眼科新药Eylea（aflibercept 阿柏西普）注射液获FDA批准扩大用于治疗DME患者的糖尿病性视网膜病变 美国FDA于2015年3月25日扩大了Eylea（aflibercept 阿柏西普）注射液新适应症，用于治疗糖尿病性黄斑水肿（DME）患者的糖尿病视网膜病变。 糖尿病视网膜病变是最常见的糖尿病眼病，也是造成美国成年人失明的主要原因之一。依据美国疾病控制与预防中心(CDC)的数据，美国当前糖尿病患者（包括1型和2型糖尿病）例数已超过2900万，而且，糖尿病也是美国20–74岁人群致盲的最主要原因。 早在2008年，美国40岁及以上的成年糖尿病患者中约有33%患有某种形式的糖尿病视网膜病变。而且，在一些DME合并糖尿病视网膜病变的病例中，在视网膜表面可见异常的新生血管生长，如果这些新生血管呈爆发式生长，就会造成重度视力下降、甚至失明。 FDA药品评价和研究中心抗菌药物办公室主任Edward Cox教授表示：“糖尿病是一个非常严重的公共健康问题，其患病人数呈逐年递增趋势。Eylea成功获批为糖尿病视网膜病变和DME患者提供了新的选择，以治疗这种可损伤视力的并发症。” 在今年2月份，FDA刚刚批准Lucentis（雷珠单抗注射液）0.3mg用于治疗DME患者的糖尿病视网膜病变。 Eylea作为一种注射剂，由医护人员帮助患者注入眼内，在初始5个月内每月注射给药一次，之后每两月注射给药一次，需要与能够有效控制血糖、血压和血脂的干预治疗措施联合使用。 Eylea治疗DME患者糖尿病视网膜病变的安全性和有效性在两项涉及679例受试者的临床研究中得到证实，在这两项研究中，受试者被随机分为Eylea治疗组和黄斑激光光凝术治疗组（利用激光束灼烧视网膜细小血管）。治疗100周后，与未接受Eylea治疗受试者相比，接受Eylea治疗受试者糖尿病视网膜病变的严重程度得到显著改善。 Eylea治疗期间最常见的不良反应包括结膜出血、眼睛疼痛、白内障、飞蚊症、眼内压增加、以及玻璃体脱离。严重不良反应包括眼内感染和视网膜脱离。 FDA授予Eylea治疗DME患者糖尿病性视网膜病变的突破性治疗药物资格。同时，如果能有初步临床证据提示某种药物在治疗危重症或威胁生命疾病方面显著优于现有治疗药物，FDA可以赞助者要求下指定这种药物为一种突破性治疗药物。此外，FDA还授予Eylea针对新适应症所提上市申请的优先评审资格。 此前，FDA已批准Eylea用于治疗湿性（新生血管性）老年性黄斑变性，这是一种以黄斑区异常新生血管生长和渗液水肿为特征的疾病。此外，Eylea还被批准用于治疗DME和视网膜静脉阻塞继发黄斑水肿，这两种疾病都可引起黄斑区渗液水肿，并最终导致视物模糊。 Eylea由新泽西再生元制药公司负责推广销售。而Lucentis则由罗氏旗下的Genentech公司负责销售推广。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EYLEA safely and effectively. See full prescribing information for EYLEA. EYLEA®(aflibercept) Injection For Intravitreal Injection Initial U.S. Approval: 2011 RECENT MAJOR CHANGES Dosage and Administration, Neovascular (Wet) Age-Related Macular Degeneration (AMD) (2.2) 5/2016 Dosage and Administration, Diabetic Macular Edema (DME) (2.4) 5/2016 Dosage and Administration, Diabetic Retinopathy (DR) in Patients with DME (2.5) 5/2016 Contraindications, Hypersensitivity (4.3) 10/2016 INDICATIONS AND USAGE EYLEA is indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1) Macular Edema Following Retinal Vein Occlusion (RVO) (1.2) Diabetic Macular Edema (DME) (1.3) Diabetic Retinopathy (DR) in Patients with DME (1.4) DOSAGE AND ADMINISTRATION Neovascular (Wet) Age-Related Macular Degeneration (AMD) The recommended dose for EYLEA is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). (2.2) Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). (2.2) Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for EYLEA is 2 mg (0.05 mL) administered by intravitreal injection once every 4 weeks (monthly). (2.3) Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in Patients with Diabetic Macular Edema The recommended dose for EYLEA is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). (2.4, 2.5) Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). (2.4, 2.5) DOSAGE FORMS AND STRENGTHS 40 mg/mL solution for intravitreal injection in a single-use vial (3) CONTRAINDICATIONS Ocular or periocular infection (4.1) Active intraocular inflammation (4.2) Hypersensitivity (4.3) WARNINGS AND PRECAUTIONS Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately. (5.1) Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2) There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.3) ADVERSE REACTIONS The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-855-395-3248 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 10/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE EYLEA is indicated for the treatment of: 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) 1.2 Macular Edema Following Retinal Vein Occlusion (RVO) 1.3 Diabetic Macular Edema (DME) 1.4 Diabetic Retinopathy (DR) in Patients with DME 2 DOSAGE AND ADMINISTRATION 2.1 Important Injection Instructions For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.1)]. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). 2.3 Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly) [see Clinical Studies (14.2), (14.3)]. 2.4 Diabetic Macular Edema (DME) The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). 2.5 Diabetic Retinopathy (DR) in Patients with DME The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). 2.6 Preparation for Administration EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used. Using aseptic technique, the intravitreal injection should be performed with a 30-gauge × ½-inch injection needle. Vial The glass vial is for single use only. Remove the protective plastic cap from the vial (see Figure 1). Clean the top of the vial with an alcohol wipe (see Figure 2). Remove the 19-gauge × 1½-inch, 5-micron, filter needle from its pouch and remove the 1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 3). Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial. Using aseptic technique withdraw all of the EYLEA vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid (see Figures 4a and 4b). Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. Remove the filter needle from the syringe and properly dispose of the filter needle. Note: Filter needle is not to be used for intravitreal injection. Remove the 30-gauge × ½-inch injection needle from the plastic pouch and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 5). When ready to administer EYLEA, remove the plastic needle shield from the needle. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 6). To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe (see Figures 7a and 7b). 2.7 Injection Procedure The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection. Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available. Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient Counseling Information (17)]. Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYLEA is administered to the other eye. After injection, any unused product must be discarded. 3 DOSAGE FORMS AND STRENGTHS Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution (2 mg) for intravitreal injection. 4 CONTRAINDICATIONS 4.1 Ocular or Periocular Infections EYLEA is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation EYLEA is contraindicated in patients with active intraocular inflammation. 4.3 Hypersensitivity EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation. 5 WARNINGS AND PRECAUTIONS 5.1 Endophthalmitis and Retinal Detachments Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately [see Dosage and Administration (2.7) and Patient Counseling Information (17)]. 5.2 Increase in Intraocular Pressure Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.7)]. 5.3 Thromboembolic Events There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies. 6 ADVERSE REACTIONS The following potentially serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications (4.3)] Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)] Increase in intraocular pressure [see Warnings and Precautions (5.2)] Thromboembolic events [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice. A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3 studies. Among those, 2110 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment. Neovascular (Wet) Age-Related Macular Degeneration (AMD) The data described below reflect exposure to EYLEA in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months [see Clinical Studies (14.1)]. Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies Adverse Reactions EYLEA (N=1824) Active Control (ranibizumab) (N=595) Conjunctival hemorrhage 25% 28% Eye pain 9% 9% Cataract 7% 7% Vitreous detachment 6% 6% Vitreous floaters 6% 7% Intraocular pressure increased 5% 7% Ocular hyperemia 4% 8% Corneal epithelium defect 4% 5% Detachment of the retinal pigment epithelium 3% 3% Injection site pain 3% 3% Foreign body sensation in eyes 3% 4% Lacrimation increased 3% 1% Vision blurred 2% 2% Intraocular inflammation 2% 3% Retinal pigment epithelium tear 2% 1% Injection site hemorrhage 1% 2% Eyelid edema 1% 2% Corneal edema 1% 1% Less common serious adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis. Macular Edema Following Retinal Vein Occlusion (RVO) The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following BRVO in one clinical study (VIBRANT) [see Clinical Studies (14.2), (14.3)]. Table 2: Most Common Adverse Reactions (≥1%) in RVO Studies  Adverse Reactions CRVO BRVO EYLEA (N=218) Control (N=142) EYLEA (N=91) Control (N=92) Eye pain 13% 5% 4% 5% Conjunctival hemorrhage 12% 11% 20% 4% Intraocular pressure increased 8% 6% 2% 0% Corneal epithelium defect 5% 4% 2% 0% Vitreous floaters 5% 1% 1% 0% Ocular hyperemia 5% 3% 2% 2% Foreign body sensation in eyes 3% 5% 3% 0% Vitreous detachment 3% 4% 2% 0% Lacrimation increased 3% 4% 3% 0% Injection site pain 3% 1% 1% 0% Vision blurred 1% <1% 1% 1% Intraocular inflammation 1% 1% 0% 0% Cataract <1% 1% 5% 0% Eyelid edema <1% 1% 1% 0% Less common adverse reactions reported in <1% of the patients treated with EYLEA in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis. Diabetic Macular Edema (DME) The data described below reflect exposure to EYLEA in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100 [see Clinical Studies (14.4)]. Table 3: Most Common Adverse Reactions (≥1%) in DME Studies Adverse Reactions Baseline to Week 52 Baseline to Week 100 EYLEA (N=578) Control (N=287) EYLEA (N=578) Control (N=287) Conjunctival hemorrhage 28% 17% 31% 21% Eye pain 9% 6% 11% 9% Cataract 8% 9% 19% 17% Vitreous floaters 6% 3% 8% 6% Corneal epithelium defect 5% 3% 7% 5% Intraocular pressure increased 5% 3% 9% 5% Ocular hyperemia 5% 6% 5% 6% Vitreous detachment 3% 3% 8% 6% Foreign body sensation in eyes 3% 3% 3% 3% Lacrimation increased 3% 2% 4% 2% Vision blurred 2% 2% 3% 4% Intraocular inflammation 2% <1% 3% 1% Injection site pain 2% <1% 2% <1% Eyelid edema <1% 1% 2% 1% Less common adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response in patients treated with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to EYLEA in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other products may be misleading. In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. There were no differences in efficacy or safety between patients with or without immunoreactivity. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg. There are no adequate and well-controlled studies in pregnant women. EYLEA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females of reproductive potential should use effective contraception prior to the initial dose, during treatment, and for at least 3 months after the last intravitreal injection of EYLEA. 8.3 Nursing Mothers It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted in human milk, a risk to the breastfed child cannot be excluded. EYLEA is not recommended during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue treatment with EYLEA, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of EYLEA in pediatric patients have not been established. 8.5 Geriatric Use In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. 11 DESCRIPTION EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells. EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of EYLEA (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability. Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors. 12.2 Pharmacodynamics Neovascular (Wet) Age-Related Macular Degeneration (AMD) In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions [see Clinical Studies (14.1)]. Macular Edema Following Retinal Vein Occlusion (RVO) Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions [see Clinical Studies (14.2), (14.3)]. Diabetic Macular Edema (DME) Reductions in mean retinal thickness were observed in VIVID and VISTA at weeks 52 and 100 compared to baseline. Anatomic data were not used to influence EYLEA treatment decisions [see Clinical Studies (14.4)]. 12.3 Pharmacokinetics EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of EYLEA, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex). Absorption/Distribution Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD, RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF. The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L. Metabolism/Elimination Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept. Specific Populations Renal Impairment Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a RVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, RVO, or DME patients. Other No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment. 13.2 Animal Toxicology and/or Pharmacology Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in humans after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies [see Clinical Studies (14)]. 14 CLINICAL STUDIES 14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with EYLEA) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 3 initial monthly doses (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered every 4 weeks (EYLEA 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Data are available through week 52. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group. Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 4 and Figure 8 below. Table 4: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and VIEW2 Studies VIEW1 VIEW2 EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks ranibizumab 0.5 mg Q4 weeks EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks ranibizumab 0.5 mg Q4 weeks Full Analysis Set N=301 N=304 N=304 N=306 N=309 N=291 BCVA = Best Corrected Visual Acuity; CI = Confidence Interval; ETDRS = Early Treatment Diabetic Retinopathy Study; LOCF = Last Observation Carried Forward (baseline values are not carried forward); 95.1% confidence intervals were presented to adjust for safety assessment conducted during the study. Efficacy Outcomes Proportion of patients who maintained visual acuity (%) (<15 letters of BCVA loss) 94% 95% 94% 95% 95% 95% Difference (%) (95.1% CI) 0.6 (-3.2, 4.4) 1.3 (-2.4, 5.0) 0.6 (-2.9, 4.0) -0.3 (-4.0, 3.3) Mean change in BCVA as measured by ETDRS letter score from Baseline 7.9 10.9 8.1 8.9 7.6 9.4 Difference in LS mean (95.1% CI) 0.3 (-2.0, 2.5) 3.2 (0.9, 5.4) -0.9 (-3.1, 1.3) -2.0 (-4.1, 0.2) Number of patients who gained at least 15 letters of vision from Baseline (%) 92 (31%) 114 (38%) 94 (31%) 96 (31%) 91 (29%) 99 (34%) Difference (%) (95.1% CI) -0.4 (-7.7, 7.0) 6.6 (-1.0, 14.1) -2.6 (-10.2, 4.9) -4.6 (-12.1, 2.9) After treatment initiation with 3 monthly doses  EYLEA group minus the ranibizumab group  Figure 8: Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and VIEW2 Studies 14.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO) The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with EYLEA) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89 years with a mean of 64 years. In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint. Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 5 and Figure 9 below. Table 5: Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in COPERNICUS and GALILEO Studies  COPERNICUS GALILEO Control EYLEA 2 mg Q4 weeks Control EYLEA 2 mg Q4 weeks N=73 N=114 N=68 N=103 Efficacy Outcomes Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 12% 56% 22% 60% Weighted Difference * (%) (95.1% CI) 44.8%‡ (32.9, 56.6) 38.3%‡ (24.4, 52.1) Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) -4.0 (18.0) 17.3 (12.8) 3.3 (14.1) 18.0 (12.2) Difference in LS mean *,§ (95.1% CI) 21.7‡ (17.3, 26.1) 14.7‡ (10.7, 18.7) Difference is EYLEA 2 mg Q4 weeks minus Control Difference and CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for baseline factors; 95.1% confidence intervals were presented to adjust for the multiple assessments conducted during the study. p<0.01 compared with Control LS mean and CI based on an ANCOVA model Figure 9: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in COPERNICUS and GALILEO Studies Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations. 14.3 Macular Edema Following Branch Retinal Vein Occlusion (BRVO) The safety and efficacy of EYLEA were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with EYLEA) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint. Detailed results from the analysis of the VIBRANT study are shown in Table 6 and Figure 10 below. Table 6: Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in VIBRANT Study VIBRANT Control EYLEA 2 mg Q4 weeks N=90 N=91 Efficacy Outcomes Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 26.7% 52.7% Weighted Difference *,† (%) (95% CI) 26.6%‡ (13.0, 40.1) Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 6.9 (12.9) 17.0 (11.9) Difference in LS mean *,§ (95% CI) 10.5‡ (7.1, 14.0) Difference is EYLEA 2 mg Q4 weeks minus Control Difference and CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200) p<0.01 compared with Control LS mean and CI based on an ANCOVA model Figure 10: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations. 14.4 Diabetic Macular Edema (DME) The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Patient ages ranged from 23 to 87 years with a mean of 63 years. Of those, 576 were randomized to EYLEA groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 5 initial monthly injections (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the EYLEA groups could receive laser and patients in the laser group could receive EYLEA. In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both EYLEA 2Q8 and EYLEA 2Q4 groups was statistically superior to the control group. This statistically superior improvement in BCVA was maintained at week 100 in both studies. Results from the analysis of the VIVID and VISTA studies are shown in Table 7 and Figure 11 below. Table 7: Efficacy Outcomes at Weeks 52 and 100 (Full Analysis Set with LOCF) in VIVID and VISTA Studies  VIVID VISTA EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks Control EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks Control Full Analysis Set N=135 N=136 N=132 N=151 N=154 N=154 Efficacy Outcomes at Week 52 Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 10.7 (9.3) 10.5 (9.6) 1.2 (10.6) 10.7 (8.2) 12.5 (9.5) 0.2 (12.5) Difference in LS mean (97.5% CI) 9.1§ (6.3, 11.8) 9.3§ (6.5, 12.0) 10.5§ (7.7, 13.2) 12.2§ (9.4, 15.0) Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 33.3% 32.4% 9.1% 31.1% 41.6% 7.8% Adjusted Difference,  (%) (97.5% CI) 24.2%§ (13.5, 34.9) 23.3%§ (12.6, 33.9) 23.3%§ (13.5, 33.1) 34.2%§ (24.1, 44.4) Efficacy Outcomes at Week 100 Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 9.4 (10.5) 11.4 (11.2) 0.7 (11.8) 11.1 (10.7) 11.5 (13.8) 0.9 (13.9) Difference  in LS mean (97.5% CI) 8.2§ (5.2, 11.3) 10.7§ (7.6, 13.8) 10.1§ (7.0, 13.3) 10.6§ (7.1, 14.2) Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 31.1% 38.2% 12.1% 33.1% 38.3% 13.0% Adjusted Difference‡,  (%) (97.5% CI) 19.0%§ (8.0, 29.9) 26.1%§ (14.8, 37.5) 20.1%§ (9.6, 30.6) 25.8%§ (15.1, 36.6) After treatment initiation with 5 monthly injections LS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, protocol specified stratification factors were included in the model. Difference is EYLEA group minus Control group p<0.01 compared with Control Difference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors. Figure 11: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 in VIVID and VISTA Studies Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation. Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations. 14.5 Diabetic Retinopathy (DR) in Patients with DME In the VIVID and VISTA studies, an efficacy outcome was the change in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (ETDRS-DRSS). The ETDRS-DRSS score was assessed at baseline and approximately every 6 months thereafter for the duration of the studies [see Clinical Studies (14.4)]. All enrolled patients had DR and DME at baseline. The majority of patients enrolled in these studies (77%) had moderate-to-severe nonproliferative diabetic retinopathy (NPDR) based on the ETDRS-DRSS. At week 100, the proportion of patients improving by at least 2 steps on the ETDRS-DRSS was significantly greater in both EYLEA treatment groups (2Q4 and 2Q8) when compared to the control group. Results from the analysis of ETDRS-DRSS at week 100 in the VIVID and VISTA studies are shown in Table 8 below. Table 8: Proportion of Patients who Achieved a ≥2-Step Improvement from Baseline in the ETDRS-DRSS Score at Week 100 (LOCF*) in VIVID and VISTA Studies  VIVID VISTA EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks Control EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks Control Evaluable Patients N=101 N=97 N=99 N=148 N=153 N=150 Number of patients with a ≥2-step improvement on ETDRS-DRSS from Baseline (%) 32 (32%) 27 (28%) 7 (7%) 56 (38%) 58 (38%) 24 (16%) Difference§(%) (97.5% CI) 24% (12, 36) 21% (9, 33) 22% (11, 33) 22% (11, 33) Non-gradable post-baseline ETDRS-DRSS values were treated as missing and were imputed using the last gradable ETDRS-DRSS values (including baseline values if all post-baseline values were missing or non-gradable) After treatment initiation with 5 monthly injections The number of evaluable patients included all patients who had valid ETDRS-DRSS data at baseline Difference with confidence interval (CI) was calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors Difference is EYLEA minus Control group p<0.01 compared with Control Results of the evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity) on the proportion of patients who achieved a ≥2-step improvement on the ETDRS-DRSS from baseline to week 100 were, in general, consistent with those in the overall population. 16 HOW SUPPLIED/STORAGE AND HANDLING Each Vial is for single eye use only. EYLEA is supplied in the following presentation [see Dosage and Administration (2.6) and (2.7)]. NDC NUMBER CARTON TYPE CARTON CONTENTS 61755-005-02 Vial one single-use, sterile, 3-mL, glass vial designed to deliver 0.05 mL of 40 mg/mL EYLEA one 19-gauge × 1½-inch, 5-micron, filter needle for withdrawal of the vial contents one 30-gauge × ½-inch injection needle for intravitreal injection one 1-mL syringe for administration one package insert Storage EYLEA should be refrigerated at 2°C to 8ºC (36°F to 46ºF). Do Not Freeze. Do not use beyond the date stamped on the carton and container label. Protect from light. Store in the original carton until time of use. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f96cfd69-da34-41ee-90a9-610a4655cd1c