Vascular Endothelial Growth Factor (VEGF) Inhibitors Ocular Use Drug Class Monograph (Medical Benefit)

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Vascular Endothelial Growth Factor (VEGF) Inhibitors Ocular Use Drug Class Monograph (Medical Benefit) Line of Business: Medi-Cal Effective Date: May 17, 2017 Revision Date: May 17, 2017 This policy

1 Vascular Endothelial Growth Factor (VEGF) Inhibitors Ocular Use Drug Class Monograph (Medical Benefit) Line of Business: Medi-Cal Effective Date: May 17, 2017 Revision Date: May 17, 2017 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutic Subcommittee. Drugs: Avastin (bevacizumab), Eylea (aflibercept), Lucentis (ranibizumab), Macugen (pegaptanib sodium) Policy/Criteria: A. Avastin (bevacizumab) a. Age related macular degeneration b. Macular edema with retinal vein occlusion c. Choroidal retinal neovascularization d. Diabetic macular edema e. Diabetic retinopathy

2 B. Lucentis (ranibizumab) a. Neovascular (Wet) Age-Related Macular Degeneration b. Macular Edema following Retinal Vein Occlusion (RVO) c. Diabetic Macular Edema (DME) d. Diabetic retinopathy e. Myopic choroidal neovascularization C. Eylea (aflibercept) a. Neovascular (Wet) Age-Related Macular Degeneration b. Macular Edema following Retinal Vein Occlusion (RVO) c. Diabetic Macular Edema (DME) d. Diabetic retinopathy D. Macugen (pegaptanib sodium) a. Neovascular (Wet) Age-Related Macular Degeneration

3 Clinical Justification: Local Coverage Article: Intraocular Bevacizumab Coding/Billing Guideline (A53008) Bevacizumab is not currently packaged and prepared by the manufacturer in doses appropriate for intravitreal injection. Physicians routinely obtain single doses prepared by qualified compounding pharmacies to minimize risk of contamination of the injected drug. Consistent with the statement of April 2006 of the American Academy of Ophthalmology (AAO) in support of this use of Bevacizumab, physicians should provide appropriate informed consent with respect to the off-label use of this drug and maintain it in the patient chart. Current scientific literature published in the peer-reviewed core medical journals supports these uses of this drug. The published experience shows that patients with wet macular degeneration may require regular injections for up to a year if new vessels appear and many may require injections even longer. The most recent clinical trial data now extends out beyond five years and demonstrates that most patients continue to require treatment beyond two years. n-fda approved indications for Bevacizumab Neovascular age related macular degeneration (AMD) Macular edema following retinal vein occlusion Diabetic macular edema Retinal vascular occlusion Cystoids macular degeneration Diabetic retinopathy Proliferative retinopathy Glaucoma with vascular disorders Retinal neovascularization with associated conditions Retinopathy of prematurity

4 American Academy of Ophthalmology Age-Related Macular Degeneration Summary Benchmarks for Preferred Practice Pattern guidelines 1. Recommended treatment for age-related macular degeneration with macular choroidal neovascularization a. Aflibercept intravitreal 2.0 mg Dosed every 4 weeks and every 8 weeks after three monthly loading doses ninferior efficacy to 0.5 mg ranibizumab dosed every 4 weeks. Every 8-week maintenance treatment regimen has been shown to have comparable results to every 4 weeks in the first year of therapy b. Bevacizumab intravitreal 1.25 mg Improvements in visual acuity and decreased retinal thickness by optical coherence tomography (OCT) following treatment. Informed consent for patients with respect to the off-label use. c. Ranibizumab intravitreal 0.5 mg Ranibizumab PRN had noninferior visual acuity improvements compared with monthly injections. There does not appear to be a significant difference in efficacy between ranibizumab and bevacizumab. 2. For VEGF inhibitor intravitreal treatments, the following are noted: a. Demonstrated improved visual and anatomic outcomes b. Considered first-line therapy for most cases of neovascular AMD c. Generally well tolerated and rarely associated with serious adverse events such as infectious endophthalmitis or retinal detachment d. There are theoretical risks for systemic arterial thromboembolic events and increased intraocular pressure e. Patients should be instructed to promptly report symptoms suggestive of endophthalmitis, retinal detachment, or decreased vision, and they should be reexamined promptly f. Monitoring of monocular near vision g. Examine at regular intervals by means of biomicroscopy of the fundus h. Optical coherence tomography, fluorescein angiography, and fundus photography may be used to detect signs of active exudation or disease progression i. A history and examination are recommended at follow-up visits j. Return exam 4 weeks after treatment; subsequent follow-up depends on the clinical findings 3. Pegaptanib sodium treatment does not improve visual acuity on average in patients with new-onset neovascular AMD and is rarely used in current clinical practice

