英文药名：EYLEA(aflibercept solution for injection  vial) 中文药名：阿普西柏溶液注射剂 生产厂家：德国拜耳 药品介绍 2015年2月27日,拜耳（Bayer）及合作伙伴再生元（Regeneron）的眼科药物（aflibercept，阿柏西普注射液）在欧盟收获第4个适应症。欧盟委员会（EC）已批准Eylea用于视网膜静脉阻塞继发黄斑水肿（RVO-ME）的治疗，包括视网膜分支静脉阻塞继发黄斑水肿（BRVO-ME）及先前已获批的视网膜中央静脉阻塞继发黄斑水肿（CRVO-ME）。建议的治疗方法为：起始治疗时每周注射一次直至达到最大视力和/或无疾病活动迹象；之后，以一种“治疗-延长”方案继续治疗，逐渐延长治疗时间间隔，以维持稳定的视觉和/或解剖学结果。 在欧盟，Eylea已获批的另外3个适应症为：湿性年龄相关性黄斑变性（wet-AMD），视网膜中央静脉阻塞继发黄斑水肿（CRVO-ME），糖尿病性黄斑水肿（DME）。 Eylea新适应症的获批，基于一项为期52周的双盲、随机、主动控制III期研究（VIBRANT）的结果。该研究在视网膜分支静脉阻塞（BRVO）继发黄斑水肿（ME）患者中开展，Eylea治疗组每月注射2mg剂量Eylea，对照组接受激光光凝治疗。数据表明，在研究的24周，Eylea治疗组有更高比例的患者最佳矫正视力（BCVA）取得了至少15个字母的改善（53% vs 27%，p＜0.001），达到了研究的主要终点。 此外，Eylea治疗组BCVA从基线平均改善达17.0个字母，对照组为6.9个字母，达到了研究的关键次要终点（p＜0.0001）。 目前，眼科治疗领域，拜耳正与罗氏及诺华展开激烈竞争。Eylea于2011年上市，但近年来发展势头迅猛，适应症个数及全球销售一再刷新并连续多次超过业界预期，已对罗氏和诺华眼科药物Lucentis（2006年上市）形成严峻挑战。此外，根据拜耳2014年10月公布的一项研究，用于治疗糖尿病性黄斑水肿（DME）时，Eylea击败了Lucentis和Avastin，该项研究结果使得Eylea在DME领域更具影响力。 不过，本月中旬，Lucentis率先赢得FDA祝福，拿下糖尿病性视网膜病变（DR）适应症，标志着对Eylea强有力的反击，该适应症也是Lucentis在美国市场收获的第4个适应症。其他3个适应症分别为：糖尿病性黄斑水肿（DME，2006年）、视网膜静脉阻塞继发黄斑水肿（RVO-ME，2010年）和湿性年龄相关性黄斑变性（wet-AMD，2012）。 Eylea 40mg/ml solution for injection in a vial 1. Name of the medicinal product Eylea 40 mg/ml solution for injection in a vial. 2. Qualitative and quantitative composition 1 ml solution for injection contains 40 mg aflibercept*. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. This provides a usable amount to deliver a single dose of 50 microlitres containing 2 mg aflibercept. Fusion protein consisting of portions of human VEGF (Vascular Endothelial Growth Factor) receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 and produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection (injection) The solution is a clear, colourless to pale yellow and iso-osmotic solution. 4. Clinical particulars 4.1 Therapeutic indications Eylea is indicated for adults for the treatment of • neovascular (wet) age-related macular degeneration (AMD) (see section 5.1), • visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO) (see section 5.1), • visual impairment due to diabetic macular oedema (DME) (see section 5.1). 4.2 Posology and method of administration Eylea is for intravitreal injection only. Eylea must only be administered by a qualified physician experienced in administering intravitreal injections. Posology wet AMD The recommended dose for Eylea is 2 mg aflibercept, equivalent to 50 microlitres. Eylea treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections. After the first 12 months of treatment with Eylea, the treatment interval may be extended based on visual and/or anatomic outcomes. In this case the schedule for monitoring should be determined by the treating physician and may be more frequent than the schedule of injections. Macular Oedema secondary to RVO (branch RVO or central RVO) The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres. After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should be discontinued. Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed. Treatment may then be continued with a treat and extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. The monitoring and treatment schedule should be determined by the treating physician based on the individual patient's response. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). Diabetic Macular Oedema The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres. Eylea treatment is initiated with one injection per month for five consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections. After the first 12 months of treatment with Eylea, the treatment interval may be extended based on visual and/or anatomic outcomes. The schedule for monitoring should be determined by the treating physician. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should be discontinued. Special populations Hepatic and/or renal impairment No specific studies in patients with hepatic and/or renal impairment have been conducted with Eylea. Available data do not suggest a need for a dose adjustment with Eylea in these patients (see section 5.2). Elderly population No special considerations are needed. There is limited experience in patients older than 75 years with DME. Paediatric population Safety and efficacy have not been established in children and adolescents. There is no relevant use of Eylea in the paediatric population in the indications wet AMD, CRVO, BRVO and DME. Method of administration Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. In general, adequate anaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine applied to the periocular skin, eyelid and ocular surface), have to be ensured. Surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended. The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections. 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, sterile equipment for paracentesis should be available. Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg aflibercept. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Injecting the entire volume of the vial could result in overdose. To expel the air bubble along with excess medicinal product, slowly depress the plunger to align the cylindrical base of the dome plunger with the black dosing line on the syringe (equivalent to 50 microlitres i.e. 2 mg aflibercept). After injection any unused product must be discarded. For handling of the medicinal product, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance aflibercept or to any of the excipients listed in section 6.1. Active or suspected ocular or periocular infection. Active severe intraocular inflammation. 