Eylea

1 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

 
 



  
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1. NAME OF THE MEDICINAL PRODUCT 
 
Eylea 40 mg/ml solution for injection in pre-filled syringe. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 ml solution for injection contains 40 mg aflibercept*. 
 
One pre-filled syringe contains 90 microlitres, equivalent to 3.6 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), 
• visual impairment due to myopic choroidal neovascularisation (myopic CNV) (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. The treatment 
interval is then extended to two months. 
 
Based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may be 
maintained at two months or further extended using a treat-and-extend dosing regimen, where 
injection intervals are increased in 2- or 4-weekly increments to maintain stable visual and/or anatomic 



  
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outcomes. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened 
accordingly to a minimum of two months during the first 12 months of treatment. 
 
There is no requirement for monitoring between injections. Based on the physician’s judgement the 
schedule of monitoring visits may be more frequent than the injection visits. 
Treatment intervals greater than four months between injections have not been studied (see Section 
5.1). 
 
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, and based on visual and/or anatomic outcomes, the 
treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the 
treatment intervals are gradually increased 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 schedule for monitoring should therefore be determined by the treating physician and may be 
more frequent than the schedule of injections. 
 
If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, 
Eylea should be discontinued. 
 
Myopic choroidal neovascularisation 
 
The recommended dose for Eylea is a single intravitreal injection of 2 mg aflibercept equivalent to 
50 microlitres.  
 



  
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Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease 
persists. Recurrences should be treated as a new manifestation of the disease. 
 
The schedule for monitoring should be determined by the treating physician. 
 
The interval between two doses should not be shorter than one month. 
 
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  
The safety and efficacy of Eylea have not been established in children and adolescents. There is no 
relevant use of Eylea in the paediatric population for the indications of wet AMD, CRVO, BRVO, 
DME and myopic CNV. 
 
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 pre-filled syringe should only be used for the treatment of a single eye. Extraction of multiple 
doses from a pre-filled syringe may increase the risk of contamination and subsequent infection. 
 
The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept. The extractable 
volume of the syringe (90 microlitres) is not to be used in total. The excess volume should be expelled 
before injecting. 
 
Injecting the entire volume of the prefilled syringe 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. 



  
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For handling of the medicinal product before administration, 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, DME or myopic CNV 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, DME and myopic CNV 
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. 



  
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• 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: 

o a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the 
last assessment of visual acuity; 

o 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.  
 
In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients who 
have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.  
 
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. 
 
Breast-feeding 
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 breast-feeding. A decision must be made whether to discontinue 
breast-feeding or to abstain from Eylea therapy taking into account the benefit of breast-feeding for 
the child and the benefit of therapy for the woman. 



  
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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 3,102 patients constituted the safety population in the eight phase III studies. Among those, 
2,501 patients were treated with the recommended dose of 2 mg. 
 
Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in 
less than 1 in 1,900 intravitreal injections with Eylea and included blindness, endophthalmitis, retinal 
detachment, cataract traumatic, cataract, vitreous haemorrhage, 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 (25%), visual acuity reduced (11%), eye pain (10%), cataract (8%), 
intraocular pressure increased (8%), vitreous detachment (7%), and vitreous floaters (7%).  
 
Tabulated list of adverse reactions 
 
The safety data described below include all adverse reactions from the eight phase III studies in the 
indications wet AMD, CRVO, BRVO, DME and myopic CNV 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. 



  
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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, DME and myopic 
CNV) or during post-marketing surveillance 
 
System 
Organ 
Class 

Very common Common Uncommon Rare 

Immune 
system 
disorders 

  Hypersensitivity***   

Eye 
disorders 

Visual acuity 
reduced, 
Conjunctival 
haemorrhage, 
Eye pain 

Retinal pigment epithelial tear*, 
Detachment of the retinal 
pigment epithelium, 
Retinal degeneration, 
Vitreous haemorrhage, 
Cataract, 
Cataract cortical, 
Cataract nuclear, 
Cataract subcapsular, 
Corneal erosion,  
Corneal abrasion, 
Intraocular pressure increased, 
Vision blurred, 
Vitreous floaters, 
Vitreous detachment, 
Injection site pain, 
Foreign body sensation in eyes, 
Lacrimation increased, 
Eyelid oedema, 
Injection site haemorrhage, 
Punctate keratitis, 
Conjunctival hyperaemia, 
Ocular hyperaemia 

Endophthalmitis**, 
Retinal detachment, 
Retinal tear,  
Iritis, 
Uveitis, 
Iridocyclitis, 
Lenticular opacities, 
Corneal epithelium 
defect, 
Injection site 
irritation, 
Abnormal sensation 
in eye, 
Eyelid irritation, 
Anterior chamber 
flare,  
Corneal oedema 

Blindness, 
Cataract 
traumatic, 
Vitritis, 
Hypopyon 

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only. 
** Culture positive and culture negative endophthalmitis 
*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated 

cases of severe anaphylactic/anaphylactoid 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, including stroke and 
myocardial infarction, following intravitreal use of VEGF inhibitors. 

A low incidence rate of arterial thromboembolic events was observed in the Eylea clinical trials in 
patients with AMD, DME, RVO and myopic CNV. Across indications no notable difference between 
the groups treated with aflibercept and the respective comparator groups were observed. 



  
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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 national reporting system 
listed in Appendix V. 
 
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), central retinal thickness [CRT] decreased soon after treatment initiation, 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


  
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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 CRT 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 CRT 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 CRT were generally maintained in the second year of the studies. 
 
The ALTAIR study was conducted in Japanese patients with treatment naïve wet AMD, showing 
similar outcomes to the VIEW studies using 3 initial monthly Eylea 2 mg injections, followed by one 
injection after a further 2 months, and then continued with a treat-and-extend regimen with variable 
treatment intervals (2- week or 4- week adjustments) up to a maximum 16 week interval according to 
pre-specified criteria. At week 52, there were mean decreases in central retinal thickness (CRT) on 
OCT of -134.4 and –126.1 microns for the 2-week adjustment group and the 4-week adjustment group, 
respectively. The proportion of patients without fluid on OCT at week 52 was 68.3% and 69.1% in the 
2- and 4-week adjustment groups, respectively. The reduction in CRT was generally maintained in 
both treatment arms in the second year of the ALTAIR study. 
 
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, increased vascular permeability, retinal 
oedema, and neovascularisation complications. 
 
In patients treated with 6 consecutive monthly injections of Eylea 2mg, there was a consistent, rapid 
and robust morphologic response (as measured by improvements in mean CRT) observed. At week 24, 
the reduction in CRT was statistically superior versus control in all three studies (COPERNICUS in 
CRVO: -457 vs. -145 microns; GALILEO in CRVO: -449 vs. -169 microns; VIBRANT in BRVO: -
280 vs. -128 microns). This decrease from baseline in CRT was maintained to the end of each study, 
week 100 in COPERNICUS, week 76 in GALILEO, and week 52 in VIBRANT. 
 
Diabetic macular oedema 
 
Diabetic macular oedema is a consequence of diabetic retinopathy and is characterised by increased 
vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.  
 
In patients treated with Eylea, the majority of whom were classified as having Type II diabetes, a rapid 
and robust response in morphology (CRT, DRSS level) was observed.  
 
In the VIVIDDME and the VISTADME studies, a statistically significant greater mean decrease in CRT 
from baseline to week 52 was observed in patients treated with Eylea than with the laser control, -
192.4 and -183.1 microns for the 2Q8 Eylea groups and -66.2 and -73.3 microns for the control 
groups, respectively. At week 100 the decrease was maintained with -195.8 and -191.1 microns for the 
2Q8 Eylea groups and -85.7 and -83.9 microns for the control groups, in the VIVIDDME and 
VISTADME studies, respectively. 
 
A ≥ 2 step improvement in DRSS was assessed in a pre-specified manner in VIVIDDME and 
VISTADME. The DRSS score was gradable in 73.7% of the patients in VIVIDDME and 98.3% of the 
patients in VISTADME. At week 52, 27.7% and 29.1% of the Eylea 2Q8 groups, and 7.5% and 14.3% 
of the control groups experienced a ≥2 step improvement in the DRSS. At week 100, the respective 
percentages were 32.6% and 37.1% of the Eylea 2Q8 groups and 8.2% and 15.6% of the control 
groups. 
 



  
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Myopic choroidal neovascularisation  
 
Myopic choroidal neovascularisation (myopic CNV) is a frequent cause of vision loss in adults with 
pathologic myopia. It develops as a wound healing mechanism consequent to Bruch’s membrane 
ruptures and represents the most vision-threatening event in pathologic myopia.  
 
In patients treated with Eylea in the MYRROR study (one injection given at start of therapy, with 
additional injections given in case of disease persistence or recurrence), CRT decreased soon after 
treatment initiation favouring Eylea at week 24 (-79 microns and -4 microns for the Eylea 2 mg 
treatment group and the control group, respectively), which was maintained through week 48. In 
addition, the mean CNV lesion size decreased.  
 
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 (VIEW1 and VIEW2) with a total of 
2,412 patients treated and evaluable for efficacy (1,817 with Eylea). Patient ages ranged from 49 to 
99 years with a mean of 76 years. In these 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. 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). 
 
In the second year of the studies, patients continued to receive the initially randomised dosage 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, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline. 
 
In the VIEW1 study, at week 52, 95.1% of patients in the Eylea 2Q8 group maintained vision 
compared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% 
of patients in the Eylea 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 
0.5Q4 group. In both studies Eylea 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 Table 2 and Figure 1 below. 
 



  
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Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined data from the 
VIEW1 and VIEW2 studiesB) 
 
Efficacy Outcome Eylea 2Q8 E) 

(Eylea 2 mg every 8 weeks 
following 3 initial monthly 

doses) 
(N = 607) 

Ranibizumab 0.5Q4 
(ranibizumab 0.5 mg every 

4 weeks) 
 

(N = 595) 
Week 52 Week 96 Week 52 Week 96 

Mean number of injections 
from baseline  7.6 11.2 12.3 16.5 

Mean number of injections 
from Week 52 to 96  4.2  4.7 

Proportion of patients with  
< 15 letters loss from 
baseline ( PPS A)) 

95.33%B) 92.42% 94.42% B) 91.60% 

 DifferenceC) 
(95% CI)D) 

0.9% 
(-1.7, 3.5)F) 

0.8% 
(-2.3, 3.8)F)   

Mean change in BCVA as 
measured by ETDRSA) 
letter score from baseline  

8.40 7.62 8.74 7.89 

Difference in LS A)           
mean change (ETDRS 
letters)C) 
(95% CI)D) 

-0.32 
(-1.87, 1.23) 

-0.25 
(-1.98, 1.49)   

Proportion of patients with 
≥ 15 letters gain from 
baseline 

30.97% 33.44% 32.44% 31.60% 

DifferenceC) 
(95% CI)D) 

-1.5% 
(-6.8, 3.8) 

1.8% 
(-3.5, 7.1)   

 

A)  BCVA: Best Corrected Visual Acuity 
 ETDRS: Early Treatment Diabetic Retinopathy Study 
 LS: Least square means derived from ANCOVA 
 PPS: Per Protocol Set 
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 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 
 



  
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Figure 1. Mean Change in Visual Acuity 
from Baseline to Week 96 for the Combined 

Data from the View1 and View2 Studies 
  

 
 
In combined data analysis of VIEW1 and VIEW2, Eylea demonstrated clinically meaningful changes 
from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function 
Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. 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). 
 
In the second year of the studies, efficacy was generally maintained through the last assessment at 
week 96, and 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. 
 
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. 
 
ALTAIR was a 96 week multicentre, randomised, open-label study in 247 Japanese patients with 
treatment naïve wet AMD, designed to assess the efficacy and safety of Eylea following two different 
adjustment intervals (2- weeks and 4- weeks) of a treat-and-extend dosing regimen. 
 
