Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy

Transcription

1 Supplement to April 2015 Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy Sponsored by Supported by an unrestricted grant from

2 Course Chair Peter Kaiser, MD Professor of Ophthalmology Cleveland Clinic Lerner College of Medicine Vitreoretinal Department Cole Eye Institute, Cleveland Clinic Cleveland, OH Nancy Holekamp, MD Pepose Vision Institute Chesterfield, MO John Kitchens, MD Retina Associates of Kentucky Lexington, KY James Major, MD, PhD Retina Consultants of Houston Houston, TX Rishi Singh, MD Associate Staff Vitreoretinal Department Cole Eye Institute, Cleveland Clinic Cleveland, OH Disclosures All faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relevant relationships with any commercial interests related to this activity. The existence of these interests or relationships is not viewed as implying bias or decreasing the value of the presentation. Disclosures are as follows: Nancy Holekamp, MD has affiliations with Genentech, Regeneron, and Allergan (Advisory Board-Marketing/Speaker s Bureau), Genentech and Katalyst (Advisory Board - Scientific), Genentech (Consultant Clinical Trial Design), Genentech, Regeneron, Allergan, and Alimera Sciences (Consultant Marketing), Katalyst (Shareholder, Intellectual Property/ Patents), Genentech, Regeneron, and Neurotech (Grant Recipient). Peter Kaiser, MD has affiliations with Alcon, Bayer, Genentech, Novartis, and Regeneron (Consultant). John Kitchens, MD has affiliations with Allergan, Optos, Regeneron, Synergetics (Consultant). James Major, MD, PhD has affiliations with Allergan (Speaker s Bureau). Rishi Singh, MD has affiliations with Alcon, Genentech, and Regeneron (Advisory Board, Grant Recipient). Cathy Pagano, CHCP and Scott Kober, MBA, CHCP (CME Matters) have disclosed that they have no relevant financial relationships specific to the subject matter within the past 12 months. A Clinical Perspective Several years ago, Protocol I changed the way many of us were treating patients by establishing anti-vegf therapy as a safe and efficacious firstline option for the treatment of diabetic macular edema. It also showed that, as time goes by, patients require fewer injections than many of us expected based upon our clinical experience. 1 With the initial release of data from the Protocol T study in February, we have only begun to tap into its wealth of valuable insight. In general, the data reassures the retinal community that anti-vegf therapy continues to be the gold standard for the treatment of DME. All three medications tested in this trial worked remarkably well and probably exceeded most expectations, in particular among patients with poorer visual acuity. 2 From my clinical perspective, the Protocol T results give me a little more insight into how to treat patients both with adequate and poorer baseline visual acuity, but most of all, they reassure me that the current anti-vegfs we are using are extremely effective and further validated the safety of these therapies from both an ocular and systemic standpoint. John Kitchens, MD References 1. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6): The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med Feb 18. [Epub ahead of print] This informational supplement is published by CME Matters, LLC. No part of this supplement may be reproduced without written consent from the publisher. The information presented does not necessarily reflect the views and opinions of CME Matters, LLC. Neither CME Matters, LLC nor faculty or authors endorse or recommend any specific techniques, products or manufacturers. All readers and participants should verify all information before treating patients or using any technique or product CME Matters, LLC. Printed in the USA. All rights reserved. Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy Since the 2004 approval of pegaptanib, the first antivascular endothelial growth factor (VEGF) agent approved by the U.S. Food and Drug Administration for intravitreal ophthalmic use, reams of data have been published on the efficacy and safety of this class of therapy. While minor differences have been found from study to study, the general consensus has been that all three of today s commonly used intravitreal anti-vegfs ranibizumab, bevacizumab, and aflibercept are safe and effective for patients with agerelated macular degeneration (AMD) and diabetic macular edema (DME), with mostly inconsequential differences regarding overall safety and efficacy. In this supplement, we will take a comprehensive look at pivotal clinical trials performed in the last 5 years, focusing on specific areas of emerging interest for retinal physicians, and discuss how practices may evolve in the future. Going Head-to-Head on Efficacy: The Historical Perspective Because of their earlier development, there are more data available comparing ranibizumab to bevacizumab than either of those agents vs. aflibercept. It should