OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULAS AND STRUCTURES

ANNOTATED BIBLIOGRAPHY

References updated: 15 May 2018

• Henderer JD, Rapuano CJ. Agents used to treat retinal neovascularization and macular degeneration. Ocular pharmacology. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D'Amico DJ, Goldbaum M, et al.; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005; 112: 1747-57. [PubMed: 16154196]

  (Among 172 patients with diabetic macular edema treated with intraocular pegaptanib or sham injections for 20 weeks, visual acuity was more likely to be improved or stable with pegaptanib, and adverse events were uncommon and largely due to the intravitreal injections).
• Pegaptanib sodium (Macugen) for macular degeneration. Med Lett Drugs Ther 2005; 47 (1212): 55-6. [PubMed: 15988400]

  (Concise review of the mechanism of action, efficacy, safety and cost of pegaptanib shortly after its approval in the US mentions that intraocular pegaptanib and bevacizumab may be associated with a higher rate of cardiovascular and cerebrovascular thromboses due to their inhibitory effects on angiogenesis).
• Ranibizumab (Lucentis) for macular degeneration. Med Lett Drugs Ther 2006; 48 (1246): 85-6. [PubMed: 17051134]

  (Concise review of the mechanism of action, efficacy, safety and costs of ranibizumab shortly after its approval for use in the US, along with comparison to other agents used in macular degeneration including bevacizumab and pegaptanib).
• de Jong PT. Age-related macular degeneration. N Engl J Med 2006; 355: 1474-85. [PubMed: 17021323]

  (Review of the clinical features, course and outcome, pathogenesis and risk factors for age related macular degeneration).
• Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006; 113: 363-72. e5. [PubMed: 16458968]

  (Among 79 patients with age related macular degeneration treated with bevacizumab by intravitreal injection monthly, there were no significant systemic side effects).
• VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D'Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET Jr, Guyer DR, Katz B. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology 2006; 113: 992-1001. [PubMed: 16647134]

  (Among 147 patients with age related macular degeneration treated with varying doses of pegaptanib for 54 weeks, ocular adverse events were common, but usually mild-to-moderate, while nonocular events were uncommon and there was no evidence of systemic toxicity).
• Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-31. [PubMed: 17021318]

  (Among 716 patients with neovascular age related macular degeneration, average visual acuity at 24 months improved in ranibizumab treated subjects, but decreased in controls; no mention of ALT changes or hepatotoxicity).
• Kourlas H, Abrams P. Ranibizumab for the treatment of neovascular age-related macular degeneration: a review. Clin Ther 2007; 29: 1850-61. [PubMed: 18035187]

  (Review and summary of 3 clinical trials of ranibizumab for macular degeneration mentions that nonocular adverse events were uncommon and similar in frequency in standard of care and ranibizumab treated subjects; no mention of ALT elevations or hepatotoxicity).
• Macugen AMD Study Group, Apte RS, Modi M, Masonson H, Patel M, Whitfield L, Adamis AP. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration. Ophthalmology 2007; 114: 1702-12. [PubMed: 17509689]

  (Among 147 patients with neovascular age-related macular degeneration from two clinical studies receiving varying high doses of pegaptanib by intravitreal injection for up to 54 weeks, nonocular adverse events were uncommon and there was no evidence of systemic toxicity).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to agents used to treat macular degeneration).
• Do DV, Nguyen QD, Shah SM, Browning DJ, Haller JA, Chu K, Yang K, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol 2009; 93: 144-9. [PubMed: 19174400]

  (Pilot study of a single intravitreal injection of aflibercept in 5 patients with diabetes and macular degeneration showed clinical improvements in 4 patients and no systemic effects).
• Wroblewski JJ, Wells JA 3rd, Adamis AP, Buggage RR, Cunningham ET Jr, Goldbaum M, Guyer DR, et al.; Pegaptanib in Central Retinal Vein Occlusion Study Group. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion. Arch Ophthalmol 2009; 127: 374-80. [PubMed: 19365011]

  (Among 98 patients with macular edema from central retinal vein occlusion treated with pegaptanib or sham intravitreal injections, visual acuity tended to be better among the pegaptanib treated patients and there was "no evidence of an increased risk of systemic adverse events").
• Tufail A, Patel PJ, Egan C, Hykin P, da Cruz L, Gregor Z, Dowler J, et al.; ABC Trial Investigators. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ 2010; 340: c2459. [PubMed: 20538634]

  (Among 131 patients with neovascular macular degeneration, improved vision at one year occurred in 32% of bevacizumab vs 3% of standard therapy treated subjects and side effects were largely related to the intravitreal injections).
• Sultan MB, Zhou D, Loftus J, Dombi T, Ice KS; Macugen 1013 Study Group. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011; 118 1107-18. [PubMed: 21529957]