All patients received monthly doses of Eylea 2 mg for 3 months, followed by one injection after a 
further 2 month interval. At week 16, patients were randomised 1:1 into two treatment groups: 1) 
Eylea treat-and-extend with 2-week adjustments and 2) Eylea treat-and-extend with 4-week 
adjustments. Extension or shortening of the treatment interval was decided based on visual and/or 
anatomic criteria defined by protocol with a maximum treatment interval of 16 weeks for both groups. 
 
The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondary 
efficacy endpoints were the proportion of patients who did not lose ≥15 letters and the proportion of 
patients who gained at least 15 letters of BCVA from baseline to week 52. 
 
At week 52, patients in the treat-and-extend arm with 2-week adjustments gained a mean of 9.0 letters 
from baseline as compared to 8.4 letters for those in the 4-week adjustment group [LS mean difference 
in letters (95% CI): -0.4 (-3.8,3.0), ANCOVA]. The proportion of patients who did not lose ≥15 letters 
in the two treatment arms was similar (96.7% in the 2-week and 95.9% in the 4-week adjustment 



  
14 

 

groups). The proportion of patients who gained ≥15 letters at week 52 was 32.5% in the 2-week 
adjustment group and 30.9% in the 4-week adjustment group. The proportion of patients who extended 
their treatment interval to 12 weeks or beyond was 42.3% in the 2-week adjustment group and 49.6 % 
in the 4-week adjustment group. Furthermore, in the 4-week adjustment group 40.7% of patients were 
extended to 16 week intervals. At the last visit up to week 52, 56.8% and 57.8% of patients in the 2-
week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 
12 weeks or beyond.  
 
In the second year of the study, efficacy was generally maintained up to and including the last 
assessment at week 96, with a mean gain from baseline of 7.6 letters for the 2-week adjustment group 
and 6.1 letters for the 4-week adjustment group. The proportion of patients who extended their 
treatment interval to 12 weeks  or beyond was 56.9% in the 2-week adjustment group and 60.2% in the 
4-week adjustment group. At the last visit prior to week 96, 64.9% and 61.2% of patients in the 2-
week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 
12 weeks or beyond. During the second year of treatment patients in both the 2-week and 4-week 
adjustment groups received an average of 3.6 and 3.7 injections, respectively. Over the 2 year 
treatment period patients received an average of 10.4 injections. 
 
Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 
and VIEW2. 
 
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 (COPERNICUS and 
GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with Eylea). Patient 
ages ranged from 22 to 89 years with a mean of 64 years. 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. 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 consecutive 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. From this timepoint all patients were treated if pre-
specified criteria were met. 
 
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. A secondary efficacy variable was change in 
visual acuity at week 24 compared to baseline. 
 
The difference between treatment groups was statistically significant in favour of Eylea in both 
studies. The maximal improvement in visual acuity was achieved at month 3 with subsequent 
stabilisation of visual acuity and CRT until month 6. The statistically significant difference was 
maintained through week 52. 
 
Detailed results from the analysis of both studies are shown in Table 3 and Figure 2 below. 



15 
 

Table 3:  Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCFC)) in COPERNICUS and GALILEO studies 
 

 
Efficacy Outcomes 

COPERNICUS GALILEO 

24 Weeks 52 Weeks 100 Weeks 24 Weeks 52 Weeks 76 Weeks 

Eylea 

2 mg Q4 

(N = 114) 

Control 

 

(N= 73) 

Eylea 

2 mg  

(N = 114) 

 ControlE) 

 (N =73) 

Eylea F) 

2 mg  

(N= 114) 

Control E,F)  

(N=73) 

Eylea 

2 mg Q4 

(N = 103) 

Control 

 

(N = 68) 

Eylea 

2 mg 

(N = 103) 

Control  

(N = 68) 

Eylea G) 

2 mg 

(N = 103) 

Control G) 

 

(N = 68) 

Proportion of patients with ≥15 
letters gain from baseline 56% 12% 55% 30% 49.1% 23.3% 60% 22% 60% 32% 57.3% 29.4% 

Weighted differenceA,B,E) 
(95% CI) 

44.8% 
(33.0, 56.6)  

25.9% 
(11.8, 40.1)  

26.7% 
(13.1, 40.3) 
p=0.0003 

 
38.3% 

(24.4, 52.1)  
27.9% 

(13.0, 42.7)  
28.0% 

(13.3, 42.6) 
p=0.0004 

 
p-value p < 0.0001  p = 0.0006  p < 0.0001  p = 0.0004  

Mean change in BCVAC) as 
measured by ETDRSC) letter 
score from baseline (SD) 

17.3 
(12.8) 

-4.0 
(18.0) 

16.2 
(17.4) 

3.8 
(17.1) 

13.0 
(17.7) 

1.5 
(17.7) 

18.0 
(12.2) 

3.3 
(14.1) 

16.9 
(14.8) 

3.8 
(18.1) 

13.7 
(17.8) 

6.2 
(17.7) 

Difference in LS meanA,C,D,E) 
(95% CI) 

21.7 
(17.4, 26.0)  

12.7 
(7.7, 17.7)  

11.8 
(6.7, 17.0) 
p < 0.0001 

 
14.7 

(10.8, 18.7)  
13.2 

(8.2, 18.2)  
7.6 

(2.1, 13.1) 
p=0.0070 

 
p-value p < 0.0001  p < 0.0001  p < 0.0001  p < 0.0001  

 
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.  



  
16 

 

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. 



17 
 

 
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) 

 



  
18 

 

In GALILEO, 86.4% (n=89) of the Eylea group and 79.4% (n=54) of the sham group had perfused 
CRVO at baseline. At week 24, this was 91.8% (n=89) in the Eylea group and 85.5% (n=47) in the 
sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the Eylea group 
and 84.0% (n=42) in the sham group. 
 
In COPERNICUS, 67.5% (n = 77) of the Eylea group and 68.5% (n = 50) of the sham group had 
perfused CRVO at baseline. At week 24, this was 87.4% (n = 90) in the Eylea group and 58.6% (n = 
34) in the sham group. These proportions were maintained at week 100 with 76.8 % (n = 76) in the 
Eylea group and 78% (n = 39) in the sham group. Patients in the sham group were eligible to receive 
Eylea from week 24. 
 
The beneficial effect of Eylea treatment on visual function was similar in the baseline subgroups of 
perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g. age, gender, 
race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results 
in the overall populations. 
 
In combined data analysis of GALILEO and COPERNICUS, 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). 
 
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 (VIBRANT) which included 
Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with 
Eylea). Patient ages ranged from 42 to 94 years with a mean of 65 years. 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. 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 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients in 
the laser group could receive rescue treatment with Eylea 2mg from week 24, administered every 4 
weeks for 3 months followed by every 8 weeks.  
 
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 and the Eylea group was superior to laser 
control.  
 
A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, which 
was statistically significant in favour of Eylea in the VIBRANT study. The course of visual 
improvement was rapid and peaked at 3 months with 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), which resulted in improvement of visual acuity by about 5 letters from 
week 24 to 52. 
 
Detailed results from the analysis of the VIBRANT study are shown in Table 4 and Figure 3 below. 



  
19 

 

 

Table 4:  Efficacy outcomes at week 24  and week 52 (Full Analysis Set with LOCF) in VIBRANT 
study 

Efficacy Outcomes VIBRANT 

24 Weeks 52 Weeks 

 Eylea 2mg Q4 

(N = 91) 

Active Control 
(laser) 

(N = 90) 

Eylea 2mg Q8 

(N = 91) D) 

Active Control 
(laser)/Eylea 2mgE) 

(N = 90) 

Proportion of patients 
with ≥15 letters gain 
from Baseline (%) 

52.7% 26.7% 57.1% 41.1% 

Weighted Difference A,B) 
(%) 

(95% CI) 

p-value  

26.6% 

(13.0, 40.1) 

p=0.0003 

 16.2% 

(2.0, 30.5) 

p=0.0296 

 

Mean change in BCVA 
as measured by ETDRS 
letter score from 
Baseline (SD) 

17.0 

(11.9) 

 6.9 

(12.9) 

17.1 

(13.1) 

12.2 (11.9) 

Difference in LS mean 
A,C) 

(95% CI) 

p-value 

 10.5 

(7.1, 14.0) 

p<0.0001 

 5.2 

(1.7, 8.7) 

p=0.0035F) 

 

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 



  
20 

 

 

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.  
 
Diabetic macular oedema 
 
The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, 
active-controlled studies in patients with DME (VIVIDDME and VISTADME). A total of 862 patients 
were treated and evaluable for efficacy, 576 with Eylea. Patient ages ranged from 23 to 87 years with a 
mean of 63 years. In the DME 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. The majority of patients in both studies had Type II diabetes. 
 
In both studies, 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 control group 
could receive Eylea.  
 
In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 
52 and both Eylea 2Q8 and Eylea 2Q4 groups demonstrated statistical significance and were superior 
to the control group. This benefit was maintained through week 100. 
 



  
21 

 

Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 5 and 
Figure 4 below. 



22 
 

 

Table 5: Efficacy outcomes at week 52 and week 100 (Full Analysis Set with LOCF) in VIVIDDME and VISTADME studies 

Efficacy 
Outcomes 

VIVIDDME VISTADME 

52 Weeks 100 Weeks 52 Weeks 100 Weeks 

Eylea 

2 mg Q8 A 

(N = 135) 

Eylea 

2 mg Q4 

(N = 136) 

Active 
Control 

(laser) 

(N = 132) 

Eylea 

2 mg Q8 A 

(N = 135) 

Eylea  

2mg Q4 

(N=136) 

Active 
Control  

(laser) 

(N = 132) 

Eylea 

2 mg Q8 A 

(N = 151) 

Eylea 

2 mg Q4 

(N = 154) 

Active 
Control 

(laser) 

(N = 154) 

Eylea 

2 mg Q8 A 

(N = 151) 

Eylea 

2 mg Q4 

(N=154) 

Active 
Control  

(laser) 

(N = 154) 

Mean change in 
BCVA as 

measured by 
ETDRS E letter 

score from 
Baseline 

10.7 10.5 1.2 9.4 11.4 0.7 10.7 12.5 0.2 11.1 11.5 0.9 

Difference in LS        
     mean B,C,E 

     (97.5% CI) 

9.1 

(6.3, 11.8) 
9.3 

(6.5, 12.0) 
 

8.2 

(5.2, 11.3) 
10.7       

(7.6, 13.8) 
 

10.45 

(7.7, 13.2) 
12.19 

(9.4, 15.0) 
 

10.1 

(7.0, 13.3) 
10.6       

(7.1, 14.2) 
 

Proportion of 
patients with ≥ 15 
letters gain from 
Baseline 

33% 32% 9% 31.1% 38.2% 12.1% 31% 42% 8% 33.1% 38.3% 13.0% 

     Adjusted   
     Difference D,C,E 
     (97.5% CI) 

24% 
(13.5, 34.9) 

23% 
(12.6, 33.9) 

 
19.0%    

(8.0, 29.9) 
26.1% 

(14.8, 37.5) 
 

23% 
(13.5, 33.1) 

34% 
(24.1, 44.4) 

 
20.1%         

(9.6, 30.6) 
25.8% 

(15.1, 36.6) 
 

 

A After treatment initiation with 5 monthly injections  



  
23 

 

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 

 



24 
 

Figure 4:  Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to 
Week 100 in VIVIDDME and VISTADME Studies 

 

 

 
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 were similar to those seen in patients 
who were VEGF inhibitor naïve. 
 
Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if 
assessed necessary by the physician. In the VISTADME study, 217 (70.7%) of Eylea patients received 
bilateral Eylea injections until week100; in the VIVIDDME study, 97 (35.8%) of Eylea patients received 
a different anti-VEGF treatment in their fellow eye. 
 