be noted that all significant data discussed in this section are specific to AMD while Protocol T was a trial of patients with DME. This may impact the generalizability of findings across these obviously unique disease states. The first notable comparative trial was the Comparison of AMD Treatments Trials (CATT), whose 1-year results were published in 2011 and 2-year results in The CATT trial randomized 1,208 patients with neovascular AMD to 1 of 4 treatment arms in the first year: 2,3 Bevacizumab monthly Bevacizumab as-needed Ranbizumab monthly Ranbizumab as-needed After 1 year, patients treated on a monthly schedule saw greater improvements in best-corrected visual acuity (BCVA) than patients treated on an as-needed basis, although ranibizumab as-needed was found to be equivalent to ranibizumab monthly (the comparison of bevacizumab as-needed to bevacizumab monthly was inconclusive). Improvements in BCVA were similar between the two agents. Importantly, patients in the as-needed group required an average of between injections vs. 12 in the monthly group. This difference has potential real-world financial and treatment burden implications. 2 In the second year of CATT, patients who initially received monthly dosing were randomized to either continue receiving Figure 1. Overall changes in visual acuity over the course of 1 year in the DRCR.net Protocol T trial monthly dosing or switch to an as-needed dosing regimen. Patients who were maintained on monthly dosing had the most improvement in BCVA, while patients who switched from monthly to as-needed dosing ended up with improvement similar to that seen in patients initially treated with as-needed dosing. 3 A similar European trial the Inhibit VEGF in Age-Related Choroidal Neovascularization (IVAN) trial had minor differences in its design, most notably the use of 3 monthly loading doses in the as-needed ranibizumab and bevacizumab treatment groups. The comparison by drug was inconclusive in regards to improvements in visual acuity. As-needed, or discontinuous, dosing was also shown to be noninferior to the monthly arms. 4 An additional French trial (GEFAL) further confirmed these efficacy findings. 5 Aflibercept was also compared to ranibizumab in 2 similarly designed phase 3 studies, the VEGF Trap-Eye Investigation of Efficacy and Safety in Wet AMD (VIEW 1, VIEW 2). Patients in these trials received either 1 of 3 aflibercept dose regimens (0.5 mg monthly, 2 mg monthly, or 2 mg every 2 months after 3 initial monthly doses) or ranibizumab 0.5 mg monthly in the first year of the trial before progressing to an asneeded protocol in year 2. No notable differences were found in any of the 4 groups regarding BCVA or safety. 6 What Protocol T Adds to the Equation As noted earlier, Protocol T is the first notable comparative trial to enroll patients with DME as opposed to AMD. 2 Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy Supplement to Ophthalmology Times April

3 Protocal T Study Design The Diabetic Retinopathy Clinical Research Net (DRCR.net) recently published 1-year results from Protocol T, a 3-way comparative effectiveness study funded by the National Institutes of Health. The trial enrolled 660 patients with DME (mean age=61±10 years) involving the central macula and at least one eye with a best corrected visual-acuity score between 78 (approximate Snellen equivalent: 20/32) and 24 (approximate Snellen equivalent: 20/320). Patients could not have received any anti-vegf treatment in the 12 months prior to the start of the study. 1 Important baseline participant characteristics are listed in Table 1. Aflibercept (N=224) Table 1. Baseline Participant Characteristics 1 Bevacizumab Ranibizumab Age (yrs) Median Diabetes (N, %) Type 1 Type 2 Uncertain 22 (10%) 196 (88%) 6 (3%) 12 (6%) 205 (94%) 1 (<1%) 16 (7%) 196 (90%) 6 (3%) Prior myocardial infarction (MI) 13 (6%) 14 (6%) 16 (7%) Prior coronary artery disease (without MI) Visual acuity Letter score Median (75th, 25th percentile) ~Snellen equivalent Median (75th percentile, 25th percentile) 20/50 or worse (letter score <69) 20/32-20/40 (letter score 78-69) 22 (10%) 27 (12%) 34 (16%) 69 (74, 59) 20/40 (20/32, 20/63) 112 (50%) 112 (50%) 69 (72, 60) 20/40 (20/40, 20/63) 107 (49%) 111 (51%) 68 (73, 58) 20/50 (20/40, 20/80) 110 (50%) 108 (50%) As per the study protocol, one eye of each patient was randomly assigned to receive 1 of 3 treatment arms aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg. Each drug was administered at baseline and then once every 4 weeks. Laser photocoagulation was added at or after 24 weeks for patients with persistent DME. The use of pre- or post-injection antibiotics was left to the discretion of each investigator. Study participants, reading-center graders, and the medical monitor of adverse events were blinded to treatment; investigators and study coordinators were not. 1 Patients in the aflibercept group required a median of 9 intravitreous injections over the course of the study compared to 10 in both the bevacizumab and ranibizumab groups. Those with baseline visual acuity (VA) of 20/40 or better needed fewer injections (median=9 in all three groups) than patients with VA of 20/50 or worse at baseline (median=10 injections in aflibercept and ranibizumab groups and 11 in the bevacizumab group). 