4.4 Special warnings and precautions for use Intravitreal injection-related reactions Intravitreal injections, including those with Eylea, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering Eylea. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including those with Eylea (see section 4.8). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Eylea while the intraocular pressure is ≥ 30 mmHg). In all cases, both the intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately. Immunogenicity As this is a therapeutic protein, there is a potential for immunogenicity with Eylea (see section 4.8). Patients should be instructed to report any signs or symptoms of intraocular inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign attributable to hypersensitivity. Systemic effects Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with CRVO, BRVO or DME with a history of stroke or transient ischaemic attacks or myocardial infarction within the last 6 months. Caution should be exercised when treating such patients Other As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO and DME the following also applies: • The safety and efficacy of Eylea therapy administered to both eyes concurrently have not been systematically studied (see section 5.1). If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events. • Concomitant use of other anti-VEGF (vascular endothelial growth factor) There is no data available on the concomitant use of Eylea with other anti-VEGF medicinal products (systemic or ocular). • Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinal detachment. When initiating Eylea therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears. • Treatment should be withheld in patients with rhegmatogenous retinal detachment or stage 3 or 4 macular holes. • In the event of a retinal break the dose should be withheld and treatment should not be resumed until the break is adequately repaired. • The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of: • a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; • a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area. • The dose should be withheld within the previous or next 28 days in the event of a performed or planned intraocular surgery. • Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus (see section 4.6). • Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept (see section 4.6). • There is limited experience with treatment of patients with ischaemic CRVO and BRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended. Populations with limited data There is only limited experience in the treatment of subjects with DME due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with Eylea in diabetic patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Adjunctive use of verteporfin photodynamic therapy (PDT) and Eylea has not been studied, therefore, a safety profile is not established. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept (see section 4.4). Pregnancy There are no data on the use of aflibercept in pregnant women. Studies in animals have shown embryo-foetal toxicity (see section 5.3). Although the systemic exposure after ocular administration is very low, Eylea should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. Breastfeeding It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed child cannot be excluded. Eylea is not recommended during breastfeeding. A decision must be made whether to discontinue breastfeeding or to abstain from Eylea therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Fertility Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility (see section 5.3). Such effects are not expected after ocular administration with very low systemic exposure. 4.7 Effects on ability to drive and use machines Injection with Eylea has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances associated either with the injection or the eye examination. Patients should not drive or use machines until their visual function has recovered sufficiently. 4.8 Undesirable effects Summary of the safety profile A total of 2,957 patients constituted the safety population in the seven phase III studies. Among those, 2,356 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in less than 1 in 2,200 intravitreal injections with Eylea and included blindness, endophthalmitis, retinal detachment, cataract traumatic, vitreous haemorrhage, cataract, vitreous detachment, and intraocular pressure increased (see section 4.4). The most frequently observed adverse reactions (in at least 5% of patients treated with Eylea) were conjunctival haemorrhage (24.9%), visual acuity reduced (10.7%), eye pain (9.9%), intraocular pressure increased (7.1%), vitreous detachment (6.8%), vitreous floaters (6.6%) and cataract (6.6%). Tabulated list of adverse reactions The safety data described below include all adverse reactions from the seven phase III studies in the indications wet AMD, CRVO, BRVO and DME with a reasonable possibility of causality to the injection procedure or medicinal product. The adverse reactions are listed by system organ class and frequency using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1,000) Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. Table 1: All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications wet AMD, CRVO, BRVO and DME) Conditions known to be associated with wet AMD. Observed in the wet AMD studies only. Culture positive and culture negative endophthalmitis including allergic reactions Description of selected adverse reactions In the wet AMD phase III studies, there was an increased incidence of conjunctival haemorrhage in patients receiving anti-thrombotic agents. This increased incidence was comparable between patients treated with ranibizumab and Eylea. Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. ATEs, as defined by Antiplatelet Trialists' Collaboration (APTC) criteria, include nonfatal myocardial infarction, nonfatal stroke, or vascular death (including deaths of unknown cause). The incidence of ATEs in the phase III wet AMD studies during the 96 weeks study duration was 3.3% (60 out of 1,824) in the combined group of patients treated with Eylea compared to 3.2% (19 out of 595) in patients treated with ranibizumab (see section 5.1). The corresponding numbers in the DME studies during the first 52 weeks were 3.3% (19 out of 578) (Eylea) and 2.8% (8 out of 287) (control group) (see section 5.1). The incidence of ATEs in the phase III CRVO studies during the 76/100 weeks study duration was 0.6% (2 out of 317) in patients treated with at least one dose of Eylea compared to 1.4% (2 out of 142) in the group of patients receiving only sham treatment (see section 5.1) whilst for the Phase III BRVO study during the 52 weeks study duration it was 0% (0 out of 91) in patients treated with Eylea compared with 2.2% (2 out of 92) in the control group (see section 5.1). One of these patients in the control group had received Eylea rescue treatment. As with all therapeutic proteins, there is a potential for immunogenicity with Eylea. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose In clinical trials doses of up to 4 mg in monthly intervals have been used and isolated cases of overdoses with 8 mg occurred. Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdose, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Ophthalmologicals / Antineovascularisation agents ATC code: S01LA05 Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc portion of human IgG1. Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology. Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity than their natural receptors, and thereby can inhibit the binding and activation of these cognate VEGF receptors. 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 potent 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. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can synergize with VEGF-A in these processes, and is also known to promote leucocyte infiltration and vascular inflammation. Pharmacodynamic effects wet AMD Wet AMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or sub-/intra-retinal haemorrhage, resulting in loss of visual acuity. In patients treated with Eylea (one injection per month for three consecutive months, followed by one injection every 2 months), retinal thickness decreased soon after treatment initiation, and the mean CNV lesion size was reduced, consistent with the results seen with ranibizumab 0.5 mg every month. In the VIEW1 study there were mean decreases in retinal thickness on optical coherence tomography (OCT) (-130 and -129 microns at week 52 for the Eylea 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively). Also at the 52 week time point, in the VIEW2 study there were mean decreases in retinal thickness on OCT (-149 and -139 microns for the Eylea 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively). The reduction of CNV size and reduction in retinal thickness were generally maintained in the second year of the studies. Macular Oedema secondary to CRVO and BRVO In CRVO and BRVO retinal ischaemia occurs and signals the release of VEGF which in turn destabilises the tight junctions and promotes endothelial cell proliferation. Up-regulation of VEGF is associated with the breakdown of the blood retina barrier and this increased vascular permeability results in retinal oedema, stimulation of endothelial cell growth and neovascularisation. In patients treated with Eylea (one injection every month for six months) there was consistent, rapid and robust response in morphology (central retinal thickness [CRT] as assessed by OCT). Improvements in mean CRT were maintained through week 24. Retinal thickness on OCT at week 24 compared to baseline was a secondary efficacy variable in the COPERNICUS and GALILEO studies (CRVO) and the VIBRANT study (BRVO). In all three studies, the mean change in CRT from baseline to week 24 was statistically significant, favouring Eylea. In the COPERNICUS and GALILEO studies the mean decrease from baseline in retinal thickness on OCT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-457 microns vs. -145 microns in COPERNICUS, and -449 microns vs. -169 microns in GALILEO). The decrease from baseline in retinal thickness was maintained to the end of study, week 100 in COPERNICUS, and to week 76 in GALILEO. In the VIBRANT study the mean decrease from baseline in retinal thickness on