An independent comparative trial (DRCR.net Protocol T) utilised a dosing regimen based on strict 
OCT and vision re-treatment criteria. In the aflibercept treatment group (n = 224) at week 52, this 
treatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to the 
administered number of doses in the Eylea 2Q8 group in VIVIDDME and VISTADME, while overall 



  
25 

 

efficacy of the aflibercept treatment group in Protocol T was comparable to the Eylea 2Q8 group in 
VIVIDDME and VISTADME. A 13.3 mean letter gain with 42% of patients gaining at least 15 letters in 
vision from baseline was observed in Protocol T. Ocular and systemic safety profiles (including 
ATEs) were similar to VIVIDDME and VISTADME. 
 
Myopic choroidal neovascularisation 
 
The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, sham-
controlled study in treatment-naïve, Asian patients with myopic CNV. A total of 121 patients were 
treated and evaluable for efficacy (90 with Eylea). Patient ages ranged from 27 to 83 years with a 
mean of 58 years. In the myopic CNV study, approximately 36% (33/91) of the patients randomised to 
treatment with Eylea were 65 years of age or older, and approximately 10% (9/91) were 75 years of 
age or older. 
 
Patients were randomly assigned in a 3:1  ratio to receive either 2 mg Eylea intravitreally or sham 
injections administered once at study start with additional injections given monthly in case of disease 
persistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patients 
initially randomised to sham were eligible to receive the first dose of Eylea. Following this, patients in 
both groups continued to be eligible for additional injections in case of disease persistence or 
recurrence. 
 
The difference between treatment groups was statistically significant in favour of Eylea for the 
primary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion of 
patients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for both 
endpoints were maintained through week 48. 
 
Detailed results from the analysis of the MYRROR study are shown in Table 6 and Figure 5 below. 



  
26 

 

 
Table 6:  Efficacy outcomes at week 24 (primary analysis) and week 48 in MYRROR study 

(Full Analysis Set with LOCFA)) 

Efficacy Outcomes MYRROR 
24 Weeks 48 Weeks 

Eylea 2mg 
(N = 90) 

Sham 
(N = 31) 

Eylea 2mg 
(N = 90) 

Sham/ 
Eylea 2mg 

(N = 31) 
Mean change in BCVA B) as measured by 
ETDRS letter score from baseline (SD) B) 

12.1 
(8.3) 

-2.0 
(9.7) 

13.5 
(8.8) 

3.9 
(14.3) 

         Difference in LS mean C,D,E) 
        (95% CI) 

14.1 
(10.8, 17.4) 

 
9.5 

(5.4, 13.7) 
 

Proportion of patients with ≥15 letters gain 
from baseline 

38.9% 9.7% 50.0% 29.0% 

        Weighted difference D,F) 
        (95% CI) 

29.2% 
(14.4, 44.0) 

 
21.0% 

(1.9, 40.1) 
 

A) LOCF: Last Observation Carried Forward 
B) BCVA: Best Corrected Visual Acuity 

ETDRS: Early Treatment Diabetic Retinopathy Study 
SD: Standard Deviation 

C) LS mean: Least square means derived from ANCOVA model 
D) CI: Confidence Interval 
E) LS mean difference and 95% CI based on an ANCOVA model with treatment group and country (country 

designations) as fixed effects, and baseline BCVA as covariant. 
F) Difference and 95% CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for country 

(country designations) 
 

Figure 5:  Mean Change from Baseline to Week 48 in Visual Acuity by Treatment Group for the 
MYRROR Study (Full Analysis Set, LOCF) 

 

 
 



  
27 

 

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, DME and myopic CNV 
populations (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 wet AMD 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, DME or myopic CNV 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, in patients with DME in the 
VIVIDDME study, and in patients with myopic CNV in the MYRROR study. 
 



  
28 

 

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. 



  
29 

 

Keep the pre-filled syringe in its blister and in the outer carton in order to protect from light. 
 
Prior to usage, the unopened blister of Eylea may be stored at room temperature (below 25°C) for up 
to 24 hours. After opening the blister, proceed under aseptic conditions. 
 
6.5 Nature and contents of container  
 
90 microlitres of solution in pre-filled syringe (type I glass) marked with a black dosing line, with a 
plunger stopper (elastomeric rubber) and a Luer lock adaptor with a tip cap (elastomeric rubber). Pack 
size of 1. 
 
6.6 Special precautions for disposal and other handling 
 
The pre-filled syringe is for single use in one eye only. 
Do not open the sterile pre-filled blister outside the clean administration room. 
 
Since the pre-filled syringe contains more volume (90 microlitres) than the recommended dose 
(50 microlitres), a part of the volume contained in the syringe 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 pre-filled syringe: 
 
1. When ready to administer Eylea, open the carton and remove the sterilised blister. Carefully peel open 

the blister ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready 
for assembly. 

2. Using aseptic technique, remove the syringe from the sterilised blister. 
3. To remove the syringe cap, hold the syringe in one 

hand while using the other hand to grasp the syringe 
cap with the thumb and fore finger. Please note: 
You should twist off (do not snap off) the syringe 
cap.  

 
 
 
 
 

 
 

4. To avoid compromising the sterility of the product, do not pull back on the plunger. 



  
30 

 

5. Using aseptic technique, firmly twist the injection 
needle onto the Luer-lock syringe tip. 

 

 
 
 

6. 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. 

 
 

 
 
7. 

 
Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger rod to 
align the cylindrical base of the plunger dome edge with the black dosing line on the syringe 
(equivalent to 50 microlitres).

  
 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

 

 
8.  

 
The pre-filled syringe is for single use only. Extraction of multiple doses from a pre-filled syringe 
may increase the risk of contamination and subsequent infection. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

 
 



  
31 

 

7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/797/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 November 2012 
Date of latest renewal: 13 July 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


  
32 

 

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), 
• visual impairment due to myopic choroidal neovascularisation (myopic CNV) (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. The treatment 
interval is then extended to two months. 
 
Based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may be 
maintained at two months or further extended using a treat-and-extend dosing regimen, where 
injection intervals are  increased in 2- or 4-weekly increments to maintain stable visual and/or 



  
33 

 

anatomic outcomes.. If visual and/or anatomic outcomes deteriorate, the treatment interval should be 
shortened accordingly to a minimum of two months during the first 12 months of treatment. 
 
There is no requirement for monitoring between injections. Based on the physician’s judgement the 
schedule of monitoring visits may be more frequent than the injection visits.. 
 
Treatment intervals greater than four months between injections have not been studied (see Section 
5.1). 
 
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, and based on visual and/or anatomic outcomes, the 
treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the 
treatment intervals are gradually increased 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 schedule for monitoring should therefore be determined by the treating physician and may be 
more frequent than the schedule of injections. 
 
If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, 
Eylea should be discontinued. 
 
Myopic choroidal neovascularisation 
 
The recommended dose for Eylea is a single intravitreal injection of 2 mg aflibercept equivalent to 
50 microlitres.  
 



  
34 

 

Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease 
persists. Recurrences should be treated as a new manifestation of the disease. 
 
The schedule for monitoring should be determined by the treating physician. 
 
The interval between two doses should not be shorter than one month. 
 
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 
The safety and efficacy of Eylea have not been established in children and adolescents. There is no 
relevant use of Eylea in the paediatric population for the indications of wet AMD, CRVO, BRVO, 
DME and myopic CNV. 
 
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.  Extraction of multiple doses from a 
single vial may increase the risk of contamination and subsequent infection. 
 
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 before administration, see section 6.6. 



  
35 

 

 
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, DME or myopic CNV 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, DME and myopic CNV 
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. 



  
36 

 

• The dose should be withheld and treatment should not be resumed earlier than the next 
scheduled treatment in the event of: 

o a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the 
last assessment of visual acuity; 

o 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.  
 
In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients who 
have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.  
 
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. 
 
Breast-feeding 
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 breast-feeding. A decision must be made whether to discontinue 
breast-feeding or to abstain from Eylea therapy taking into account the benefit of breast-feeding for 
the child and the benefit of therapy for the woman. 
 



  
37 

 

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 3,102 patients constituted the safety population in the eight phase III studies. Among those, 
2,501 patients were treated with the recommended dose of 2 mg. 
 
Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in 
less than 1 in 1,900 intravitreal injections with Eylea and included blindness, endophthalmitis, retinal 
detachment, cataract traumatic, cataract, vitreous haemorrhage, 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 (25%), visual acuity reduced (11%), eye pain (10%), cataract (8%), 
intraocular pressure increased (8%), vitreous detachment (7%), and vitreous floaters (7%).  
  
Tabulated list of adverse reactions 
 
The safety data described below include all adverse reactions from the eight phase III studies in the 
indications wet AMD, CRVO, BRVO, DME and myopic CNV 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. 



  
38 

 

 
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, DME and myopic 
CNV) or during post-marketing surveillance 
 

System 
Organ 
Class 

Very common Common Uncommon Rare 

Immune 
system 
disorders 

  Hypersensitivity***   

Eye 
disorders 

Visual acuity 
reduced, 
Conjunctival 
haemorrhage, 
Eye pain 

Retinal pigment epithelial tear*, 
Detachment of the retinal 
pigment epithelium, 
Retinal degeneration, 
Vitreous haemorrhage, 
Cataract, 
Cataract cortical, 
Cataract nuclear, 
Cataract subcapsular,  
Corneal erosion,  
Corneal abrasion, 
Intraocular pressure increased, 
Vision blurred, 
Vitreous floaters, 
Vitreous detachment, 
Injection site pain, 
Foreign body sensation in 
eyes, 
Lacrimation increased, 
Eyelid oedema, 
Injection site haemorrhage, 
Punctate keratitis, 
Conjunctival hyperaemia, 
Ocular hyperaemia 

Endophthalmitis**, 
Retinal detachment, 
Retinal tear, 
Iritis, 
Uveitis, 
Iridocyclitis, 
Lenticular opacities, 
Corneal epithelium 
defect, 
Injection site 
irritation, 
Abnormal sensation 
in eye, 
Eyelid irritation, 
Anterior chamber 
flare, 
Corneal oedema 

Blindness, 
Cataract 
traumatic, 
Vitritis, 
Hypopyon 

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only. 
** Culture positive and culture negative endophthalmitis 
*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated 

cases of severe anaphylactic/anaphylactoid 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, including stroke and 
myocardial infarction, following intravitreal use of VEGF inhibitors. 



  
39 

 

A low incidence rate of arterial thromboembolic events was observed in the Eylea clinical trials in 
patients with AMD, DME, RVO and myopic CNV. Across indications no notable difference between 
the groups treated with aflibercept and the respective comparator groups were observed. 
 
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 national reporting system 
listed in Appendix V. 
 
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. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


  
40 

 

In patients treated with Eylea (one injection per month for three consecutive months, followed by one 
injection every 2 months), central retinal thickness [CRT] 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 CRT 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 CRT 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 CRT were generally maintained in the second year of the studies. 
 

The ALTAIR study was conducted in Japanese patients with treatment naïve wet AMD, showing 
similar outcomes to the VIEW studies using 3 initial monthly Eylea 2 mg injections, followed by one 
injection after a further 2 months, and then continued with a treat-and-extend regimen with variable 
treatment intervals (2-week or 4-week adjustments) up to a maximum 16 week interval according to 
pre-specified criteria. At week 52, there were mean decreases in central retinal thickness (CRT) on 
OCT of -134.4 and –126.1 microns for the 2-week adjustment group and the 4-week adjustment group, 
respectively. The proportion of patients without fluid on OCT at week 52 was 68.3% and 69.1% in the 
2- and 4-week adjustment groups, respectively. The reduction in CRT was generally maintained in 
both treatment arms in the second year of the ALTAIR study. 
 
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, increased vascular permeability, retinal 
oedema, and neovascularisation complications. 
 
