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Medication Policy Manual Policy No: dru241 Topic: Macugen®, pegaptanib Date of Origin: May 13, 2011 Committee Approval Date : May 8, 2015 Next Review Date: May 2016 Effective Date: September 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Pegaptanib (Macugen) is an inhibitor of vascular endothelial growth factor (VEGF) that is injected directly into the eye to prevent the formation of new blood vessels and reduce blood vessel leakage and inflammation. © 2015 OmedaRx. All rights reserved. dru241.4 Page 1 of 9 Policy/Criteria I. Most contracts require prior authorization approval of pegaptanib (Macugen) prior to coverage. Pegaptanib (Macugen) may be considered medically necessary when criteria A and B below are met: A. At least one of the following diagnostic criteria 1 or 2 below are met: 1. A diagnosis of neovascular (wet) age-related macular degeneration. (See Appendix 1) OR 2. A diagnosis of diabetic macular edema. (See Appendix 1) AND B. II. III. Treatment with bevacizumab (Avastin®) has been ineffective, not tolerated, or is contraindicated. Administration, Quantity Limitations, and Authorization Period A. OmedaRx does not consider pegaptanib (Macugen) to be a self-administered medication. B. Authorization shall be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective as supported by clinical documentation indicating stabilization or improvement in vision Pegaptanib (Macugen) is considered investigational when used for all other conditions, including but not limited to: - Cystoid macular degeneration - Glaucoma associated vascular disorders - Pathologic myopia - Radiation maculopathy - Retinal neovascularization - Retinal vein occlusion - In combination with other VEGF inhibitors, including but not limited to aflibercept (Eylea), bevacizumab (Avastin), and ranibizumab (Lucentis) Position Statement - - Bevacizumab (Avastin®) is the best value VEGF inhibitor for the treatment of ocular conditions. Bevacizumab (Avastin) does not require prior authorization for ocular conditions. Clinical trials of intravitreal VEGF inhibitors, including pegaptanib (Macugen), for the treatment of neovascular (wet) age-related macular degeneration (wAMD) and diabetic macular edema (DME) have shown evidence of efficacy for maintaining or improving visual acuity. © 2015 OmedaRx. All rights reserved. dru241.4 Page 2 of 9 There is moderate certainty that pegaptanib (Macugen) is less effective in improving visual acuity relative to bevacizumab (Avastin) and ranibizumab (Lucentis) in the treatment of wAMD, and insufficient evidence to determine that one product is clinically superior to another in the treatment of DME. - Clinical guidelines support the use of VEGF inhibitors, including bevacizumab (Avastin), for the treatment of wAMD and DME. - Pegaptanib (Macugen) has been studied in other vascular-related ocular conditions. The clinical benefit of pegaptanib (Macugen) in these indications is uncertain to date. - Clinical Efficacy Neovascular (wet) Age-related Macular Degeneration (AMD) - There is moderate certainty that VEGF inhibitors, including pegaptanib (Macugen), are effective for maintaining or improving vision in patients with wAMD based on high quality systematic reviews. * * * - - - One high quality systematic review of bevacizumab (Avastin) in the treatment of wAMD concluded that it improves visual acuity and central retinal thickness (moderate correlate to visual acuity) and is more effective than photodynamic therapy (without verteporfin). [1] One high quality systematic review of VEGF inhibitors concluded that pegaptanib (Macugen) and ranibizumab (Lucentis) reduce the risk of visual acuity loss in patients with wAMD versus sham or laser therapy. It also concluded that ranibizumab (Lucentis®) may improve visual acuity; however, the review did not include trials which evaluated bevacizumab (Avastin) or aflibercept (Eylea®). [2] One high quality systematic review of VEGF inhibitors concluded that bevacizumab (Avastin), pegaptanib (Macugen), and ranibizumab (Lucentis) are more effective than sham or laser treatment in maintaining or improving visual acuity in patients with wAMD after one year of treatment. [3] There is moderate certainty that pegaptanib (Macugen) is less effective than bevacizumab (Avastin) and ranibizumab (Lucentis) in improving visual acuity in patients with wAMD based on a high quality systematic review which demonstrated that pegaptanib (Macugen) was associated with smaller improvements in visual acuity compared to the other two VEGF inhibitors. This same study also concluded that there were no major differences with respect to vision related outcomes in trials comparing bevacizumab (Avastin) and ranibizumab (Lucentis). [3] The