  (Among 282 patients with diabetic macular edema treated with pegaptanib or placebo for up to 2 years, there were no differences in nonocular adverse events between the two groups).
• CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364: 1897-908. [PMC free article: PMC3157322] [PubMed: 21526923]

  (Among 1208 patients with neovascular age related macular degeneration, ranibizumab and bevacizumab had similar effects on visual acuity and systemic adverse effects were uncommon; no mention of ALT elevations or hepatotoxicity).
• Comparison of Age-related Macular Degeneration Treatments Trials(CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012; 119: 1388-98. [PubMed: 32200813]

  (Among 1107 patients who were followed during year 2 of ranibizumab or bevacizumab therapy for neovascular age related macular degeneration, systemic adverse events could not be definitely linked to the intravitreal injections of anti-VEGF therapy; no mention of ALT elevations or hepatotoxicity).
• Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, et al.; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119: 2537-48. [PubMed: 23084240]

  (Among 2419 patients with neovascular age related macular degeneration treated with intravitreal injections of aflibercept or ranibizumab, response rates were similar with the two drugs and the incidence of systemic adverse events was similar; no mention of ALT elevations or hepatotoxicity).
• Tang PA, Cohen SJ, Kollmannsberger C, Bjarnason G, Virik K, MacKenzie MJ, Lourenco L, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res 2012; 18: 6023-31. [PubMed: 22977191]

  (Among 75 patients with metastatic colorectal cancer treated with aflibercept, few had an objective response and adverse events included fatigue, hypertension and proteinuria; no mention of ALT elevations or hepatotoxicity).
• Ho AC, Scott IU, Kim SJ, Brown GC, Brown MM, Ip MS, Recchia FM. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology 2012; 119: 2179-88. [PubMed: 22917890]

  (Systematic review of safety and efficacy of anti-VEGF therapies of diabetic macular edema mentions that there is no greater risk of systemic adverse events from intravitreal infusions of anti-VEGF therapies including bevacizumab, ranibizumab, pegaptanib and aflibercept).
• Aflibercept (eylea) for age-related macular degeneration. Med Lett Drugs Ther 2012; 54 (1383): 9-10. [PubMed: 22354219]

  (Concise review of the mechanism of action, efficacy, safety and costs of aflibercept shortly after its approval in the US mentions that adverse events were virtually identical to ranibizumab and largely ophthalmologic).
• Gotlieb WH, Amant F, Advani S, Goswami C, Hirte H, Provencher D, Somani N, et al. Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 2012; 13: 154-62. [PubMed: 22192729]

  (Among 55 women with advanced ovarian cancer and ascites treated with intravenous aflibercept or placebo, side effects included fatigue and dehydration; ALT elevations occurred in 10% of aflibercept, but no placebo recipient and one patient developed both ALT and bilirubin elevations during first 30 days of therapy).
• Mackay HJ, Buckanovich RJ, Hirte H, Correa R, Hoskins P, Biagi J, Martin LP, et al. A phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California Cancer Phase II Consortia. Gynecol Oncol 2012; 125: 136-40. [PMC free article: PMC3303987] [PubMed: 22138373]

  (Among 63 women with gynecologic soft tissue sarcomas who were treated with intravenous aflibercept, no objective responses occurred and side effects were common; 6 [10%] patients had mild Alk P elevations, but there was no mention of ALT elevations or hepatotoxicity).
• Heier JS, Clark WL, Boyer DS, Brown DM, Vitti R, Berliner AJ, Kazmi H, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS Study. Ophthalmology 2014; 121: 1414-20. e1. [PubMed: 24679444]

  (Among 188 patients with macular edema due to central retinal vein occlusion for up to 2 years, improvement in visual acuity was greater with aflibercept than sham intravitreal injections, and rates of nonocular adverse events were similar; ALT elevations and hepatotoxicity were not mentioned).
• Semeraro F, Morescalchi F, Duse S, Gambicorti E, Romano MR, Costagliola C. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview. Expert Opin Drug Saf 2014; 13: 785-802. [PubMed: 24809388]

  (Review of the evidence for systemic absorption of anti-VEGF agents used in ophthalmology and their possible adverse effects, focusing upon thromboembolic cardiovascular and cerebrovascular events).
• Perkins SL, Cole SW. Ziv-aflibercept (Zaltrap) for the treatment of metastatic colorectal cancer. Ann Pharmacother 2014; 48: 93-8. [PubMed: 24259608]

  (Review of efficacy and safety of aflibercept as therapy of metastatic colorectal cancer does not include ALT elevations or hepatotoxicity in list of adverse events occurring in more than 10% of patients).
• Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014; 121: 193-201. [PubMed: 24084500]