OCT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-280 microns vs. -128 microns). This decrease from baseline was maintained to week 52. Diabetic macular oedema Diabetic macular oedema is characterised by increased vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity. In patients treated with Eylea, rapid and robust response in morphology (central retinal thickness [CRT]) as assessed by OCT was seen soon after treatment initiation. The mean change in CRT from baseline to week 52 was statistically significant favoring Eylea. In the VIVID-DME study there were mean decreases in retinal thickness on optical coherence tomography (OCT) (-192.4 and -66.2 microns at week 52 for the Eylea 2Q8 and laser group, respectively). Also at the 52 week time point, in the VISTA-DME study there were mean decreases in retinal thickness on OCT (-183.1 and -73.3 microns for the Eylea 2Q8 and laser group, respectively). Clinical efficacy and safety wet AMD The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD. A total of 2,412 patients were treated and evaluable for efficacy (1,817 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 at 2 mg every 8 weeks following 3 initial monthly doses (Eylea 2Q8); 2) Eylea administered at 2 mg every 4 weeks (Eylea 2Q4); 3) Eylea administered at 0.5 mg every 4 weeks (Eylea 0.5Q4); and 4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years. In the second year of the studies, patients continued to receive the dosage strength to which they were initially randomised but on a modified dosing schedule guided by assessment of visual and anatomic outcomes with a protocol-defined maximum dosing interval of 12 weeks. In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Set who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. In the VIEW1 study, at week 52, 95.1% of patients in the Eylea 2Q8 treatment group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. Eylea treatment was shown to be non-inferior and clinically equivalent to the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% of patients in the Eylea 2Q8 treatment group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. Eylea treatment was shown to be non-inferior and clinically equivalent to the ranibizumab 0.5Q4 group. Detailed results from the combined analysis of both studies are shown in the Table 2 and Figure 1 below. Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined data from the VIEW1 and VIEW2 studiesB) A) BCVA: Best Corrected Visual Acuity ETDRS: Early Treatment Diabetic Retinopathy Study LS: Least square means derived from ANCOVA B) Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) for all analyses except proportion of patients with maintained visual acuity at week 52 which is Per Protocol Set (PPS) C) The difference is the value of the Eylea group minus the value of the ranibizumab group. A positive value favours Eylea. D) Confidence interval (CI) calculated by normal approximation E) After treatment initiation with three monthly doses F) A confidence interval lying entirely above -10% indicates a non-inferiority of Eylea to ranibizumab G) Beginning at week 52, all groups were treated using a modified quarterly treatment paradigm where patients could be dosed as frequently as every 4 weeks but not less frequently than every 12 weeks based upon pre-specified retreatment criteria Figure 1. Mean Change in Visual Acuity from Baseline to Week 96 for the Combined Data from the View1 and View2 Studies *) From Baseline to Week 52, Eylea was dosed every 8 weeks following 3 initial monthly doses. From Baseline to Week 52, ranibizumab 0.5 mg was dosed every 4 weeks. Beginning at Week 52, all groups were treated using a modified quarterly treatment paradigm where patients could be dosed as frequently as every 4 weeks but not less frequently than every 12 weeks based upon pre-specified retreatment criteria. The proportion of patients at week 96 gaining at least 15 letters from baseline was 33.44% in the Eylea 2Q8 group, and 31.60% in the ranibizumab 0.5Q4 group. In combined data analysis of the VIEW1 and VIEW2 studies Eylea demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA). No clinically meaningful differences were found between Eylea and the reference product ranibizumab in changes of NEI VFQ-25 total score and subscales (near activities, distance activities, and vision-specific dependency) at week 52 from baseline. Decreases in mean CNV area were evident in all dose groups in both studies. Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, lesion type, lesion size) in each study and in the combined analysis were consistent with the results in the overall populations. In the second year of the studies, efficacy was generally maintained through the last assessment at week 96. In the second year of the studies, 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month. Elderly Population In the clinical studies, approximately 89% (1,616/1,817) of the patients randomised to treatment with Eylea were 65 years of age or older and approximately 63% (1,139/1,817) were 75 years of age or older. Macular Oedema secondary to CRVO The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to 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 the control group receiving sham injections every 4 weeks for a total of 6 injections. After 6 monthly injections, patients received treatment only if they met pre-specified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. Starting from this timepoint all patients were offered treatment if they met pre-specified criteria. 