American Academy of Ophthalmology (AAO) guidelines recommend aflibercept (Eylea), bevacizumab (Avastin), or ranibizumab (Lucentis) for the treatment of wAMD. The AAO does not recommend the use of pegaptanib (Macugen) in the treatment of wAMD due to evidence showing that it does not improve visual acuity on average in patients with new onset wAMD unlike other currently available VEGF inhibitors. [4] Guidelines from the National Institute for Health and Clinical Excellence (NICE) recommend ranibizumab (Lucentis) for the treatment of wet AMD. NICE does not recommend treatment with pegaptanib (Macugen) for wet AMD due to an increase in © 2015 OmedaRx. All rights reserved. dru241.4 Page 3 of 9 overall costs for their population. [5] These guidelines have not been updated since the approval of aflibercept (Eylea). Diabetic Macular Edema (DME) - There is moderate certainty that VEGF inhibitors, including pegaptanib (Macugen), improve visual acuity in patients with DME; however, there is insufficient evidence demonstrating that one VEGF inhibitor is clinically superior to another in the treatment of DME based on one high-quality systematic review and two randomized controlled trials. * * - Pegaptanib (Macugen) has demonstrated improvements in visual acuity and vision related quality of life versus sham injection when used for the treatment of DME. [6,7] Pegaptanib (Macugen) has not been directly compared with any other VEGF inhibitor in the treatment of DME. A Cochrane systematic review concluded that aflibercept (Eylea), bevacizumab (Avastin), and ranibizumab (Lucentis) are more effective than laser photocoagulation in improving visual acuity (i.e. likelihood of gaining three or more lines of vision). Although there were no significant sub-group differences in visual acuity between the VEGF inhibitors, there was insufficient power to detect a difference between them. [8] AAO guidelines do not list pegaptanib (Macugen) as a treatment option for DME. Aflibercept (Eylea), bevacizumab (Avastin), and ranibizumab (Lucentis) are the recommended VEGF inhibitors for this condition, of which bevacizumab (Avastin) is the lowest cost option. [9] Retinal Vein Occlusion Small, preliminary studies have reported inconsistent results of pegaptanib (Macugen) in the treatment of macular edema due to both branch and central retinal vein occlusion. Larger, wellcontrolled clinical trials are needed to determine the clinical benefit of pegaptanib (Macugen) in this condition. [10,11] Other Uses - - - Published data evaluating pegaptanib (Macugen) in other conditions such as retinopathy of prematurity, or in combination with bevacizumab (Avastin) for wet AMD are preliminary. Larger well-controlled trials are needed to determine the clinical benefit of pegaptanib (Macugen) in these settings. [12-14] The use of pegaptanib (Macugen) in conjunction with other VEGF inhibitors, including aflibercept (Eylea), bevacizumab (Avastin), and ranibizumab (Lucentis) is considered investigational as there is no evidence evaluating the efficacy or safety of pegaptanib (Macugen) when used in this manner. Trials of pegaptanib (Macugen) in a variety of other conditions are ongoing and are considered investigational due to lack of published data. [15] © 2015 OmedaRx. All rights reserved. dru241.4 Page 4 of 9 Safety - There is low certainty in the evidence demonstrating differences in adverse events between intravitreous VEGF inhibitors. * * - - A meta-analysis evaluating the cardiovascular (CV) safety of intravitreal VEGF inhibitors in patients with wet AMD, DME, or retinal vein occlusion concluded that VEGF inhibitors, specifically bevacizumab (Avastin) and ranibizumab (Lucentis), are not associated with a significant increase in risk of systemic CV and hemorrhagic events or in overall mortality, stroke, or CV mortality in elderly patients. However, the studies and meta-analysis were not sufficiently powered to correctly assess these risks. [16] The trial conducted by the CATT research group comparing ranibizumab (Lucentis) to bevacizumab (Avastin) for the treatment of wet AMD found the following regarding safety: [17,18] A statistically significant difference was seen at 52 weeks in the rates of serious systemic adverse events between the ranibizumab (Lucentis) and bevacizumab (Avastin) groups (19.0% vs 24.1%, P = 0.04). A significant difference was also seen at 2 years [39.9% bevacizumab (Avastin) vs 31.7% ranibizumab (Lucentis); adjusted risk ratio 1.30; 95% CI: 1.07, 1.57; P = 0.009]. This difference was largely due to hospitalizations for infections such as pneumonia and urinary tract infections. It is uncertain if these events were related to either medication. Intravitreal VEGF inhibitors have also been associated with inflammation, blurred vision, corneal