5 MOA Usual Dosing Administration Dosage adjustment in renal impairment PK/PD Drug-drug interaction Common Side effects Serious allergic and hypersensitivity Avastin (bevacizumab) Eylea (aflibercept) Binds VEGF and prevents its interaction to its Binds VEGF-A and PGF to inhibit the activation receptors (Flt-1 and KDR) on endothelial cells of VEGFR-1 and VEGFR-2 receptors 1.25 mg monthly for 3 months, then given 2 mg monthly for the first 3 months, then 2 mg monthly or as needed once every 2 months Intravitreal injection Distribution: 46 ml/kg Protein binding: ~97% Metabolism: Reticuloendothelial system Half-life elimination: 5-10 days Time to peak, plasma: ~8 days Excretion: Reticuloendothelial system paclitaxel/carboplatin Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis Pregnancy Advise pregnant women of potential risk to fetus. Lactation t recommended t recommended Storage and stability Store at 2 8 C (36 46 F) How supplied 100 mg or 400 mg vials Absorption: Levels undetectable after 2 weeks Distribution: ~6 L Metabolism: Proteolysis Half-life elimination: 5-6 days Time to peak, plasma: 1-3 days Excretion: Target mediated disposition via binding to free endogenous VEGF Conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, vitreous detachment Yes; Anaphylaxis, rash, Hypersensitivity reaction Category C; should be used during pregnancy only if the benefits outweigh the risks 1 single-use, 3-mL glass vial with 0.05 ml of 40 mg/ml aflibercept Lucentis (ranibizumab) Macugen (pegaptanib sodium) MOA Binds and inhibits the biologic activity of Selective VEGF antagonist that binds to the 165 all isoforms of human VEGF-A isoform of VEGF-A Usual Dosing 0.5 mg monthly 0.3 mg once every six weeks Administration Intravitreal injection Dosage adjustment in renal impairment PK/PD Absorption: Slow Distribution: ~8.91 ml Metabolism: t extensively metabolized Absorption: Slow Metabolism: Metabolized by endo- and exonucleases Bioavailability: %