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 at week 24 compared to baseline. Change in visual acuity at week 24 compared to baseline was a secondary efficacy variable in both COPERNICUS and GALILEO studies. The difference between treatment groups was statistically significant in favour of Eylea in both studies. In both pivotal studies the maximal improvement in visual acuity has been achieved at month 3 with subsequent stabilisation of the effect on visual acuity and central retinal thickness until month 6. The statistically significant difference was maintained through week 52. Detailed results from the analysis of both studies are shown in the Table 3 and Figure 2 below. Table 3: Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCFC)) in COPERNICUS and GALILEO studies A) Difference is Eylea 2 mg Q4 weeks minus control B) Difference and confidence interval (CI) are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200) C) BCVA: Best Corrected Visual Acuity ETDRS: Early Treatment Diabetic Retinopathy Study LOCF: Last Observation Carried Forward SD: Standard deviation LS: Least square means derived from ANCOVA D) LS mean difference and confidence interval based on an ANCOVA model with factors treatment group, region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200) E) In COPERNICUS study, control group patients could receive Eylea on an as-needed basis as frequently as every 4 weeks during week 24 to week 52; patients had visits every 4 weeks. F) In COPERNICUS study, both control group and Eylea 2mg patients received Eylea 2 mg on an as-needed basis as frequently as every 4 weeks starting from Week 52 to Week 96; patients had mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary. G) In GALILEO study, both control group and Eylea 2mg patients received Eylea 2 mg on an as-needed basis every 8 weeks starting from Week 52 to Week 68; patients had mandatory visits every 8 weeks. Figure 2: Mean change from baseline to week 76/100 in visual acuity by treatment group for the COPERNICUS and GALILEO studies (Full Analysis Set) The proportion of perfused patients in the Eylea group was high in the GALILEO study at baseline 86.4%; (n = 89). Perfusion at week 24 primary endpoint was 91.8% (n = 89). The patients were largely able to maintain their perfusion status until week 76 84.3%; (n = 75). The number of perfused patients that started on sham was 79.4% (n = 54) at baseline. Perfusion at week 24 primary endpoint was 85.5% (n = 47). Patients in the sham group were switched to Eylea according to pre-specified criteria at week 52, 83.7% (n = 41) were perfused at this time. The patients were able to maintain their perfusion status until week 76, 84.0% (n = 42). The proportion of perfused patients in the Eylea group in the COPERNICUS study at baseline was 67.5% (n = 77). Perfusion at week 24 primary endpoint was 87.4%; (n = 90). After week 24, patients in the Eylea group were treated according to pre-specified criteria. At week 100 76.8 % (n = 76) of patients were perfused. The percentage of perfused patients that started on sham was 68.5% (n = 50) at baseline. Perfusion at week 24 primary endpoint was 58.6% (n = 34). Patients in the sham arm were eligible to receive Eylea from week 24. The proportion of perfused patients increased to 83.9% (n = 47) at week 52 and was largely maintained until week 100 78%; (n = 39). The beneficial effect of Eylea treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients. In combined data analysis of the GALILEO and COPERNICUS studies, Eylea demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA). Treatment effects in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, retinal perfusion status, CRVO duration) in each study were in general consistent with the results in the overall populations. Elderly population In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older. Macular Oedema secondary to BRVO The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO which included Hemi-Retinal Vein Occlusion. 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 8 weeks following 6 initial monthly injections or laser photocoagulation administered at baseline (laser control group). Patients in the laser control group could receive additional laser photocoagulation (called 'rescue laser treatment') beginning at week 12, if needed. The minimum interval between laser photocoagulation treatments was 12 weeks. Beginning at week 24, patients in the laser treatment group could receive rescue treatment with Eylea 2mg, if needed, administered every 4 weeks for 3 months followed by intravitreal injections every 8 weeks, based on pre-specified criteria. 