edema, eye discharge and irritation, and hypertension. [19-21] Additional serious adverse effects reported with intravitreous VEGF inhibitors include endophthalmitis, retinal detachment and iatrogenic traumatic cataract. After injection, patients should be advised to seek immediate care if the treated eye becomes red, painful, sensitive to light, or they notice a change in vision. [19-21] Bevacizumab (Avastin) is listed in national treatment guidelines and is recognized by the Centers for Medicare and Medicaid Services as a safe and effective treatment option for wet AMD and DME. [22,23] * Bevacizumab (Avastin), when used in the eye, must be extemporaneously compounded to achieve the appropriate dose. In 2011, a group of cases of endophthalmitis were reported with the use of bevacizumab (Avastin) which was determined to be the result of unsafe practices by one compounding pharmacy. [24-26] * * While the use of bevacizumab (Avastin) continues to be associated with the risk of endophthalmitis, all intravitreal injections, including commercially available preparations of aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis) carry this risk. [19-21,27,28] In 2013, the FDA passed the Drug Quality and Security Act which provides better oversight of compounding pharmacies. A list of FDA approved compounding facilities is available online. [29] In addition, the American Society © 2015 OmedaRx. All rights reserved. dru241.4 Page 5 of 9 of Retina Specialists has published online safety information about compounding pharmacies to help retina specialists choose high-quality providers of bevacizumab (Avastin). [24,30] Dosing - Aflibercept (Eylea) 2 mg is injected intravitreously (into the eye) every 4 weeks for 12 weeks, then every 8 weeks. [21] Bevacizumab (Avastin) 1.25 mg is injected intravitreously (into the eye) monthly or as needed. [17,18] Pegaptanib (Macugen) 0.3 mg is injected intravitreously (into the eye) every 6 weeks. [20] Ranibizumab (Lucentis) 0.5 mg is injected intravitreously (into the eye) every 1 to 3 months. [19] Appendix 1: List of covered diagnoses [31-33] Covered Diagnosis neovascular (wet) age-related macular degeneration Diabetic Macular Edema Synonyms Exudative senile macular degeneration Age-related macular degeneration Diabetic macular edema with diabetic retinopathy Center involving diabetic macular edema Diabetic retinal edema Macular edema associated with Retinal Vein Occlusion © 2015 OmedaRx. All rights reserved. dru241.4 Clinically significant diabetic macular edema (CSME) Macular edema associated with Central vein occlusion Macular edema associated with Branch vein occlusion Page 6 of 9 Cross References Avastin®, bevacizumab, OmedaRx Medication Policy Manual, Policy No. dru215 Eylea™, aflibercept, OmedaRx Medication Policy Manual, Policy No. dru267 Lucentis®, ranibizumab, OmedaRx Medication Policy Manual, Policy No. dru242 Codes Number Description HCPCS J2503 Injection, pegaptanib sodium, 0.3 mg ICD-9 362.01362.06 Diabetic retinopathy ICD-9 362.07 Diabetic macular edema ICD-9 362.16 Retinal neovascularization not otherwise specified ICD-9 362.3X Retinal vascular occlusion ICD-9 362.52 Exudative senile macular degeneration of retina ICD-9 362.53 Cystoid macular degeneration ICD-9 362.63 Glaucoma associated vascular disorders ICD-9 362.83 Macular edema References 1. Schouten, JS, La Heij, EC, Webers, CA, Lundqvist, IJ, Hendrikse, F. A systematic review on the effect of bevacizumab in exudative age-related macular degeneration. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2009 Jan;247(1):1-11. PMID: 18843500 2. Vedula, SS, Krzystolik, MG. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2008(2):CD005139. PMID: 18425911 3. Solomon, SD, Lindsley, K, Vedula, SS, Krzystolik, MG, Hawkins, BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. The Cochrane database of systematic reviews. 2014;8:CD005139. PMID: 25170575 4. American Academy of Ophthamology: Preferred practice pattern for wet age-related macular degeneration. [cited 03/27/2015]; Available from: http://one.aao.org/preferred-practicepattern/age-related-macular-degeneration-ppp-2015 5. Lumizyme [package insert]. Cambridge, MA: Genzyme Corporation; August 2014 6. Loftus, JV, Sultan, MB, Pleil, AM. Changes in vision- and health-related quality of life in patients with diabetic macular edema treated with pegaptanib sodium or sham. United States, 2011. p. 7498-505. 7. Sultan, MB, Zhou, D, Loftus, J, Dombi, T, Ice, KS. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. United States, 2011. p. 1107-18. © 2015 OmedaRx. All rights reserved. dru241.4 Page 7 of 9 8. Virgili, G, Parravano, M, Menchini, F, Evans, JR. Anti-vascular endothelial growth factor for diabetic macular oedema. The Cochrane database of systematic reviews. 