  (Among 2457 patients with neovascular age related macular degeneration, improvement and stability of visual acuity was similar with intravitreal injections of aflibercept and ranibizumab, and nonocular adverse events were similar).
• Korobelnik JF, Holz FG, Roider J, Ogura Y, Simader C, Schmidt-Erfurth U, Lorenz K, et al.; GALILEO Study Group. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology 2014; 121: 202-8. [PubMed: 24084497]

  (Among 177 patients with macular edema due to central retinal vein occlusion, visual acuity improved with aflibercept and nonocular adverse events were similar in the sham and aflibercept treated subjects; no mention of hepatotoxicity).
• Chang AA, Broadhead GK, Hong T, Joachim N, Syed A, Schlub TE, Toth L, et al. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration: 12-month safety and eficacy outcomes. Ophthalmic Res 2015; 55: 84-90. [PubMed: 26637166]

  (Among 49 patients with macular degeneration treated with intra-vitreal aflibercept every 1 to 2 months for 1 year, there were 22 serious adverse events, but none were liver related).
• Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, Heier JS, et al. intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID Studies. Ophthalmology 2015; 122: 2044-52. [PubMed: 26198808]

  (Among 872 patients treated with intra-vitreal aflibercept every 4 or 8 weeks or with laser photocoagulation for up to 2 years, adverse event rates including myocardial infarction and stroke were similar in all three groups; no mention of liver related adverse events).
• Scott LJ, Chakravarthy U, Reeves BC, Rogers CA. Systemic safety of anti-VEGF drugs: a commentary. Expert Opin Drug Saf 2015; 14: 379-88. [PubMed: 25489638]

  (Review of trials of different anti-VEGF agents for macular degeneration found no increase in rates of all-cause mortality as well as arterio-thrombotic and gastrointestinal serious adverse events; no specific mention of hepatotoxicity).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to drugs used to treat macular degeneration).
• Ziemssen F, Sobolewska B, Deissler H, Deissler H. Safety of monoclonal antibodies and related therapeutic proteins for the treatment of neovascular macular degeneration: addressing outstanding issues. Expert Opin Drug Saf 2016; 15: 75-87. [PubMed: 26568279]

  (Review of safety of monoclonal anti-VEGF therapy of macular degeneration states that systemic levels and effects are detectable after intra-vitreal injections and that extraocular serious adverse effects may include cerebrovascular events; no mention of hepatotoxicity).
• Avery RL, Gordon GM. Systemic Safety of prolonged monthly anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis. JAMA Ophthalmol 2016; 134: 21-9. [PubMed: 26513684]

  (Metaanalysis of 4 controlled trials of long term intra-vitreal anti-VEGF therapy of diabetic macular edema found increased risk for arterio-thrombotic events and death, occurring in 30 of 791 [4%] treated vs 7 of 537 [1.3%] controls; no mention of hepatotoxicity).
• Kitchens JW, Do DV, Boyer DS, Thompson D, Gibson A, Saroj N, Vitti R, et al. Comprehensive review of ocular and systemic safety events with intravitreal aflibercept injection in randomized controlled trials. Ophthalmology 2016; 123: 1511-20. [PubMed: 27084563]

  (Review of safety outcomes from more than 4000 patients enrolled in 10 controlled trials of intravitreal aflibercept therapy of macular degeneration, found no increase in systemic adverse events with aflibercept treatment compared to controls).
• Mansour AM, Ashraf M, Dedhia CJ, Charbaji A, Souka AAR, Chhablani J. Long-term safety and efficacy of ziv-aflibercept in retinal diseases. Br J Ophthalmol 2017; 101: 1374-6. [PubMed: 28270485]

  (Among 55 patients with macular degeneration treated off-label with ziv-aflibercept by intravitreal injection, visual acuity improved and "systemic adverse effects were not registered").
• Bevacizumab-Ranibizumab International Trials Group. Serious adverse events with bevacizumab or ranibizumab for age-related macular degeneration: meta-analysis of individual patient data. Ophthalmol Retina 2017; 1: 375-81. [PMC free article: PMC5640431] [PubMed: 29038796]

  (Independent review of pooled data from 3052 patients participating in 5 large randomized controlled trials comparing bevacizumab and ranibizumab as therapy of macular degeneration, found rates of systemic serious adverse events to be the same with the two anti-VEGF monoclonal antibodies).
• Thulliez M, Angoulvant D, Pisella PJ, Bejan-Angoulvant T. Overview of systematic reviews and meta-analyses on systemic adverse events associated with intravitreal anti-vascular endothelial growth factor medication use. JAMA Ophthalmol 2018; 136 (5): 557-66. [PubMed: 29566105]

  (Review of 21 systematic reviews suggested that intravitreal therapy of macular degeneration is not associated with a higher rate of systemic adverse events).