J Ophthalmol, 2009;93:589-593. 9. Costagliola C, Cipollone U, Rinaldi M, et al. Inravitreal bevacizumab (Avastin®) injection for neovascular glaucoma: a survey of 23 cases throughout 12-month follow-up. Br J Clin Pharmacol, 2008;66(5):667-673. 10. di Lauro R, De Ruggiero P, di Lauro R, di Lauro MT, Romano MR. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2010;248:785-791. 11. Rizzo S, Genovesi-Ebert F, Di Bartolo E, Vento A, Miniaci S, Williams G. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol. 2008 Jun;246(6):837-842. 12. Arevalo JF, Sanchez JG, Wu L, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema. Ophthalmology. August 2009;116(8):1488-1497. 13. Roh MI, Byeon SH, Kwon OW. Repeated intravitreal injection of bevacizumab for clinically significant diabetic macular edema. Retina, the Journal of Retinal and Vitreous Diseases. 2008; 28(9): 1314-1318. 14. Kook D, Wolf A, Kreutzer T, et al. Long-term effect of intravitreal bevacizumab (Avastin) in patients with chronic diffuse diabetic macular edema. Retina, the Journal of Retinal and Vitreous Diseases. 2008; 28(8): 1053-1060. 15. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;334:1432– 1444. 16. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004 Dec 30;351(27):2805-16. 17. Product Dossier: EyleaTM (aflibercept). Tarrytown; November 2011. Regeneron Pharmaceuticals, Inc. Data reviewed February 14, 2012. 18. Visudyne [Prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals: April 2016. 19. Macugen [Prescribing information]. San Dimas, CA: Gilead Sciences, Inc.: October 2011. 20. Eylea [Prescribing Information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.: May 2016. 21. American Hospital Formulary Service Drug Information. Available at: http://www.medicinescomplete.com/mc/ahfs/current/. Accessed June 14, 2016 Page 8 of 9 CLINICAL POLICY aflibercept, ranibizumab, pegaptanib, verteporfin 22. JuneGlassman AR et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. NEJM February, 2015 published online ahead of print (DOI: 10.1056/NEJMoa1414264) 23. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed June 2016. 24. Clinical Pharmacology Web site. Available at: http://cpip.gsm.com/. Accessed June 14, 2016. Reviews, Revisions, and Approvals Date Policy created Corrected Lucentis product availability to 0.5 mg/0.05 mL 02/17 04/17 P&T Approval Date 05/17 Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. This Clinical Policy is not intended to dictate to providers how to practice medicine, nor does it constitute a contract or guarantee regarding payment or results. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This policy is the property of Envolve Pharmacy Solutions. Unauthorized copying, use, and distribution of this Policy or any information contained herein is strictly prohibited. By accessing this policy, you agree to be bound by the foregoing terms and conditions, in addition to the Site Use Agreement for Health Plans associated with Envolve Pharmacy Solutions. ©2017 Envolve Pharmacy Solutions. All rights reserved. All materials are exclusively owned by Envolve Pharmacy Solutions and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Envolve Pharmacy Solutions. You may not alter or remove any trademark, copyright or other notice contained herein. Page 9 of 9