1 Laser photocoagulation (focal, grid, or both) was required in 37% of patients treated with aflibercept, compared to 56% in those treated with bevacizumab and 46% in those treated with ranibizumab. The percentage of patients treated with aflibercept who needed photocoagulation was not affected by baseline VA, although patients with poorer VA (20/50 or worse at baseline) in the other two treatment arms required photocoagulation at a higher rate (65% in the bevacizumab arm and 50% in the ranibizumab arm). 1 The primary endpoint in the study was mean improvement in VA. While all 3 anti-vegfs induced improvement in overall VA letter score after 1 year, improvement in the aflibercepttreated eyes was significantly greater than eyes treated with bevacizumab or ranibizumab (13.3 vs. 9.7 and 11.2, respectively; P<0.001 for aflibercept vs. bevacizumab and P=0.03 vs. ranibizumab), although this improvement was not deemed to be clinically meaningful by the study authors (Figure 1). 1 Initial VA factored into the level of improvement among patients with baseline VA letter score between 78 to 69 (Snellen equivalent 20/32 to 20/42), there was no significant difference between the three agents, while among those with baseline VA letter score less than 69 (Snellen equivalent 20/50 or worse), there was a significantly higher mean improvement among patients treated with aflibercept (18.9±11.5 for aflibercept vs. 11.8±12.0 for bevacizumab and 14.2±10.6 for ranibizumab). 1 While patients in all three groups showed improvement in mean VA by 4 weeks, aflibercept s greater efficacy among patients with worse initial VA (Snellen equivalent 20/50 or worse) became apparent even at this early time point. 1 Patients treated with aflibercept also demonstrated greater decrease in central subfield thickness (169±138 µm for aflibercept vs. 101±121 µm with bevacizumab and 147±134 µm with ranibizumab). Thickness had decreased to less than 250 µm in 66% of eyes treated with aflibercept, 36% with bevacizumab, and 58% with ranibizumab. 1 Going Head-to-Head on Overall Ocular Safety: The Historical Perspective While all three anti-vegf agents have an excellent overall safety profile, there have been issues examined in clinical trials that warrant discussion. Endophthalmitis Infectious endophthalmitis is typically the most feared adverse event following intravitreal anti-vegf administration. Because diabetic patients are especially susceptible to systemic infections, this is particularly a concern among individuals being treated for DME. In most clinical trials, the rate of endophthalmitis among patients treated with an anti-vegf is <1%. In the VIEW 1 and 2 trials, for instance, there were 3 patients in both the ranibizumab-treated and aflibercept 2 mg monthly groups (1% prevalence in both) who developed endophthalmitis; no patients in the other two arms did so. 6 The CATT, IVAN, and GEFAL trials all demonstrated an incidence of endophthalmitis of <1 across all treatment groups%. 2-5 Several retrospective analyses of real-world case databases have also found a similar rate of endophthalmitis of <1%. 7,8 Bevacizumab Compounding Concerns One of the primary concerns regarding the use of intravitreal bevacizumab involves potential compounding inconsistencies and contamination risk. In the summer of 2011, Compounding Pharmacy Practices and Procedures For those practices that obtain bevacizumab from an external compounding pharmacy, it may be worthwhile to tour the facility and get a better sense of their practices and procedures. While a comprehensive checklist is available on the International Academy of Compounding Pharmacists website, here are some of the more pertinent questions you may want to ask when evaluating a compounding pharmacy: Are they licensed/registered in the state in which it is located? 2. How often do they aliquot bevacizumab from the larger vial into smaller concentrations? 3. Does the facility use vacuum hoods during the compounding process? 4. What kind of syringes (i.e., tuberculin vs. insulin) are being used? 5. How is the aliquoted drug packaged and transported to actual practices? 6. Is the lot number for individual vials recorded and stored? If so, how? four separate clusters of Streptococcus endophthalmitis tied to intravitreal bevacizumab were identified one each in Los Angeles, Miami, Minneapolis, and Nashville The most widely publicized of these outbreaks occurred in south Florida, where 12 patients at 4 community retinal practices received intravitreal bevacizumab that later tested culture positive for Streptococcus mitas/oralis. Contamination seems to have occurred at the compounding pharmacy that supplied the intravitreal bevacizumab as numerous problems in sterile technique were noted by public health investigators. Only 1 of the 12 affected patients recovered useful vision in her affected eye at 12 months, while 7 patients required either evisceration or enucleation. 