In patients treated with 6 consecutive monthly injections of Eylea 2mg, there was a consistent, rapid 
and robust morphologic response (as measured by improvements in mean CRT) observed. At week 24, 
the reduction in CRT was statistically superior versus control in all three studies (COPERNICUS in 
CRVO: -457 vs. -145 microns; GALILEO in CRVO: -449 vs. -169 microns; VIBRANT in BRVO: -
280 vs. -128 microns). This decrease from baseline in CRT was maintained to the end of each study, 
week 100 in COPERNICUS, week 76 in GALILEO, and week 52 in VIBRANT. 
 
Diabetic macular oedema 
 
Diabetic macular oedema is a consequence of diabetic retinopathy and is characterised by increased 
vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.  
 
In patients treated with Eylea, the majority of whom were classified as having Type II diabetes, a rapid 
and robust response in morphology (CRT, DRSS level) was observed.  
 
In the VIVIDDME and the VISTADME studies, a statistically significant greater mean decrease in CRT 
from baseline to week 52 was observed in patients treated with Eylea than with the laser control, -
192.4 and -183.1 microns for the 2Q8 Eylea groups  and -66.2 and -73.3 microns for the control 
groups, respectively. At week 100 the decrease was maintained with -195.8 and -191.1 microns for the 
2Q8 Eylea groups and -85.7 and -83.9 microns for the control groups, in the VIVIDDME and 
VISTADME studies, respectively. 
 
A ≥ 2 step improvement in DRSS was assessed in a pre-specified manner in VIVIDDME and 
VISTADME. The DRSS score was gradable in 73.7% of the patients in VIVIDDME and 98.3% of the 
patients in VISTADME. At week 52, 27.7% and 29.1% of the Eylea 2Q8 groups, and 7.5% and 14.3% 
of the control groups experienced a ≥2 step improvement in the DRSS. At week 100, the respective 



  
41 

 

percentages were 32.6% and 37.1% of the Eylea 2Q8 groups and 8.2% and 15.6% of the control 
groups. 
 
Myopic choroidal neovascularisation  
 
Myopic choroidal neovascularisation (myopic CNV) is a frequent cause of vision loss in adults with 
pathologic myopia. It develops as a wound healing mechanism consequent to Bruch’s membrane 
ruptures and represents the most vision-threatening event in pathologic myopia.  
 
In patients treated with Eylea in the MYRROR study (one injection given at start of therapy, with 
additional injections given in case of disease persistence or recurrence), CRT decreased soon after 
treatment initiation favouring Eylea at week 24 (-79 microns and -4 microns for the Eylea 2 mg 
treatment group and the control group, respectively), which was maintained through week 48. In 
addition, the mean CNV lesion size decreased.  
 
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 (VIEW1 and VIEW2) with a. total of 
2,412 patients treated and evaluable for efficacy (1,817 with Eylea). Patient ages ranged from 49 to 
99 years with a mean of 76 years. In these 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. 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). 
 
In the second year of the studies, patients continued to receive the initially randomised dosage 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, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline.  
 
In the VIEW1 study, at week 52, 95.1% of patients in the Eylea 2Q8 group maintained vision 
compared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% 
of patients in the Eylea 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 
0.5Q4 group. In both studies Eylea 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 Table 2 and Figure 1 below. 
 



  
42 

 

Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined data from the 
VIEW1 and VIEW2 studiesB) 
 

Efficacy Outcome Eylea 2Q8 E) 
(Eylea 2 mg every 8 weeks 
following 3 initial monthly 

doses) 
(N = 607) 

Ranibizumab 0.5Q4 
(ranibizumab 0.5 mg every 

4 weeks) 
 

(N = 595) 
Week 52 Week 96  Week 52 Week 96  

Mean number of injections 
from baseline 7.6 11.2 12.3 16.5 

Mean number of injections 
from Week 52 to 96  4.2  4.7 

Proportion of patients with  
< 15 letters loss from 
baseline (PPS A)) 

95.33%B) 92.42% 94.42% B) 91.60% 

DifferenceC) 
(95% CI)D) 

0.9% 
(-1.7, 3.5)F) 

0.8% 
(-2.3, 3.8)F)   

Mean change in BCVA as 
measured by ETDRSA) 
letter score from baseline  

8.40 7.62 8.74 7.89 

Difference in LS A)           
mean change (ETDRS 
letters)C) 

(95% CI)D) 

-0.32 
(-1.87, 1.23) 

-0.25 
(-1.98, 1.49)   

Proportion of patients with 
≥ 15 letters gain from 
baseline 

30.97% 33.44% 32.44% 31.60% 

DifferenceC) 
(95% CI)D) 

-1.5% 
(-6.8, 3.8) 

1.8% 
(-3.5, 7.1)   

 

A)  BCVA: Best Corrected Visual Acuity 
 ETDRS: Early Treatment Diabetic Retinopathy Study 
 LS: Least square means derived from ANCOVA 
 PPS: Per Protocol Set 
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 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 
 



  
43 

 

Figure 1. Mean Change in Visual Acuity 
from Baseline to Week 96 for the Combined 

Data from the View1 and View2 Studies 
  

 
 
In combined data analysis of VIEW1 and VIEW2 Eylea demonstrated clinically meaningful changes 
from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function 
Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. 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). 
 
In the second year of the studies, efficacy was generally maintained through the last assessment at 
week 96, and 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. 
 
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. 
 
ALTAIR was a 96 week multicentre, randomised, open-label study in 247 Japanese patients with 
treatment naïve wet AMD, designed to assess the efficacy and safety of Eylea following two different 
adjustment intervals (2-weeks and 4-weeks) of a treat-and-extend dosing regimen. 
 
All patients received monthly doses of Eylea 2 mg for 3 months, followed by one injection after a 
further 2 month interval. At week 16, patients were randomised 1:1 into two treatment groups: 1) 
Eylea treat-and-extend with 2-week adjustments and 2) Eylea treat-and-extend with 4-week 
adjustments. Extension or shortening of the treatment interval was decided based on visual and/or 
anatomic criteria defined by protocol with a maximum treatment interval of 16 weeks for both groups. 
 
The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondary 
efficacy endpoints were the proportion of patients who did not lose ≥15 letters and the proportion of 
patients who gained at least 15 letters of BCVA from baseline to week 52. 



  
44 

 

At week 52, patients in the treat-and-extend arm with 2-week adjustments gained a mean of 9.0 letters 
from baseline as compared to 8.4 letters for those in the 4-week adjustment group [LS mean difference 
in letters (95% CI): -0.4 (-3.8,3.0), ANCOVA]. The proportion of patients who did not lose ≥15 letters 
in the two treatment arms was similar (96.7% in the 2-week and 95.9% in the 4-week adjustment 
groups). The proportion of patients who gained ≥15 letters at week 52 was 32.5% in the 2-week 
adjustment group and 30.9% in the 4-week adjustment group. The proportion of patients who extended 
their treatment interval to 12 weeks or beyond was 42.3% in the 2-week adjustment group and 49.6 % 
in the 4-week adjustment group. Furthermore, in the 4-week adjustment group 40.7% of patients were 
extended to 16 week intervals. At the last visit  up to week 52, 56. 8% and 57.8% of patients in the 2-
week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 
12 weeks or beyond.  
 
In the second year of the study, efficacy was generally maintained up to and including the last 
assessment at week 96, with a mean gain from baseline of 7.6 letters for the 2-week adjustment group 
and 6.1 letters for the 4-week adjustment group. The proportion of patients who extended their 
treatment interval to 12 weeks  or beyond was 56.9% in the 2-week adjustment group and 60.2% in the 
4-week adjustment group. At the last visit prior to week 96, 64.9% and 61.2% of patients in the 2-
week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 
12 weeks or beyond. During the second year of treatment patients in both the 2-week and 4-week 
adjustment groups received an average of 3.6 and 3.7 injections, respectively. Over the 2 year 
treatment period patients received an average of 10.4 injections. 
 
Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 
and VIEW2. 
 
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 (COPERNICUS and 
GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with Eylea). Patient 
ages ranged from 22 to 89 years with a mean of 64 years. 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. 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 consecutive 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. From this timepoint all patients were treated if pre-
specified criteria were met. 
 
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. A secondary efficacy variable was change in 
visual acuity at week 24 compared to baseline. 
 
The difference between treatment groups was statistically significant in favour of Eylea in both 
studies. The maximal improvement in visual acuity was achieved at month 3 with subsequent 
stabilisation of visual acuity and CRT until month 6. The statistically significant difference was 
maintained through week 52. 
 
Detailed results from the analysis of both studies are shown in Table 3 and Figure 2 below. 

 



45 
 

Table 3:  Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCFC)) in COPERNICUS and GALILEO studies 
 

Efficacy Outcomes COPERNICUS GALILEO 

24 Weeks 52 Weeks 100 Weeks 24 Weeks 52 Weeks 76 Weeks 

Eylea 

2 mg Q4 

(N = 114) 

Control 

 

(N= 73) 

Eylea 

2 mg  

(N = 114) 

 ControlE) 

 (N =73) 

Eylea F) 

2 mg  

(N= 114) 

Control E,F)  

(N=73) 

Eylea 

2 mg Q4 

(N = 103) 

Control 

 

(N = 68) 

Eylea 

2 mg 

(N = 103) 

Control  

(N = 68) 

Eylea G) 

2 mg 

(N = 103) 

Control G) 

 

(N = 68) 

Proportion of patients with≥15 
letters gain from baseline 56% 12% 55% 30% 49.1% 23.3% 60% 22% 60% 32% 57.3% 29.4% 

Weighted differenceA,B,E) 
(95% CI) 

44.8% 
(33.0, 56.6)  

25.9% 
(11.8, 40.1)  

26.7% 
(13.1, 40.3) 

p=0.0003 
 

38.3% 
(24.4, 52.1)  

27.9% 
(13.0, 42.7)  

28.0% 
(13.3, 42.6) 

p=0.0004 
 

p-value p < 0.0001  p = 0.0006  p < 0.0001  p = 0.0004  

Mean change in BCVA C) as 
measured by ETDRSC) letter 
score from baseline (SD) 

17.3 
(12.8) 

-4.0 
(18.0) 

16.2 
(17.4) 

3.8 
(17.1) 

13.0 
(17.7) 

1.5 
(17.7) 

18.0 
(12.2) 

3.3 
(14.1) 

16.9 
(14.8) 

3.8 
(18.1) 

13.7 
(17.8) 

6.2 
(17.7) 

Difference in LS meanA,C,D,E) 
(95% CI) 

21.7 
(17.4, 26.0)  

12.7 
(7.7, 17.7)  

11.8 
(6.7, 17.0) 

p < 0.0001 
 

14.7 
(10.8, 18.7)  

13.2 
(8.2, 18.2)  

7.6 
(2.1, 13.1) 

p=0.0070 
 

p-value p < 0.0001  p < 0.0001  p < 0.0001  p < 0.0001  
 
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.  



  
46 

 

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. 



47 
 

 

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) 

 

In GALILEO, 86.4% (n=89) of the Eylea group and 79.4% (n=54) of the sham group had perfused 
CRVO at baseline. At week 24, this was 91.8% (n=89) in the Eylea group and 85.5% (n=47) in the 
sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the Eylea group 
and 84.0% (n=42) in the sham group. 
 



  
48 

 

In COPERNICUS, 67.5% (n = 77) of the Eylea group and 68.5% (n = 50) of the sham group had 
perfused CRVO at baseline. At week 24, this was 87.4% (n = 90) in the Eylea group and 58.6% (n = 
34) in the sham group. These proportions were maintained at week 100 with 76.8 % (n = 76) in the 
Eylea group and 78% (n = 39) in the sham group. Patients in the sham group were eligible to receive 
Eylea from week 24. 
 
The beneficial effect of Eylea treatment on visual function was similar in the baseline subgroups of 
perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g. age, gender, 
race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results 
in the overall populations. 
 
In combined data analysis of GALILEO and COPERNICUS, 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). 
 