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 group was superior to laser control for the primary endpoint. Change in visual acuity at week 24 compared to baseline was a secondary efficacy variable in the VIBRANT study. The difference between treatment groups was statistically significant in favour of Eylea. The course of visual improvement was rapid and maximal improvement was achieved at month 3 with subsequent stabilisation of the effect on visual acuity and central retinal thickness until month 6 and subsequent maintenance of the effect until month 12. In the laser group 67 patients received rescue treatment with Eylea beginning at week 24 (Active Control/ Eylea 2mg group). In this treatment group visual acuity improved by about 5 letters from week 24 to 52. Detailed results from the analysis of the VIBRANT study are shown in the Table 4 and Figure 3 below. Table 4: Efficacy outcomes at week 24 and week 52 (Full Analysis Set with LOCF) in VIBRANT study A) Difference is Eylea 2 mg Q4 weeks minus Laser Control B) Difference and 95% CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200) C) LS mean difference and 95% CI based on an ANCOVA model with treatment group, baseline BCVA category (> 20/200 and ≤ 20/200) and region (North America vs. Japan) as fixed effects, and baseline BCVA as covariate D) From Week 24 on the treatment interval in the Eylea treatment group was extended for all subjects from 4 weeks to 8 weeks through week 48. E) Beginning at Week 24 subjects in the Laser Group could receive rescue treatment with Eylea, if they met at least one pre-specified eligibility criterion. At total of 67 subjects in this group received Eylea rescue treatment. The fixed regimen for Eylea rescue was three times Eylea 2mg every 4 weeks followed by injections every 8 weeks. F) Nominal p-value Figure 3: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in VIBRANT Study At baseline, the proportion of perfused patients in the Eylea and laser groups was 60% and 68%, respectively. At week 24 these proportions were 80% and 67%, respectively. In the Eylea group the proportion of perfused patients was maintained through week 52. In the laser group, where patients were eligible for rescue treatment with Eylea from week 24, the proportion of perfused patients increased to 78% by week 52. Elderly population In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older. Diabetic Macular Oedema The safety and efficacy of Eylea were assessed in two randomised, multi-center, double-masked, active-controlled studies in patients with DME. A total of 862 randomised and treated patients were evaluable for efficacy. Of those, 576 were randomised to the Eylea groups in two studies (VIVIDDME and VISTADME). 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 (active control). 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. Patient ages ranged from 23 to 87 years with a mean of 63 years. The majority of patients in both studies had Type II diabetes. In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at Week 52 as measured by ETDRS letter score. Both Eylea 2Q8 and Eylea 2Q4 groups were shown to have efficacy that was statistically significantly superior to the laser control group. Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 5 and Figure 4 below. Table 5: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIVIDDME and VISTADME Studies A After treatment initiation with 5 monthly injections B LS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, region (Europe/Australia vs. Japan) had been included as factor for VIVIDDME, and history of MI and/or CVA as a factor for VISTADME). C Difference is Eylea group minus active control (laser) group D Difference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel weighting scheme adjusted by region (Europe/Australia vs. Japan) for VIVIDDME and medical history of MI or CVA for VISTADME E BCVA: Best Corrected Visual Acuity ETDRS: Early Treatment Diabetic Retinopathy Study LOCF: Last Observation Carried Forward LS: Least square means derived from ANCOVA CI: Confidence interval Figure 3: Mean change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in VIVIDDME and VISTADME Studies The VISTADME second year outcomes are in line with the results from the primary and secondary endpoints obtained at week 52. Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study and in the combined analysis were generally consistent with the results in the overall populations. In the VIVIDDME and VISTADME studies, 36 (9%) and 197 (43%) patients received prior anti-VEGF therapy, respectively, with a 3-month or longer washout period. 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. Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if determined to be necessary by the physician. In the VISTADME study, 198 (65%) of Eylea patients received bilateral Eylea injections; in the VIVIDDME study, 70 (26%) of Eylea patients received a different anti-VEGF treatment in their fellow eye. Elderly population In the DME phase III studies, approximately 47% (268/576) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. Efficacy and safety outcomes were consistent with the outcomes of the overall population. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Eylea in all subsets of the paediatric population in wet AMD, CRVO, BRVO and DME (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Eylea is administered directly into the vitreous to exert local effects in the eye. Absorption / Distribution Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitreal administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF. In a pharmacokinetic sub-study in 6 neovascular wAMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 microgram/ml (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and were undetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks. The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times below the aflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% in animal models, in which blood pressure changes were observed after circulating levels of free aflibercept attained approximately 10 microgram/ml and returned to baseline when levels fell below approximately 1 microgram/ml. 