10 As a result of these outbreaks, the U.S. Food and Drug Administration sent a letter to health care professionals warning that repackaging of sterile drugs such as bevacizumab without proper aseptic technique may compromise product, sterility and that providers should ensure they obtain products from appropriate, reliable sources. 12 The importance of that warning was further cemented with the devastating outbreak of fungal meningitis in 2012 that was tied to the New England Compounding Center and resulted in 64 deaths. Although none of these infections were tied to intravitreal bevacizumab, the outbreak led to increased discussion at the state and federal levels to tighten regulations on compounding pharmacies. 13 In October 2014, the American Academy of Ophthalmology published guidance regarding the sourcing of bevacizumab. This guidance emphasized the following when sourcing intravitreal bevacizumab: 14 Compounding pharmacies should be accredited by the Pharmacy Compounding Accrediting Board, which 4 Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy Supplement to Ophthalmology Times April

4 Table 2. Ocular and Systemic Adverse Events Through 1 Year in Protocol T Study Eye Event Aflibercept (N=224) adheres to quality standard for aseptic compounding of sterile medications (United States Pharmacopeia General Chapter <797>: Pharmaceutical Compounding Sterile Preparations) Lot numbers of bevacizumab should be recorded in the patient s medical record as well as in a separate logbook or spreadsheet should these need to be tracked at a later time Even under ideal circumstances, there are often variations in the protein concentrations of bevacizumab obtained from compounding pharmacies. A recent study by Yannuzzi et al assessed samples from 11 different compounding pharmacies in the United States and found significant variations in sample protein concentration both between pharmacies as well as from samples taken from the same pharmacy. The clinical relevance of this variation is, however, unclear, and it is important to note that no microbial contaminants or endotoxin were detected in any of the samples. 15 Interestingly, a handful of ophthalmology practices, including the Cincinnati Eye Institute, have set up their own compounding pharmacies to specifically handle the compounding of intravitreal bevacizumab. These pharmacies are required to meet the same accreditation standards as more general compounding pharmacies. Bevacizumab Ranibizumab Endophthalmitis P Value Inflammation 2 (1%) 2 (1%) 2 (1%) 1.0 Elevation in IOP 32 (14%) 19 (9%) 23 (11%) 0.18 Nonstudy Eye Event Endophthalmitis 1 (1%) 0 1 (1%) 0.77 Inflammation 3 (2%) 1 (1%) Elevation in IOP 15 (12%) 11 (9%) 11 (9%) 0.77 Systemic Events Nonfatal myocardial infarction 4 (2%) 1 (<0.5%) 3 (1%) Nonfatal stroke 0 4 (2%) 4 (2%) Death from potential vascular or unknown cause 2 (1%) 4 (2%) 3 (1%) Any serious adverse event 59 (26%) 46 (21%) 55 (25%) 0.40 Increases in Intraocular Pressure Transient short-term increases in intraocular pressure (IOP) are a well-known complication of intravitreal administration. Studies have shown that there is often an immediate increase in IOP within the first minute post-injection, but that these levels typically return to at or near-normal levels with 1 hour. 17, 18 Of more significant concern are long-term increases in IOP that may be associated to anti-vegfs. A post-hoc analysis of the MARINA and ANCHOR trials, which both involved the use of ranibizumab in patients with wet AMD, showed that 2.1% (MARINA) and 3.6% (ANCHOR) of eyes met criteria for long-term increase in IOP. 19, 20 A prevalence of between 0% and 5% in long-term increases in IOP following anti-vegf administration has been confirmed in additional retrospective analyses. It is typically recommended that clinicians regularly monitor IOP levels in their patients receiving intravitreal anti-vegfs. What Protocol T Adds to the Equation Ocular safety issues were rare across all three treatment arms in Protocol T (Table 1). Endophthalmitis occurred in one treated eye in both the aflibercept and ranibizumab cohorts (both <1%). Ocular inflammation other than endophthalmitis occurred in two study eyes in each study group, as well as in three contralateral eyes in the aflibercept group and one in the bevacizumab group. 1 There were no issues identified related to the compounding of bevacizumab in the study all single-use vials utilized in the study were repackaged at a central pharmacy and distributed to coordinating centers. 1 Elevations in IOP (defined either as an increase 10 mm Hg or more from baseline at any visit, reading of 30 mm Hg at any visit, or the initiation of a new medication to lower IOP), were seen in 12% of patients in the aflibercept group, 9% in the bevacizumab group, and 9% in the ranibizumab group. These percentages are slightly higher than found in AMD trials, although direct comparisons are difficult due to differing definitions of an elevation of IOP in these trials. 1 Going Head-to-Head on Systemic Safety: The Historical Perspective Ranibizumab, bevacizumab, and aflibercept differ in their pharmacokinetics, structure, and molecular weight. Ranibizumab is the smallest molecule, comprised of the fragment, antigen-binding (Fab) region alone, while both bevacizumab and aflibercept also contain the fragment, crystallizable (Fc) region. Because it lacks this Fc region, the half-life of ranibizumab is much shorter compared to the other two anti-vegf agents. 21 As use of the three anti-vegfs has proliferated in the treatment of AMD and DME, several studies have measured levels of VEGF in the bloodstream following intravitreal administration to determine systemic exposure to each agent. Most recently, a study by Avery et al demonstrated that mean systemic exposure to bevacizumab following first and third dosing was highest among the anti-vegfs, while exposure to ranibizumab was the lowest. Aflibercept, meanwhile, showed the greatest suppression of free plasma VEGF through day 7 following initial intravitreal administration. 21 This data confirmed work done in previous trials, perhaps most notably the IVAN trial. 22 The primary issue for clinicians, however, isn t about whether there is a differences in systemic levels of anti- VEGFs in the bloodstream following intravitreal administration but rather whether it impacts overall systemic safety. On this issue, opinions are mixed. Overall Safety in Patients >85 years of Age In 2014, a well-publicized Public Assessment Report was published by the European Medicines Agency that pooled available data regarding the use of aflibercept in neovascular AMD. This report observed a higher number of cerebrovascular accidents during the first year of treatment in patients treated with aflibercept compared to those treated with ranibizumab (n=35, 1.9% vs. n=2, 0.3%). This difference was further magnified among patients aged 85 and older, where there were 20 cases of cerebrovascular accidents in patients treated with aflibercept (7.1%) vs. only 1 case in those treated with ranibizumab (1.1%) after one year. After two years of treatment, 27 cases were reported among patients >85 years treated with aflibercept (9.5%) vs. three cases in those treated with ranibizumab (3.4%). 23 There are, however, a few important caveats that should be kept in mind when interpreting these data: 23 There were approximately three times more patients treated with aflibercept than ranibizumab across the entire analysis as well as within each individual subgroup. As a result, a threefold increase of any adverse event in any patient groups would have been considered normal. So while the 20:1 and 27:3 ratios indeed exceed relative equivalency, the differences are not, perhaps, as striking as they may seem on their face. - In a larger patient subgroup (75-to-85- year old patients), the number of cerebrovascular events at 2 years was only 20 in the aflibercept group vs. 9 in the ranibizumab group, which is well under the 3:1 ratio. The analysis looked only at non-adjudicated events that were determined by a single physician and could therefore be subject to individual bias. Regarding cardiovascular events, there were an equivalent amount of raw events in the >85 age groups at 1 year (8 in each), but this represented 9.2% of ranibizumab patients and 2.8% of aflibercept patients. At 2 years, there were 21 cardiovascular events among patients treated with aflibercept (7.4%) vs. 9 in the ranibizumab group (10.3%). Serious systemic adverse events and hospitalizations rates in Protocol T were similar across the three treatment groups. A post-hoc analysis of the rate of combined cardiac and vascular adverse effects were highest in the ranibizumab-treated group, though the study authors suggested this may have been due to chance since previous trials had not shown an increased cardiovascular risk with ranibizumab. 1 While the Protocol T enrollment was not large enough to enable significant conclusions to be drawn from a subset analysis by patient age (e.g., in the >85 age group), there were limited cerebrovascular and cardiovascular events found in the full patient pool. 1 Among patients with both unilateral and bilateral anti- VEGF treatment during the course of the study, there were 2 cases of stroke in the bevacizumab and ranibizumab groups (2% for both) and none in the aflibercept group. 1 There were more cardiovascular events in the ranibizumab group at 1 year compared to the other two groups excluding hypertension, there were 37 cardiac events in the ranibizumab group (17%) vs. 20 in the aflibercept group (9%) and 19 in the bevacizumab group (9%). 1 So How Has the Decision-Making Equation Now Changed? In conjunction with the publication of Protocol T data, an editorial was published in the New England Journal of Medicine by Daniel Martin, MD, and Maureen Maguire, MD, that provide an analysis of the Protocol T data. Their primary 6 Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy Supplement to Ophthalmology Times April

5 conclusions were as follows: All three anti-vegf agents produce substantial improvement at 1 year in patients with DME 2. Given the large cost difference among the three agents (approximately $50 per dose for bevacizumab, $1,200 for ranibizumab and $1,950 for aflibercept), bevacizumab should be considered as first-line therapy in patients with baseline VA of 20/40 or better. In Protocol T, approximately 50% of patients presented with baseline VA in this range Aflibercept should be considered first-line therapy in patients who present with baseline VA of 20/50 or worse, with bevacizumab as the primary alternative. 4. Current requirements for a patient-specific prescription, drug-specific rebates offered to physicians by pharmaceutical companies, and policies of the Centers for Medicare and Medicaid Services to reimburse based on the percentage of cost of a drug should be eliminated so that patients may have access to the safest, most efficacious, and least expensive drug for their particular circumstance. Retinal physicians will, of course, have to make their own judgments regarding any changes they may make as a result of the growing body of data regarding anti-vegf use in AMD and DME, and payor influence on drug choice must not be ignored. Additional real-world comparative data will only help further educate and justify use of specific agents in the future. References 1. The Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med Feb 18. [Epub ahead of print] 2. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364: Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119: IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119: Kodjikian L, Souied EH, Mimoun G, et al; GEFAL Study Group. Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial. Ophthalmology. 2013;120: 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: Lyall DA, Tey A, Foot B, Roxburgh ST, Virdi M, Robertson C, MacEwen CJ. Post-intravitreal anti-vegf endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond). 2012;26: Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC. Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012;119: Gonzalez S, Rosenfeld PJ, Stewart MW, et al. Avastin doesn t blind people, people blind people. Am J Ophthalmol. 2012;153: Goldberg RA, Flynn HW, Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: One-year outcomes and investigative results. Ophthalmology. 2013;120: Goldberg RA, Flynn HW, Isom RF, et al. An outbreak of Streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153: U.S. Food and Drug Administration. FDA alerts health care professionals of infection risk from repackaged Avastin intravitreal injections. Available at Accessed March 18, Centers for Disease Control and Prevention. Multistate outbreak of fungal meningitis and other infections. Available at meningitis.html. Accessed March 18, American Academy of Ophthalmology. Verifying the source of compounded bevacizumab for intravitreal injections October Available at one.aao. org/clinical-statement/verifying-source-of-compounded-bevacizumab-intravi-2. Accessed March 18, Yannuzzi NA, Klufas MA, Quach L, et al. Evaluation of compounded bevacizumab prepared for intravitreal injection. JAMA Ophthalmol. 2015;133: International Association of Compounding Pharmacists. Compounding Pharmacy Assessment Questionnaire (CPAQ ). Available at c.ymcdn.com/sites/ pdf. Accessed March 18, Gismondi M, Salati C, Salvetat ML, Zeppieri M, Brusini P. Short-term effect of intravitreal injection of Ranibizumab (Lucentis) on intraocular pressure. J Glaucoma. 2009;18: Kim JE, Mantravadi AV, Hur EY, Covert DJ. Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol. 2008;146: Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355: Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355: Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab, or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98: Chakravarthy U, Rogers C, Reeves B, et al. Alterations in serum vascular endothelial growth factor after intraocular administration of anti-vegf drugs, is there an association with safety outcomes? Presented at the 2014 Association for Research in Vision and Ophthalmology annual meeting. Abstract European Medical Agency Committee for Medicinal Products for Human Use Assessment Report. Elyea Available at eu/docs/en_gb/document_library/epar_-_public_assessment_report/human/002392/wc pdf. Accessed March 18, Martin DF, Maguire MG. Treatment choice for diabetic macular edema. N Engl J Med Feb 18 [Epub ahead of print]. Sponsored by Supported by an unrestricted grant from 8 Safety and Efficacy Concerns in the Use of Intravitreal Anti-VEGF Therapy