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 (VIBRANT) which included 
Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with 
Eylea). Patient ages ranged from 42 to 94 years with a mean of 65 years. 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. 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 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients in 
the laser group could receive rescue treatment with Eylea 2mg from week 24, administered every 4 
weeks for 3 months followed by every 8 weeks.  
 
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 and the Eylea group was superior to laser 
control.  
 
A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, which 
was statistically significant in favour of Eylea in the VIBRANT study. The course of visual 
improvement was rapid and peaked at 3 months with 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), which resulted in improvement of visual acuity by about 5 letters from 
week 24 to 52. 
 
Detailed results from the analysis of the VIBRANT study are shown in Table 4 and Figure 3 below. 



  
49 

 

 

Table 4:  Efficacy outcomes at week 24 and week 52 (Full Analysis Set with LOCF) in VIBRANT 
study 

Efficacy Outcomes VIBRANT 

24 Weeks 52 Weeks 

 Eylea 2mg Q4 

(N = 91) 

Active Control 
(laser) 

(N = 90) 

Eylea 2mg Q8 

(N = 91)D) 
Active Control 
(laser)/Eylea 

2mgE) 

(N = 90) 

Proportion of patients 
with ≥15 letters gain 
from Baseline (%) 

52.7% 26.7% 57.1% 41.1% 

Weighted Difference A,B) 
(%) 

(95% CI) 

p-value  

26.6% 

(13.0, 40.1) 

p=0.0003 

 16.2% 

(2.0, 30.5) 

p=0.0296 

 

Mean change in BCVA 
as measured by ETDRS 
letter score from 
Baseline (SD) 

17.0 

(11.9) 

 6.9 

(12.9) 

17.1 

(13.1) 

12.2 (11.9) 

Difference in LS mean 
A,C) 

(95% CI) 

p-value 

 10.5 

(7.1, 14.0) 

p<0.0001 

 5.2 

(1.7, 8.7) 

p=0.0035F) 

 

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 

 

 



  
50 

 

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.  
 
Diabetic macular oedema 
 
The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, 
active-controlled studies in patients with DME (VIVIDDME and VISTADME). A total of 862 patients 
were treated and evaluable for efficacy, 576 with Eylea. Patient ages ranged from 23 to 87 years with a 
mean of 63 years. In the DME 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. The majority of patients in both studies had Type II diabetes.  
 
In both studies, 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 control group 
could receive Eylea. 
 
In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 
52 and both Eylea 2Q8 and Eylea 2Q4 groups demonstrated statistical significance and were superior 
to the control group. This benefit was maintained through week 100. 
 
Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 5 and 
Figure 4 below. 



51 
 

 

Table 5: Efficacy outcomes at week 52 and week 100 (Full Analysis Set with LOCF) in VIVIDDME and VISTADME studies 

Efficacy 
Outcomes 

VIVIDDME VISTADME 

52 Weeks 100 Weeks 52 Weeks 100 Weeks 

Eylea 

2 mg Q8 A 

(N = 135) 

Eylea 

2 mg Q4 

(N = 136) 

Active 
Control 

(laser) 

(N = 132) 

Eylea 

2 mg Q8 A 

(N = 135) 

Eylea  

2mg Q4 

(N=136) 

Active 
Control  

(laser) 

(N = 132) 

Eylea 

2 mg Q8 A 

(N = 151) 

Eylea 

2 mg Q4 

(N = 154) 

Active 
Control 

(laser) 

(N = 154) 

Eylea 

2 mg Q8 A 

(N = 151) 

Eylea 

2 mg Q4 

(N=154) 

Active 
Control  

(laser) 

(N = 154) 

Mean change in 
BCVA as 

measured by 
ETDRS E letter 

score from 
Baseline 

10.7 10.5 1.2 9.4 11.4 0.7 10.7 12.5 0.2 11.1 11.5 0.9 

Difference in LS        
     mean B,C,E 

     (97.5% CI) 

9.1 

(6.3, 11.8) 
9.3 

(6.5, 12.0) 
 

8.2 

(5.2, 11.3) 
10.7       

(7.6, 13.8) 
 

10.45 

(7.7, 13.2) 
12.19 

(9.4, 15.0) 
 

10.1 

(7.0, 13.3) 
10.6       

(7.1, 14.2) 
 

Proportion of 
patients with ≥ 15 
letters gain from 
Baseline 

33% 32% 9% 31.1% 38.2% 12.1% 31% 42% 8% 33.1% 38.3% 13.0% 

     Adjusted   
     Difference D,C,E 
     (97.5% CI) 

24% 
(13.5, 34.9) 

23% 
(12.6, 33.9) 

 
19.0%    

(8.0, 29.9) 
26.1% 

(14.8, 37.5) 
 

23% 
(13.5, 33.1) 

34% 
(24.1, 44.4) 

 
20.1%         

(9.6, 30.6) 
25.8% 

(15.1, 36.6) 
 

 

A After treatment initiation with 5 monthly injections  



  
52 

 

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 



53 
 

Figure 4:  Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to 
Week 100 in VIVIDDME and VISTADME Studies 

 
 

 
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 were similar to those seen in patients 
who were VEGF inhibitor naïve. 
 
Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if 
assessed necessary by the physician. In the VISTADME study, 217 (70.7%) of Eylea patients received 
bilateral Eylea injections until week100; in the VIVIDDME study, 97 (35.8%) of Eylea patients received 
a different anti-VEGF treatment in their fellow eye. 
 
An independent comparative trial (DRCR.net Protocol T) utilised a dosing regimen based on strict 
OCT and vision re-treatment criteria. In the aflibercept treatment group (n = 224) at week 52, this 
treatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to the 
administered number of doses in the Eylea 2Q8 group in VIVIDDME and VISTADME, while overall 
efficacy of the aflibercept treatment group in Protocol T was comparable to the Eylea 2Q8 group in 
VIVIDDME and VISTADME. A 13.3 mean letter gain with 42% of patients gaining at least 15 letters in 



  
54 

 

vision from baseline was observed in Protocol T. Ocular and systemic safety profiles (including 
ATEs) were similar to VIVIDDME and VISTADME. 
 
Myopic choroidal neovascularisation 
 
The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, sham-
controlled study in treatment-naïve, Asian patients with myopic CNV. A total of 121 patients were 
treated and evaluable for efficacy (90 with Eylea). Patient ages ranged from 27 to 83 years with a 
mean of 58 years. In the myopic CNV study, approximately 36% (33/91) of the patients randomised to 
treatment with Eylea were 65 years of age or older, and approximately 10% (9/91) were 75 years of 
age or older. 
 
Patients were randomly assigned in a 3:1 ratio to receive either 2 mg Eylea intravitreally or sham 
injections administered once at study start with additional injections given monthly in case of disease 
persistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patients 
initially randomised to sham were eligible to receive the first dose of Eylea. Following this, patients in 
both groups continued to be eligible for additional injections in case of disease persistence or 
recurrence. 
 
The difference between treatment groups was statistically significant in favour of Eylea for the 
primary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion of 
patients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for both 
endpoints were maintained through week 48. 
 
Detailed results from the analysis of the MYRROR study are shown in Table 6 and Figure 5 below. 
 
Table 6:  Efficacy outcomes at week 24 (primary analysis) and week 48 in MYRROR study 

(Full Analysis Set with LOCFA)) 

Efficacy Outcomes MYRROR 
24 Weeks 48 Weeks 

Eylea 2mg 
(N = 90) 

Sham 
(N = 31) 

Eylea 2mg 
(N = 90) 

Sham/ 
Eylea 2mg 

(N = 31) 
Mean change in BCVA B) as measured by 
ETDRS letter score from baseline (SD) B) 

12.1 
(8.3) 

-2.0 
(9.7) 

13.5 
(8.8) 

3.9 
(14.3) 

         Difference in LS mean C,D,E) 
        (95% CI) 

14.1 
(10.8, 17.4) 

 
9.5 

(5.4, 13.7) 
 

Proportion of patients with ≥15 letters gain 
from baseline 

38.9% 9.7% 50.0% 29.0% 

        Weighted difference D, F) 
        (95% CI) 

29.2% 
(14.4, 44.0) 

 
21.0% 

(1.9, 40.1) 
 

A) LOCF: Last Observation Carried Forward 
B) BCVA: Best Corrected Visual Acuity 

ETDRS: Early Treatment Diabetic Retinopathy Study 
SD: Standard Deviation 

C) LS mean: Least square means derived from ANCOVA model 
D) CI: Confidence Interval 
E) LS mean difference and 95% CI based on an ANCOVA model with treatment group and country (country 

designations) as fixed effects, and baseline BCVA as covariant. 
F) Difference and 95% CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for country 

(country designations) 
 



  
55 

 

Figure 5:  Mean Change from Baseline to Week 48 in Visual Acuity by Treatment Group for the 
MYRROR Study (Full Analysis Set, LOCF) 

 

 
 
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, DME and myopic CNV 
populations (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 wet AMD 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. 
 



  
56 

 

In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV 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, in patients with DME in the 
VIVIDDME study, and in patients with myopic CNV in the MYRROR 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. 
 
 



  
57 

 

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 stored 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 in one eye 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. 
 



  
58 

 

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. 



  
59 

 

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 onto the Luer-lock syringe tip. 

 

  

8. 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. 

 
9. Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger so that 

the plunger tip aligns with the line that marks 0.05 ml on the syringe. 

  

 

 

 
10. The vial is for single use only. Extraction of multiple doses  from a single vial may increase the risk 

of contamination and subsequent infection. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 



  
60 

 

 
 
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 
Date of latest renewal: 13 July 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


  
61 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 



  
62 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance  
 
Regeneron Pharmaceuticals, Inc. 
81 Columbia Turnpike 
Rensselaer, New York 12144 
USA 
 
Name and address of the manufacturer responsible for batch release 

Bayer AG 
Müllerstraße 178 
13353 Berlin 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT   
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
Pharmacovigilance system 



  
63 

 

The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the 
Marketing Authorisation is in place and functioning before and whilst the medicinal product is on the 
market. 
 
 
• Additional risk minimisation measures 
 
The MAH has agreed to provide EU Educational Material for Eylea. Prior to launch and during the 
product’s lifecycle in each Member State the Marketing Authorisation Holder (MAH) will agree the 
final educational material with the National Competent Authority. 
The MAH ensures that, following discussions and agreement with the National Competent Authorities 
in each Member State where Eylea is marketed, ophthalmological clinics where Eylea is expected to 
be used are provided with an updated physician information pack containing the following elements: 
• Physician information  
• Intravitreal injection procedure video  
• Intravitreal injection procedure pictogram  
• Patient information packs  
 
The physician information in the educational material contains the following key elements:  
• The Summary of Product Characteristics  
• Who should be treated with Eylea 
• Sterile techniques, including periocular and ocular disinfection to minimise the risk of infection  
• Use of antibiotics according to national guidelines 
• Use of povidone iodine or equivalent 
• Techniques for the intravitreal injection  
• Confirmation that the vial is for single use only 
• The need to expel excess volume of the syringe before injecting Eylea to avoid overdose 
• Patient monitoring after intravitreal injection including monitoring for visual acuity and increase 

of intraocular pressure post-injection 
• Key signs and symptoms of intravitreal injection related adverse events including 

endophthalmitis, increased intraocular pressure, retinal pigment epithelial tear and cataract 
• Management of intravitreal injection related adverse events 
• Female patients of childbearing potential have to use effective contraception and pregnant 

women should not use Eylea  
• Eylea is not recommended during breast-feeding. A decision must be made whether to 

discontinue breast-feeding or to abstain from Eylea therapy taking into account the benefit of 
breast-feeding for the child and the benefit of therapy for the woman 

 
The patient information pack of the educational material includes a patient information booklet and an 
audio-CD that contain following key elements:  
• Patient information leaflet 
• Who should be treated with Eylea 
• How to prepare for Eylea treatment  
• What are the steps following treatment with Eylea  
• Key signs and symptoms of serious adverse events including endophthalmitis, intraocular 

pressure increased, retinal pigment epithelial tear and cataract 
• When to seek urgent attention from their health care provider  
• Female patients of childbearing potential have to use effective contraception and pregnant 

women should not use Eylea  
 

• Obligation to conduct post-authorisation measures  
 
The MAH shall complete, within the stated timeframe, the below measures: 
 



  
64 

 

Description Due date 
Post-authorisation efficacy study (PAES) 
To perform a post-authorisation randomised study in patients with neovascular 
(wet) AMD with the primary objective of comparing the standard regime of 
injections every 8 weeks with a reactive regimen based on visual and anatomic 
outcomes, based on a CHMP approved protocol. 