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 (2.91 microgram/ml) in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely. In pharmacokinetic sub-studies in patients with CRVO, BRVO, or DME mean Cmax of free aflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/ml and individual values not exceeding 0.14 microgram/ml. Thereafter, plasma concentrations of free aflibercept declined to values below or close to the lower limit of quantitation generally within one week; undetectable concentrations were reached before the next administration after 4 weeks in all patients. Elimination As Eylea is a protein-based therapeutic, no metabolism studies have been conducted. Free aflibercept binds VEGF to form a stable, inert complex. As with other large proteins, both free and bound aflibercept are expected to be cleared by proteolytic catabolism. Renal impairment No special studies in patients with renal impairment have been conducted with Eylea. Pharmacokinetic analysis of patients in the VIEW2 study, of which 40% had renal impairment (24% mild, 15% moderate, and 1% severe), revealed no differences with respect to plasma concentrations of active drug after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients with CRVO in the GALILEO study and in patients with DME in the VIVIDDME study. 5.3 Preclinical safety data Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures considered substantially in excess of the maximum human exposure after intravitreal administration at the intended clinical dose indicating little relevance to clinical use. Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at systemic exposures in excess of the maximum human exposure. The systemic exposure based on Cmax and AUC for free aflibercept were approximately 200- and 700-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold higher based on Cmax and AUC, respectively. No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. An effect of aflibercept on intrauterine development was shown in embryo-foetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on Cmax and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at doses ranging from 3 to 30 mg/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. Based on Cmax and AUC for free aflibercept observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4,900-fold and 1,500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible. 6. Pharmaceutical particulars 6.1 List of excipients Polysorbate 20 Sodium dihydrogen phosphate, monohydrate (for pH adjustment) Disodium hydrogen phosphate, heptahydrate (for pH adjustment) Sodium chloride Sucrose Water for injection 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in a refrigerator (2°C to 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. Prior to usage, the unopened vial of Eylea may be kept at room temperature (below 25°C) for up to 24 hours. After opening the vial, proceed under aseptic conditions. 6.5 Nature and contents of container 100 microlitres of solution in a vial (type I glass) with a stopper (elastomeric rubber), and an 18 G filter needle. Pack size of 1. 6.6 Special precautions for disposal and other handling The vial is for single use only. Since the vial contains more volume (100 microlitres) than the recommended dose (50 microlitres), a part of the volume contained in the vial has to be discarded prior to the administration. The solution should be inspected visually for any foreign particulate matter and/or discolouration or any variation in physical appearance prior to administration. In the event of either being observed, discard the medicinal product. For the intravitreal injection, a 30 G x ½ inch injection needle should be used. Instructions for use of vial: 1.Remove the plastic cap and disinfect the outer part of the rubber stopper of the vial. 2. Attach the 18 G, 5-micron filter needle supplied in the carton to a 1-ml sterile, Luer-lock syringe. 3.Push the filter needle into the centre 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. 4. 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. 5.Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 6.Remove the filter needle and properly dispose of it. Note: Filter needle is not to be used for intravitreal injection. 7.Using aseptic technique, firmly twist a 30 G x ½ inch injection needle to the Luer-lock syringe tip. 8. When ready to administer Eylea, remove the plastic needle shield. 9. 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. 10. Eliminate all bubbles and expel excess drug by slowly depressing the plunger so that the plunger tip aligns with the line that marks 0.05 ml on the syringe. 11. The vial is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bayer Pharma AG D-13342 Berlin Germany 8. Marketing authorisation number(s) EU/1/12/797/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 22 November 2012 10. Date of revision of the text 02/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. https://www.medicines.org.uk/emc/medicine/27224