2014;10:CD007419. PMID: 25342124 9. American Academyof Ophthamology: Preferred Practice Pattern for Diabetic Retinopathy. [cited 03/27/2015]; Available from: http://one.aao.org/preferred-practice-pattern/diabeticretinopathy-ppp--2014 10. Wroblewski, JJ, Wells, JA, 3rd, Gonzales, CR. Pegaptanib sodium for macular edema secondary to branch retinal vein occlusion. United States, 2010. p. 147-54. 11. Wroblewski, JJ, Wells, JA, 3rd, Adamis, AP, et al. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion. United States, 2009. p. 374-80. 12. Autrata, R, Krejcirova, I, Senkova, K, Holousova, M, Dolezel, Z, Borek, I. Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone I and posterior zone II. Italy, 2012. p. 687-94. 13. Mintz-Hittner, HA. Intravitreal pegaptanib as adjunctive treatment for stage 3+ ROP shown to be effective in a prospective, randomized, controlled multicenter clinical trial. Italy, 2012. p. 685-6. 14. Schmid-Kubista, KE, Krebs, I, Ansari-Shahrezaei, S, Haas, P, Hagen, S, Binder, S. Comparing treatment of neovascular age-related macular degeneration with sequential intravitreal Avastin and Macugen versus intravitreal mono-therapy--a pilot study. Current eye research. 2011 Oct;36(10):958-63. PMID: 21950702 15. de Souza Brito, F, Tricoci, P. Novel anti-platelet agents: focus on thrombin receptor antagonists. Journal of cardiovascular translational research. 2013 Jun;6(3):415-24. PMID: 23435863 16. Thulliez, M, Angoulvant, D, Le Lez, ML, et al. Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol. 2014;132:1317-26. PMID: 25058694 17. Martin, DF, Maguire, MG, Ying, GS, Grunwald, JE, Fine, SL, Jaffe, GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. The New England journal of medicine. 2011 May 19;364(20):1897-908. PMID: 21526923 18. Martin, DF, Maguire, MG, Fine, SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. United States, 2012. p. 1388-98. 19. Mauer, M, Kopp, J. Treatment of Fabry Disease. In: UpToDate, Curhan, GC. (Ed). UptoDate, Waltham, MA, 2015. 20. National Heart, Lung and Blood Institute (NHLBI). Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. September 1998. [cited 02/02/2015]; Available from: http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf 21. Sirrs, SM, Bichet, DG, Casey, R, et al. Outcomes of patients treated through the Canadian Fabry disease initiative. Molecular genetics and metabolism. 2014 Apr;111(4):499-506. PMID: 24534763 22. Cupler, EJ, Berger, KI, Leshner, RT, et al. Consensus treatment recommendations for lateonset Pompe disease. Muscle & nerve. 2012 Mar;45(3):319-33. PMID: 22173792 23. Local Coverage Determination (LCD) for Drugs and Biologics (Non-chemotherapy) (L32013). Centers for Medicare and Medicaid Services. [cited 04/23/2014]; Available from: http://www.cms.gov/medicare-coverage-database/details/lcddetails.aspx?LCDId=32013&ContrId=268&ver=27&ContrVer=1&Date=04%2f23%2f2013&Do cID=L32013&bc=iAAAAAgAAAAAAA%3d%3d& 24. American Society of Retina Specialists Publishes Compounding Pharmacy Information to Promote Safety of Avastin for Treating Macular Degeneration. [cited 04/22/2014]; Available © 2015 OmedaRx. All rights reserved. dru241.4 Page 8 of 9 from: http://www.prweb.com/releases/2011/10/prweb8848851.htm 25. Goldberg, RA, Flynn, HW, Jr., Isom, RF, Miller, D, Gonzalez, S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. United States, 2012. p. 204-8 e1. 26. Goldberg, RA, Flynn, HW, Jr., Miller, D, Gonzalez, S, Isom, RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013 Jul;120(7):1448-53. PMID: 23453511 27. Schwartz, SG, Flynn, HW, Jr. Endophthalmitis Associated with Intravitreal Anti-Vascular Endothelial Growth Factor Injections. Current ophthalmology reports. 2014 Mar 1;2(1):1-5. PMID: 24579059 28. Casparis, H, Wolfensberger, TJ, Becker, M, et al. Incidence of presumed endophthalmitis after intravitreal injection performed in the operating room: a retrospective multicenter study. Retina. 2014 Jan;34(1):12-7. PMID: 23945639 29. U.S. Food and Drug Administration. Registered Human Drug Compounding Outsourcing Facilities [cited 03/23/2015]; Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompoundi ng/ucm378645.htm 30. Compounding Quality Act: Title I of the Drug Quality and Security Act of 2013. [cited 04/22/2014]; Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompoundi ng/default.htm 31. Fraser, C. Diabetic retinopathy: Prevention and treatment In: UpToDate, Nathan, DM. (Ed). UptoDate, Waltham, MA, 2015. 32. Covert, D, Han, D. Retinal vein occlusion: Treatment. In: UpToDate, Trobe, J (Ed). UptoDate Waltham, MA, 2015. 33. Arroyo, J. Age-related macular degeneration: Treatment and prevention In: UpToDate, Trobe, J (Ed). UptoDate, Waltham, MA, 2015. © 2015 OmedaRx. All rights reserved. dru241.4 Page 9 of 9