6 Drug-drug interaction Common Side effects Bioavailability: ~50% Half-life elimination: ~9 days Time to peak, plasma: ~1 day Excretion: aqueous humor verteporfin photodynamic therapy Conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure Half-life elimination: ~10 days Time to peak, plasma: 1-4 days Excretion: urine as unchanged drug and metabolites pegloticase Anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, vitreous opacities Serious allergic and hypersensitivity Pregnancy Use only if clearly needed Category B; use only if clearly needed Lactation Use with caution Use with caution Storage and stability Store at 2 8 C (36 46 F) How supplied 1 single-use container with 0.05 ml of 10 mg/ml ranibizumab (0.5 mg dose prefilled syringe or vial) or 6 mg/ml ranibizumab (0.3 mg dose vial) Sterile foil pouch with a single-use glass syringe pre-filled with 0.3 mg of drug in a 90 µl volume pack. References: 1. Ahn, S. J., Ahn, J., Park, S., Kim, et al. Intraocular Pharmacokinetics of Ranibizumab in Vitrectomized Versus nvitrectomized EyesPharmacokinetics of Ranibizumab in Vitrectomized Eyes. Investigative ophthalmology & visual science, 2014; 55(1), American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern Guidelines. Age-Related Macular Degeneration. San Francisco, CA: American Academy of Ophthalmology; Available at: 3. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology, 2007;114(5): Bausch & Lomb Inc. Macugen (pegaptanib sodium injection) package insert. Bridgewater, NJ: Bausch & Lomb Inc CMS Medicare Carriers: Local Coverage Article Intraocular Bevacizumab Coding/Billing Guidelines (A52902). Available at: Accessed December 31, Eyetech Inc. Macugen (pegaptanib sodium injection) package insert. Palm Beach Gardens, Florida: Eyetech, Inc. Dec Genentech Inc. Avastin (bevacizumab) solution for intravenous infusion [product information]. South San Francisco, CA: Genentech, Inc Genentech Inc. Avastin (bevacizumab) solution for intravenous infusion [product information]. South San Francisco, CA: Genentech, Inc

7 9. Genentech Inc. Lucentis (ranibizumab injection) Intravitreal Injection [product information]. South San Francisco, CA: Genentech, Inc. Aug Genentech Inc. Lucentis (ranibizumab injection) Intravitreal Injection [product information]. South San Francisco, CA: Genentech, Inc Genentech, South San Francisco, CA: Personal communication. 12. Gragoudas, E. S., Adamis, A. P., Cunningham Jr, E. T., Feinsod, M., & Guyer, D. R. Pegaptanib for neovascular age-related macular degeneration. New England Journal of Medicine, 2004;351(27), Heier JS, Brown DM, Chong V, et al, VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119: Hoang QV, Mendonca LS, Della Torre KE, et al. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology 2012;119: Johnson, R. N. Ranibizumab treatment of retinal vein occlusion. Expert Review of Ophthalmology, 2012; 7(6), Kazazi-Hyseni F, Beijnen JH, Schellens JHM. (2010). Bevacizumab. The oncologist. 17. Krohne, T. U., Liu, Z., Holz, F. G., & Meyer, C. H. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. American journal of ophthalmology, 2012; 154(4), Matthew, M., Kowalski, K.G., Kuan, Y., Dana, J. Population pharmacokinetics of pegaptanib sodium (Macugen ) in patients with diabetic macular edema. Clinical Ophthalmology, 2015; 9, Medical Review Criteria Guideline for Managing Care (Apollo) Age-Related Macular Degeneration (AMD/ARMD) Therapy 20. Medical Review Criteria Guideline for Managing Care (Apollo) AMD Intraocular Injection Treatments (Macugen, Lucentis) 21. Regeneron Pharmaceuticals Inc. Eylea (aflibercept) Injection for intravitreal injection product information. Tarrytown, NY: Regeneron Pharmaceuticals, Inc. October Regeneron Pharmaceuticals Inc. Eylea (aflibercept) Injection for intravitreal injection product information. Tarrytown, NY: Regeneron Pharmaceuticals, Inc Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355: Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al, Pan American Collaborative Retina Group (PACES). Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACES). Graefes Arch Clin Exp Ophthalmol 2008;246:81-7. Change Control Date Change 05/17/2017 Revised criteria for Lucentis to include FDA approved indications of : o Diabetic retinopathy o Myopic choroidal neovascularization Revised criteria for Eylea to include FDA approved indications of : o Diabetic retinopathy

Ophthalmic VEGF Inhibitors. Eylea (aflibercept), Macugen (pegaptanib) Description

Ophthalmic VEGF Inhibitors. Eylea (aflibercept), Macugen (pegaptanib) Description Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 Subject: Ophthalmic VEGF Inhibitors Page: 1 of 5 Last Review Date: September 20, 2018 Ophthalmic VEGF Inhibitors