Final study report 
submission: 30 
November 2021  

Post-authorisation efficacy study (PAES) 
To perform an interventional post-authorisation efficacy study in patients with 
diabetic macular oedema with the primary objective of comparing, after the first 
initial year of Eylea treatment, the standard regime of injections every 8 weeks 
with alternative treatment regimens, i.e. extended treatment intervals  based on 
visual and anatomic outcomes (PRN and treat-and-extend). 

Final study report 
submission:  
November 2020 

 
 

 
 



  
65 

 

 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 



  
66 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 

A. LABELLING 
 



  
67 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON 
Pre-filled syringe 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Eylea 40 mg/ml solution for injection in pre-filled syringe 
Aflibercept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Aflibercept 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
Polysorbate 20 
Sodium dihydrogen phosphate, monohydrate (for pH adjustment) 
Disodium hydrogen phosphate, heptahydrate (for pH adjustment) 
Sodium chloride 
Sucrose 
Water for injection 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled syringe  
 
One pre-filled syringe contains 3.6 mg aflibercept in 90 microlitres (40 mg/ml) in iso-osmotic 
solution. 
Delivers a single dose of 2 mg/0.05 ml. 
 
The excess volume should be expelled before injecting 
 
1 pre-filled syringe (3.6 mg/90 microlitres) 
Single dose: 2 mg/0.05 ml 
Excess volume to be expelled. 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Intravitreal use. 
For single use only. 
Read the package leaflet before use. 
Open the sterile blister in clean administration room only. 
 



  
68 

 

 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in refrigerator (2°C to 8°C). 
Do not freeze. 
Keep the pre-filled syringe in its blister in the outer carton to protect from light. 
Prior to use, the unopened blister may be stored at room temperature (below 25°C) for up to 24 hours. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/797/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 



  
69 

 

16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



  
70 

 

PARTICULARS TO APPEAR ON THE BLISTER FOIL  
Pre-filled syringe 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Eylea 40 mg/ml solution for injection 
Aflibercept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Aflibercept  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
One pre-filled syringe contains 3.6 mg/90 microlitres (40 mg/ml) in iso-osmotic solution. 
Delivers a single dose of 2 mg/0.05 ml. 
 
The excess volume should be expelled before injecting. 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Intravitreal use. 
For single use only. 
Read the package leaflet before use. 
Open the sterile blister in clean administration room only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in refrigerator (2°C to 8°C). 
Do not freeze. 
Keep the pre-filled syringe in its blister in the outer carton to protect from light. 



  
71 

 

Prior to use, the unopened blister may be stored at room temperature (below 25°C) for up to 24 hours. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/797/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 



  
72 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
LABEL 
Pre-filled syringe 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Eylea 40 mg/ml solution for injection 
Aflibercept 
Intravitreal use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Single dose = 2 mg/50 microlitres 
 
3.6 mg/90 microlitres 
 
 
6. OTHER 
 



  
73 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON 
Vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Eylea 40 mg/ml solution for injection in a vial 
 
Aflibercept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Aflibercept 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
Polysorbate 20 
Sodium dihydrogen phosphate, monohydrate (for pH adjustment) 
Disodium hydrogen phosphate, heptahydrate (for pH adjustment) 
Sodium chloride 
Sucrose 
Water for injection 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in a vial  
 
One vial contains 4 mg aflibercept in 100 microlitres (40 mg/ml) in iso-osmotic solution. 
Delivers a single dose of 2 mg/0.05 ml. 
 
The excess volume should be expelled before injecting 
 
1 vial (4 mg/0.1 ml) 
18G filter needle 
Single dose: 2 mg/0.05 ml 
Excess volume to be expelled. 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Intravitreal use. 
Vial for single use only. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 



  
74 

 

 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in refrigerator (2°C to 8°C). 
Do not freeze. 
Keep the vial in the outer carton to protect from light. 
Prior to use, the unopened vial may be stored at room temperature (below 25°C) for up to 24 hours. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/797/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 



  
75 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



  
76 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
LABEL 
Vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Eylea 40 mg/ml solution for injection 
Aflibercept 
Intravitreal use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Single dose = 2 mg/50 microlitres 
 
Extractable content = 4 mg/100microlitres 
 
 
6. OTHER 
 



  
77 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 



  
78 

 

Package Leaflet: Information for the patient 
 

Eylea 40 mg/ml solution for injection in a pre-filled syringe 
Aflibercept 

 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Eylea is and what it is used for 
2. What you need to know before you are given Eylea  
3. How you will be given Eylea  
4. Possible side effects 
5. How to store Eylea  
6. Contents of the pack and other information 
 
 
1. What Eylea is and what it is used for 
 
Eylea is a solution which is injected into the eye to treat eye conditions in adults called  
 
- neovascular (wet) age-related macular degeneration (wet AMD),  
- impaired vision due to macular oedema secondary to retinal vein occlusion (branch RVO (BRVO) 

or central RVO (CRVO)), 
- impaired vision due to diabetic macular oedema (DME), 
- impaired vision due to myopic choroidal neovascularisation (myopic CNV). 
 
Aflibercept, the active substance in Eylea, blocks the activity of a group of factors, known as Vascular 
Endothelial Growth Factor A (VEGF-A) and Placental Growth Factor (PlGF).  
 
In patients with wet AMD and myopic CNV, these factors, in excess are involved in the abnormal 
formation of new blood vessels in the eye. These new blood vessels can cause the leak of blood 
components into the eye and eventual damage to tissues in the eye responsible for vision.  
 
In patients with CRVO, a blockage occurs in the main blood vessel that transports blood away from 
the retina. VEGF levels are elevated in response causing the leakage of fluid into the retina and 
thereby causing a swelling of the macula, (the portion of the retina responsible for fine vision), which 
is called macular oedema. When the macula swells with fluid, central vision becomes blurry. 
 
In patients with BRVO, one or more branches of the main blood vessel that transports blood away 
from the retina is blocked. VEGF levels are elevated in response causing the leakage of fluid into the 
retina and thereby causing macular oedema. 
 
Diabetic macular oedema is a swelling of the retina occurring in patients with diabetes due to leaking 
of fluid from blood vessels within the macula. The macula is the portion of retina responsible for fine 
vision. When the macula swells with fluid, central vision becomes blurry. 
 
Eylea has been shown to stop the growth of new abnormal blood vessels in the eye which often leak 
fluid or bleed. Eylea can help to stabilise, and in many cases, improve the vision loss related to wet 
AMD, CRVO, BRVO, DME and myopic CNV. 



  
79 

 

 
 
2. What you need to know before you are given Eylea 
 
You will not be given Eylea: 
- if you are allergic to aflibercept or any of the other ingredients of this medicine (listed in 

section 6 ). 
- if you have an active or suspected infection in or around the eye (ocular or periocular infection). 
- if you have severe inflammation of the eye (indicated by pain or redness).  
 
Warnings and precautions 
 
Talk to your doctor before you are given Eylea: 
 
- if you have glaucoma. 
- if you have a history of seeing flashes of light or floaters and if you have a sudden increase of size 

and number of floaters. 
- if surgery was performed or is planned on your eye within the previous or next four weeks. 
- if you have a severe form of CRVO or BRVO (ischaemic CRVO or BRVO), treatment with Eylea 

is not recommended. 
 
Furthermore, it is important for you to know that: 
 
- the safety and efficacy of Eylea when administered to both eyes at the same time has not been 

studied and if used in this way may lead to an increased risk of experiencing side effects. 
- injections with Eylea may cause an increase in eye pressure (intraocular pressure) in some patients 

within 60 minutes of the injection. Your doctor will monitor this after each injection. 
- if you develop an infection or inflammation inside the eye (endophthalmitis) or other 

complications, you may have eye pain or increased discomfort, worsening eye redness, blurred or 
decreased vision, and increased sensitivity to light. It is important to have any symptoms 
diagnosed and treated as soon as possible.  

- your doctor will check whether you have other risk factors that may increase the chance of a tear 
or detachment of one of the layers at the back of the eye (retinal detachment or tear, and retinal 
pigment epithelial detachment or tear), in which case Eylea must be given with caution. 

- Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to 
the unborn child.  

- women of childbearing potential have to use effective contraception during treatment and for at 
least three further months after the last injection of Eylea. 

 
The systemic use of VEGF inhibitors, substances similar to those contained in Eylea, is potentially 
related to the risk of blood clots blocking blood vessels (arterial thromboembolic events) which may 
lead to heart attack or stroke. There is a theoretical risk of such events following injection of Eylea 
into the eye. There are limited data on safety in treating patients with CRVO, BRVO, DME and 
myopic CNV who have had a stroke or a mini-stroke (transient ischaemic attack) or a heart attack 
within the last 6 months. If any of these apply to you, Eylea will be given with caution.  
 
There is only limited experience in the treatment of  
- patients with DME due to type I diabetes. 
- diabetics with very high average blood sugar values (HbA1c over 12%). 
- diabetics with an eye disease caused by diabetes called proliferative diabetic retinopathy. 
 
There is no experience in the treatment of  
- patients with acute infections. 
- patients with other eye conditions such as a detachment of the retina or a hole in the macula. 
- diabetics with uncontrolled high blood pressure.  
- non-Asian patients with myopic CNV. 



  
80 

 

- patients previously treated for myopic CNV. 
- patients with damage outside the central part of the macula (extrafoveal lesions) for myopic CNV. 
 
If any of the above applies to you, your doctor will consider this lack of information when treating you 
with Eylea. 
 
Children and adolescents 
The use of Eylea in children or adolescents under 18 has not been studied because wet AMD, CRVO, 
BRVO, DME and myopic CNV occur mainly in adults. Therefore, its use in this age group is not 
relevant. 
 
Other medicines and Eylea 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding 
- Women of childbearing potential have to use effective contraception during treatment and for at 

least three further months after the last injection of Eylea. 
 
- There is no experience of using Eylea in pregnant women. Eylea should not be used during 

pregnancy unless the potential benefit outweighs the potential risk to the unborn child. If you 
are pregnant or planning to become pregnant, discuss this with your doctor before treatment 
with Eylea. 

 
- Eylea is not recommended during breast-feeding as it is not known whether Eylea passes into 

human milk. Ask your doctor for advice before starting Eylea treatment. 
 
Driving and using machines 
After your injection with Eylea, you may experience some temporary visual disturbances. Do not drive 
or use machines as long as these last. 
 
Important information about some of the ingredients of Eylea 
This medicine contains less than 1 mmol (23 mg) of sodium per dose which means it is essentially 
“sodium-free”. 
 
 
3. How you will be given Eylea 
 
A doctor experienced in giving eye injections will inject Eylea into your eye under aseptic (clean and 
sterile) conditions.  
 
The recommended dose is 2 mg aflibercept (50 microlitres).  
Eylea is given as an injection into your eye (intravitreal injection).  
 
Before the injection your doctor will use a disinfectant eyewash to clean your eye carefully to prevent 
infection. Your doctor will also give you a local anaesthetic to reduce or prevent any pain you might 
have with the injection.  
 
wet AMD 
 
Patients with wet AMD will be treated with one injection per month for three consecutive doses, 
followed by another injection after a further two months.  
 
Your doctor will then decide whether the treatment interval between injections may be kept at every 
two months or be gradually extended in 2- or 4-weekly intervals if your condition has been stable. If 
your condition worsens, the interval between injections can be shortened, but to not less than every 
two months in the first year of treatment.  



  
81 

 

 
Unless you experience any problems or are advised differently by your doctor, there is no need for you 
to see your doctor between the injections. 
 
Macular oedema secondary to RVO (branch RVO or central RVO) 
 
Your doctor will determine the most appropriate treatment schedule for you. You will start your 
treatment with a series of monthly Eylea injections.  
 
The interval between two injections should not be shorter than one month. 
 
Your doctor may decide to stop treatment with Eylea, if you are not benefiting from continued 
treatment. 
 
Your treatment will continue with  monthly injections until your condition is stable. Three or more 
monthly injections may be needed. 
 
Your doctor will monitor your response to treatment and may continue your treatment by gradually 
increasing the interval between your injections to maintain a stable condition. If your condition starts 
to worsen with a longer treatment interval, your doctor will shorten the interval accordingly. 
 
Based on your response to treatment your doctor will decide on the schedule for follow up 
examinations and treatments.  
 
Diabetic macular oedema (DME) 
 
Patients with DME will be treated with one injection per month for the first five consecutive doses 
followed by one injection every two months thereafter.  
 
Unless you experience any problems or are advised differently by your doctor, there is no need for you 
to see your doctor between the injections. 
 
After the first 12 months of treatment with Eylea, the treatment interval may be extended based on 
your doctor’s examination. Your doctor will decide on the schedule for follow up examinations. 
 
Your doctor may decide to stop treatment with Eylea if it is determined that you are not benefiting 
from continued treatment. 
 
Myopic CNV 
 
Patients with myopic CNV will be treated with one single injection. You will receive further injections 
only if your doctor’s examinations reveal that your condition has not improved. 
 
The interval between two injections should not be shorter than one month. 
 
If your condition goes away and then comes back, your doctor may re-start the treatment. 
 
Your doctor will decide on the schedule for follow up examinations. 
 
If a dose of Eylea is missed 
Make a new appointment for an examination and injection. 
 
Stopping treatment with Eylea 
Consult your doctor before stopping the treatment.  
 
If you have any further questions on the use of this medicine, ask your doctor. 



  
82 

 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reactions (hypersensitivity) could potentially occur. These may be serious and require that 
you contact your doctor immediately. 
 
With administration of Eylea, there may be some side effects affecting the eyes which are due to the 
injection procedure. Some of these may be serious and include blindness, a serious infection or 
inflammation inside the eye (endophthalmitis), detachment, tear or bleeding of the light-sensitive 
layer at the back of the eye (retinal detachment or tear), clouding of the lens (cataract), bleeding in 
the eye (vitreous haemorrhage), detachment of the gel-like substance inside the eye from the retina 
(vitreous detachment) and increase of pressure inside the eye, see section 2. These serious side 
effects affecting the eyes occurred in less than 1 in 1,900 injections in clinical studies. 
 
If you experience a sudden decrease in vision, or an increase in pain and redness in your eye after your 
injection, contact your doctor immediately.  
 
List of side effects reported 
The following is a list of the side effects reported to be possibly related to the injection procedure or to 
the medicine. Please do not get alarmed, you might not experience any of these. Always discuss any 
suspected side effects with your doctor. 
 
Very common side effects (may affect more than 1 in 10 people): 
- deterioration of eyesight  
- bloodshot eye caused by bleeding from small blood vessels in the outer layers of the eye  
- eye pain 
 
Common side effects (may affect up to 1 in 10 people): 
- detachment or tear of one of the layers in the back of the eye, resulting in flashes of light with 

floaters sometimes progressing to a loss of vision (retinal pigment epithelial tear*/detachment, 
retinal detachment/tear) 

- degeneration of the retina (causing disturbed vision) 
- bleeding in the eye (vitreous haemorrhage) 
- certain forms of clouding of the lens (cataract) 
- damage to the front layer of the eyeball (the cornea)  
- increase in eye pressure  
- moving spots in vision (floaters) 
- detachment of the gel-like substance inside the eye from the retina (vitreous detachment, resulting 

in flashes of light with floaters) 
- a feeling of having something in the eye 
- increased tear production 
- swelling of the eyelid  
- bleeding at the injection site 
- redness of the eye  
* Conditions known to be associated with wet AMD; observed in wet AMD patients only. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
- allergic reactions (hypersensitivity)** 
- serious inflammation or infection inside the eye (endophthalmitis) 
- inflammation in the iris or other parts of the eye (iritis, uveitis, iridocyclitis, anterior chamber 

flare) 
- abnormal sensation in the eye 
- eyelid irritation 



  
83 

 

- swelling of the front layer of the eyeball (cornea) 
** Allergic reactions like rash, itching (pruritus), hives (urticaria), and a few cases of severe allergy 
(anaphylactic/anaphylactoid) reactions were reported. 
 
Rare side effects (may affect up to 1 in 1,000 people): 
- blindness 
- clouding of the lens due to injury (traumatic cataract) 
- inflammation of the gel-like substance inside the eye 
- pus in the eye  

 
In the clinical trials, there was an increased incidence of bleeding from small blood vessels in the outer 
layers of the eye (conjunctival haemorrhage) in patients with wet AMD receiving blood thinners. This 
increased incidence was comparable between patients treated with ranibizumab and Eylea. 
 
The systemic use of VEGF inhibitors, substances similar to those contained in Eylea, is potentially 
related to the risk of blood clots blocking blood vessels (arterial thromboembolic events) which may 
lead to heart attack or stroke. There is a theoretical risk of such events following injection of Eylea 
into the eye.  
 
As with all therapeutic proteins, there is a possibility for an immune reaction (formation of antibodies) 
with Eylea.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects, you can help provide more information on the safety of this medicine. 
 
 
5. How to store Eylea 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use this medicine after the expiry date which is stated on the carton and label after EXP. 

The expiry date refers to the last day of that month. 
• Store in a refrigerator (2°C to 8°C). Do not freeze. 
• Prior to usage, the unopened blister may be stored at room temperature (below 25°C) for up to 

24 hours. 
• Keep the pre-filled syringe in its blister and in the outer carton in order to protect from light. 
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away any medicines you no longer use. These measures will help protect the 
environment. 

 
 
6. Contents of the pack and other information 
 
What Eylea contains  
- The active substance is: aflibercept. One pre-filled syringe contains 90 microlitres, equivalent to 

3.6 mg aflibercept. One pre-filled syringe delivers a dose of 2 mg aflibercept in 50 microlitres.  
- The other ingredients are: polysorbate 20, sodium dihydrogen phosphate monohydrate (for pH 

adjustment), disodium hydrogen phosphate heptahydrate (for pH adjustment), sodium chloride, 
sucrose, water for injection. 

 
What Eylea looks like and contents of the pack 
Eylea is a solution for injection (injection) in a pre-filled syringe (3.6 mg/90 microlitres). The solution 
is colourless to pale yellow. 
Pack size of 1. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


  
84 

 

Marketing Authorisation Holder 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
 
Bayer AG 
Müllerstraße 178 
13353 Berlin 
Germany  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 

Ireland 
Bayer Limited 
Tel: +353-(0)1-2999 313 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  



  
85 

 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 

United Kingdom 
Bayer plc 
Tel: +44-(0)118 206 3000 

  
This leaflet was last revised in {MM/YYYY}  
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  
 
<-------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for healthcare professionals only: 
 
Each pre-filled syringe should only be used for the treatment of a single eye. 
Do not open the sterile pre-filled blister outside the clean administration room. 
 
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. 
 
Prior to usage, the unopened blister of Eylea may be stored at room temperature (below 25°C) for up 
to 24 hours. After opening the blister, proceed under aseptic conditions. 
For the intravitreal injection, a 30 G x ½ inch injection needle should be used. 
 
 
Instructions for use of pre-filled syringe: 
 
1. When ready to administer Eylea, open the carton and remove the sterilised blister. Carefully peel open 

the blister ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready 
for assembly. 

2. Using aseptic technique, remove the syringe from the sterilised blister. 
 

3. To remove the syringe cap, hold the syringe in one 
hand while using the other hand to grasp the syringe 
cap with the thumb and fore finger. Please note: 
You should twist off (do not snap off) the syringe 
cap.  

 
 

4. To avoid compromising the sterility of the product, do not pull back on the plunger. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


  
86 

 

5. Using aseptic technique, firmly twist the injection 
needle onto the Luer-lock syringe tip. 

 

 
 

  
6. 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. 

 
 
7. 

 
Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger rod to 
align the cylindrical base of the plunger dome edge with the black dosing line on the syringe 
(equivalent to 50 microlitres).

  
 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

 

 
8.  

 
The pre-filled syringe is for single use only. Extraction of multiple doses from a pre-filled syringe 
may increase the risk of contamination and subsequent infection. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 



  
87 

 

Package Leaflet: Information for the patient 
 

Eylea 40 mg/ml solution for injection in a vial 
Aflibercept 

 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Eylea is and what it is used for 
2. What you need to know before you are given Eylea  
3. How you will be given Eylea  
4. Possible side effects 
5. How to store Eylea  
6. Contents of the pack and other information 
 
 
1. What Eylea is and what it is used for 
 
Eylea is a solution which is injected into the eye to treat eye conditions in adults called  
 
- neovascular (wet) age-related macular degeneration (wet AMD),  
- impaired vision due to macular oedema secondary to retinal vein occlusion (branch RVO (BRVO) 

or central RVO (CRVO)), 
- impaired vision due to diabetic macular oedema (DME), 
- impaired vision due to myopic choroidal neovascularisation (myopic CNV). 
 
Aflibercept, the active substance in Eylea, blocks the activity of a group of factors, known as Vascular 
Endothelial Growth Factor A (VEGF-A) and Placental Growth Factor (PlGF).  
 
In patients with wet AMD and myopic CNV, these factors, in excess are involved in the abnormal 
formation of new blood vessels in the eye. These new blood vessels can cause the leak of blood 
components into the eye and eventual damage to tissues in the eye responsible for vision.  
 
In patients with CRVO, a blockage occurs in the main blood vessel that transports blood away from 
the retina. VEGF levels are elevated in response causing the leakage of fluid into the retina and 
thereby causing a swelling of the macula, (the portion of the retina responsible for fine vision), which 
is called macular oedema. When the macula swells with fluid, central vision becomes blurry. 
 
In patients with BRVO, one or more branches of the main blood vessel that transports blood away 
from the retina is blocked. VEGF levels are elevated in response causing the leakage of fluid into the 
retina and thereby causing macular oedema. 
 
Diabetic macular oedema is a swelling of the retina occurring in patients with diabetes due to leaking 
of fluid from blood vessels within the macula. The macula is the portion of retina responsible for fine 
vision. When the macula swells with fluid, central vision becomes blurry. 
 
Eylea has been shown to stop the growth of new abnormal blood vessels in the eye which often leak 
fluid or bleed. Eylea can help to stabilise, and in many cases, improve the vision loss related to wet 
AMD, CRVO, BRVO, DME and myopic CNV. 



  
88 

 

 
 
2. What you need to know before you are given Eylea 
 
You will not be given Eylea: 
- if you are allergic to aflibercept or any of the other ingredients of this medicine (listed in 

section 6 ). 
- if you have an active or suspected infection in or around the eye (ocular or periocular infection). 
- if you have severe inflammation of the eye (indicated by pain or redness).  
 
Warnings and precautions 
 
Talk to your doctor before you are given Eylea: 
 
- if you have glaucoma. 
- if you have a history of seeing flashes of light or floaters and if you have a sudden increase of size 

and number of floaters. 
- if surgery was performed or is planned on your eye within the previous or next four weeks. 
- if you have a severe form of CRVO or BRVO (ischaemic CRVO or BRVO), treatment with Eylea 

is not recommended. 
 
Furthermore, it is important for you to know that: 
 
- the safety and efficacy of Eylea when administered to both eyes at the same time has not been 

studied and if used in this way may lead to an increased risk of experiencing side effects. 
- injections with Eylea may cause an increase in eye pressure (intraocular pressure) in some patients 

within 60 minutes of the injection. Your doctor will monitor this after each injection. 
- if you develop an infection or inflammation inside the eye (endophthalmitis) or other 

complications, you may have eye pain or increased discomfort, worsening eye redness, blurred or 
decreased vision, and increased sensitivity to light. It is important to have any symptoms 
diagnosed and treated as soon as possible.  

- your doctor will check whether you have other risk factors that may increase the chance of a tear 
or detachment of one of the layers at the back of the eye (retinal detachment or tear, and retinal 
pigment epithelial detachment or tear), in which case Eylea must be given with caution. 

- Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to 
the unborn child.  

- women of childbearing potential have to use effective contraception during treatment and for at 
least three further months after the last injection of Eylea. 

 
The systemic use of VEGF inhibitors, substances similar to those contained in Eylea, is potentially 
related to the risk of blood clots blocking blood vessels (arterial thromboembolic events) which may 
lead to heart attack or stroke. There is a theoretical risk of such events following injection of Eylea 
into the eye. There are limited data on safety in treating patients with CRVO, BRVO, DME and 
myopic CNV who have had a stroke or a mini-stroke (transient ischaemic attack) or a heart attack 
within the last 6 months. If any of these apply to you, Eylea will be given with caution.  
 
There is only limited experience in the treatment of  
- patients with DME due to type I diabetes. 
- diabetics with very high average blood sugar values (HbA1c over 12%). 
- diabetics with an eye disease caused by diabetes called proliferative diabetic retinopathy. 
 
There is no experience in the treatment of  
- patients with acute infections. 
- patients with other eye conditions such as a detachment of the retina or a hole in the macula. 
- diabetics with uncontrolled high blood pressure.  
- non-Asian patients with myopic CNV. 



  
89 

 

- patients previously treated for myopic CNV. 
- patients with damage outside the central part of the macula (extrafoveal lesions) for myopic CNV. 
 
If any of the above applies to you, your doctor will consider this lack of information when treating you 
with Eylea. 
 
Children and adolescents 
The use of Eylea in children or adolescents under 18 has not been studied because wet AMD, CRVO, 
BRVO, DME and myopic CNV occur mainly in adults. Therefore, its use in this age group is not 
relevant. 
 
Other medicines and Eylea 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding 
- Women of childbearing potential have to use effective contraception during treatment and for at 

least three further months after the last injection of Eylea. 
 
- There is no experience of using Eylea in pregnant women. Eylea should not be used during 

pregnancy unless the potential benefit outweighs the potential risk to the unborn child. If you 
are pregnant or planning to become pregnant, discuss this with your doctor before treatment 
with Eylea. 

 
- Eylea is not recommended during breast-feeding as it is not known whether Eylea passes into 

human milk. Ask your doctor for advice before starting Eylea treatment. 
 
Driving and using machines 
After your injection with Eylea, you may experience some temporary visual disturbances. Do not drive 
or use machines as long as these last. 
 
Important information about some of the ingredients of Eylea 
This medicine contains less than 1 mmol (23 mg) of sodium per dose which means it is essentially 
“sodium-free”. 
 
 
3. How you will be given Eylea 
 
A doctor experienced in giving eye injections will inject Eylea into your eye under aseptic (clean and 
sterile) conditions.  
 
The recommended dose is 2 mg aflibercept (50 microlitres).  
Eylea is given as an injection into your eye (intravitreal injection).  
 
Before the injection your doctor will use a disinfectant eyewash to clean your eye carefully to prevent 
infection. Your doctor will also give you a local anaesthetic to reduce or prevent any pain you might 
have with the injection.  
 
wet AMD 
 
Patients with wet AMD will be treated with one injection per month for three consecutive doses, 
followed by another injection after a further  two months.  
 
Your doctor will then decide whether the treatment interval between injections may be kept at every 
two months or be gradually extended in 2- or 4-weekly intervals if your condition has been stable. If 
your condition worsens, the interval between injections can be shortened, but to not less than every 
two months in the first year of treatment.  



  
90 

 

 
Unless you experience any problems or are advised differently by your doctor, there is no need for you 
to see your doctor between the injections. 
 
Macular oedema secondary to RVO (branch RVO or central RVO) 
 
Your doctor will determine the most appropriate treatment schedule for you. You will start your 
treatment with a series of monthly Eylea injections.  
 
The interval between two injections should not be shorter than one month. 
 
Your doctor may decide to stop treatment with Eylea, if you are not benefiting from continued 
treatment. 
 
Your treatment will continue with  monthly injections until your condition is stable. Three or more 
monthly injections may be needed. 
 
Your doctor will monitor your response to treatment and may continue your treatment by gradually 
increasing the interval between your injections to maintain a stable condition. If your condition starts 
to worsen with a longer treatment interval, your doctor will shorten the interval accordingly. 
 
Based on your response to treatment your doctor will decide on the schedule for follow up 
examinations and treatments.  
 
Diabetic macular oedema (DME) 
 
Patients with DME will be treated with one injection per month for the first five consecutive doses 
followed by one injection every two months thereafter.  
 
Unless you experience any problems or are advised differently by your doctor, there is no need for you 
to see your doctor between the injections. 
 
After the first 12 months of treatment with Eylea, the treatment interval may be extended based on 
your doctor’s examination. Your doctor will decide on the schedule for follow up examinations. 
 
Your doctor may decide to stop treatment with Eylea if it is determined that you are not benefiting 
from continued treatment. 
 
Myopic CNV 
 
Patients with myopic CNV will be treated with one single injection. You will receive further injections 
only if your doctor’s examinations reveal that your condition has not improved. 
 
The interval between two injections should not be shorter than one month. 
 
If your condition goes away and then comes back, your doctor may re-start the treatment. 
 
Your doctor will decide on the schedule for follow up examinations. 
 
If a dose of Eylea is missed 
Make a new appointment for an examination and injection. 
 
Stopping treatment with Eylea 
Consult your doctor before stopping the treatment.  
 
If you have any further questions on the use of this medicine, ask your doctor. 



  
91 

 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reactions (hypersensitivity) could potentially occur. These may be serious and require that 
you contact your doctor immediately. 
 
With administration of Eylea, there may be some side effects affecting the eyes which are due to the 
injection procedure. Some of these may be serious and include blindness, a serious infection or 
inflammation inside the eye (endophthalmitis), detachment, tear or bleeding of the light-sensitive 
layer at the back of the eye (retinal detachment or tear), clouding of the lens (cataract), bleeding in 
the eye (vitreous haemorrhage), detachment of the gel-like substance inside the eye from the retina 
(vitreous detachment) and increase of pressure inside the eye, see section 2. These serious side 
effects affecting the eyes occurred in less than 1 in 1,900 injections in clinical studies. 
 
If you experience a sudden decrease in vision, or an increase in pain and redness in your eye after your 
injection, contact your doctor immediately.  
 
List of side effects reported 
The following is a list of the side effects reported to be possibly related to the injection procedure or to 
the medicine. Please do not get alarmed, you might not experience any of these. Always discuss any 
suspected side effects with your doctor. 
 
Very common side effects (may affect more than 1 in 10 people): 
- deterioration of eyesight  
- bloodshot eye caused by bleeding from small blood vessels in the outer layers of the eye  
- eye pain 
 
Common side effects (may affect up to 1 in 10 people): 
- detachment or tear of one of the layers in the back of the eye, resulting in flashes of light with 

floaters sometimes progressing to a loss of vision (retinal pigment epithelial tear*/detachment, 
retinal detachment/tear) 

- degeneration of the retina (causing disturbed vision) 
- bleeding in the eye (vitreous haemorrhage) 
- certain forms of clouding of the lens (cataract) 
- damage to the front layer of the eyeball (the cornea) 
- increase in eye pressure  
- moving spots in vision (floaters) 
- detachment of the gel-like substance inside the eye from the retina (vitreous detachment, resulting 

in flashes of light with floaters) 
- a feeling of having something in the eye 
- increased tear production 
- swelling of the eyelid  
- bleeding at the injection site 
- redness of the eye  
* Conditions known to be associated with wet AMD; observed in wet AMD patients only. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
- allergic reactions (hypersensitivity)** 
- serious inflammation or infection inside the eye (endophthalmitis) 
- inflammation in the iris or other parts of the eye (iritis, uveitis, iridocyclitis, anterior chamber 

flare) 
- abnormal sensation in the eye 
- eyelid irritation 



  
92 

 

- swelling of the front layer of the eyeball (cornea) 
** Allergic reactions like rash, itching (pruritus), hives (urticaria), and a few cases of severe allergy 
(anaphylactic/anaphylactoid) reactions were reported. 
 
Rare side effects (may affect up to 1 in 1,000 people): 
- blindness 
- clouding of the lens due to injury (traumatic cataract) 
- inflammation of the gel-like substance inside the eye 
- pus in the eye  

 
In the clinical trials, there was an increased incidence of bleeding from small blood vessels in the outer 
layers of the eye (conjunctival haemorrhage) in patients with wet AMD receiving blood thinners. This 
increased incidence was comparable between patients treated with ranibizumab and Eylea. 
 
The systemic use of VEGF inhibitors, substances similar to those contained in Eylea, is potentially 
related to the risk of blood clots blocking blood vessels (arterial thromboembolic events) which may 
lead to heart attack or stroke. There is a theoretical risk of such events following injection of Eylea 
into the eye.  
 
As with all therapeutic proteins, there is a possibility for an immune reaction (formation of antibodies) 
with Eylea.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects, you can help provide more information on the safety of this medicine. 
 
 
5. How to store Eylea 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use this medicine after the expiry date which is stated on the carton and label after EXP. 

The expiry date refers to the last day of that month. 
• Store in a refrigerator (2°C to 8°C). Do not freeze. 
• Prior to usage, the unopened vial may be stored at room temperature (below 25°C) for up to 

24 hours. 
• Keep the vial in its outer carton in order to protect from light. 
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away any medicines you no longer use. These measures will help protect the 
environment. 

 
 
6. Contents of the pack and other information 
 
What Eylea contains  
- The active substance is: aflibercept. One vial contains 100 microlitres, equivalent to 4 mg 

aflibercept. One vial delivers a dose of 2 mg aflibercept in 50 microlitres. 
- The other ingredients are: polysorbate 20, sodium dihydrogen phosphate monohydrate (for pH 

adjustment), disodium hydrogen phosphate heptahydrate (for pH adjustment), sodium chloride, 
sucrose, water for injection. 

 
What Eylea looks like and contents of the pack 
Eylea is a solution for injection (injection) in a vial (4 mg/100 microlitres). The solution is colourless 
to pale yellow. 
Pack size of 1. 
 

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Marketing Authorisation Holder 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer  
Bayer AG  
Müllerstraße 178  
13353 Berlin  
Germany 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 

Ireland 
Bayer Limited 
Tel: +353-(0)1-2999 313 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  



  
94 

 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 

United Kingdom 
Bayer plc 
Tel: +44-(0)118 206 3000 

  
This leaflet was last revised in {MM/YYYY}  
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  
 
<-------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for healthcare professionals only: 
 
Each vial should only be used for the treatment of a single eye. 
 
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. 
 
Prior to usage, the unopened vial of Eylea may be stored at room temperature (below 25°C) for up to 
24 hours. After opening the vial, proceed under aseptic conditions. 
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. 

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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 onto the Luer-lock syringe tip. 

 

  

8. 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. 

 



  
96 

 

9. Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger so that 
the plunger tip aligns with the line that marks 0.05 ml on the syringe. 

  

 

 

 
10. The vial is for single use only. Extraction of multiple doses from a single vial may increase the risk 

of contamination and subsequesnt infection. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET