EYLEA 114.3mg / ml solution for injection medication leaflet

Eylea 114.3 mg/ml solution for injection

Eylea 114.3 mg/ml solution for injection in pre-filled syringe

1 ml solution for injection contains 114.3 mg aflibercept*.

Eylea 114.3 mg/ml solution for injection

Each vial contains 30.1 mg aflibercept in 0.263 ml solution. This provides a usable amount to deliver asingle dose of 0.07 ml containing 8 mg aflibercept.

Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Each pre-filled syringe contains 21 mg aflibercept in 0.184 ml solution. This provides a usable amountto deliver a single dose of 0.07 ml containing 8 mg aflibercept.

* Aflibercept is a fusion protein consisting of portions of human VEGF (vascular endothelial growthfactor) 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.

Each ml solution for injection contains 0.3 mg polysorbate 20 (E 432).

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to slightly opalescent, colourless to pale yellow, iso-osmotic solution, pH 5.8.

Eylea is indicated in adults for the treatment of

- neovascular (wet) age-related macular degeneration (nAMD) (see section 5.1)

- visual impairment due to diabetic macular oedema (DME) (see section 5.1).

Eylea must only be administered by a qualified physician experienced in intravitreal injections.

The recommended dose is 8 mg aflibercept, equivalent to 0.07 ml solution. The posology is the samefor the nAMD and DME indications. The 8 mg dose requires use of Eylea 114.3 mg/ml.

For patients who are initiating treatment, Eylea is administered with 1 injection per month for3 consecutive doses. Injection intervals may then be extended up to every 4 months based on thephysician’s judgement of visual and/or anatomic outcomes. Subsequently, the treatment intervals maybe further extended up to 6 months, such as with a treat-and-extend dosing regimen, while maintainingstable visual and/or anatomic outcomes (see section 5.1).

For patients who have previously been treated with Eylea 40 mg/ml or other anti-VEGF medicinalproducts and are switching to Eylea 114.3 mg/ml, the treatment regimen can differ from that used fortreatment-naïve patients. Treatment intervals should be determined based on visual and/or anatomicoutcomes (see section 5.1).

- In patients with stable visual and anatomic outcomes, previous treatment intervals can bemaintained or extended after the first injection of Eylea 114.3 mg/ml, such as with atreat-and-extend dosing regimen.

- In patients with suboptimal visual and/or anatomic outcomes, treatment with Eylea 114.3 mg/mlmay begin with 1 injection per month for up to 3 consecutive doses followed by adjustment ofinjection intervals, such as with a treat-and-extend dosing regimen.

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordinglybased on the physician’s discretion. The shortest interval between 2 injections is 2 months in themaintenance phase.

Eylea at monthly doses of 8 mg has not been studied for more than 3 consecutive doses.

The frequency of monitoring visits should be based on the patient’s status and at the physician’sdiscretion. For events in which treatment should be withheld see section 4.4.

No specific studies in patients with renal or hepatic impairment have been conducted.

Available data do not suggest a need for a dose adjustment with Eylea in these patients (seesection 5.2).

Available data do not suggest a need for a dose adjustment with Eylea in these patients.

The safety and efficacy of Eylea 114.3 mg/ml in children and adolescents below 18 years have notbeen established. There is no relevant use of Eylea 114.3 mg/ml in the paediatric population in thenAMD and DME indications.

Eylea is for intravitreal injection only.

Intravitreal injections must be carried out according to medical standards and applicable guidelines bya qualified physician experienced in administering intravitreal injections. In general, adequateanaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine applied tothe periocular skin, eyelid and ocular surface), have to be ensured. Surgical hand disinfection, sterilegloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended.

The injection needle should be inserted 3.5 to 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 of0.07 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 inintraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nervehead or tonometry. If required, sterile equipment for paracentesis should be available.

Following intravitreal injection, patients should be instructed to report any symptoms suggestive ofendophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Each vial or pre-filled syringe should only be used for the treatment of a single eye.

After injection, discard any unused product or waste material in accordance with local requirements.

For handling of the medicinal product before administration, see section 6.6.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Ocular or periocular infection.

- Active severe intraocular inflammation.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Intravitreal injections, including those with Eylea, have been associated with endophthalmitis,intraocular inflammation, retinal detachment, retinal tear and traumatic cataract (see section 4.8).

Proper aseptic injection techniques must always be used when administering Eylea. Patients should beinstructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned eventswithout delay and should be managed appropriately.

Intraocular pressure increased

Transient increases in intraocular pressure have been seen within 60 minutes of an intravitrealinjection, including those with Eylea (see section 4.8). Both the intraocular pressure and perfusion ofthe optic nerve head must therefore be monitored and managed appropriately. Special precaution isneeded in patients with poorly controlled glaucoma (do not inject Eylea while the intraocular pressureis ≥ 30 mmHg).

As this is a therapeutic protein, there is a potential for immunogenicity with aflibercept (seesection 5.1). Patients should be instructed to report any signs or symptoms of intraocularinflammation, e.g. pain, photophobia, or redness, which may be a clinical sign attributable tohypersensitivity.

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events havebeen reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk thatthese may relate to VEGF inhibition (see section 4.8).

There are limited data on safety in the treatment of patients with nAMD and DME with a history ofstroke, transient ischaemic attacks or myocardial infarction within the last 6 months. Caution shouldbe exercised when treating such patients.

The safety and efficacy of bilateral treatment with Eylea 114.3 mg/ml per eye have not been studied(see section 5.1). If bilateral treatment is performed at the same time this could lead to an increasedsystemic exposure, which could increase the risk of systemic adverse events.

There are limited data available on the concomitant use of Eylea with other anti-VEGF medicinalproducts (systemic or ocular).

Treatment should be withheld in the event of:

- a decrease in best corrected visual acuity (BCVA) of ≥ 30 letters compared with the lastassessment of visual acuity

- a rhegmatogenous retinal detachment or stage 3 or 4 macular holes

- a retinal break

- a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is≥ 50 % of the total lesion area

- performed or planned intraocular surgery within the previous or next 28 days.

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGFtherapy for nAMD include a large and/or high pigment epithelial retinal detachment. When initiatingaflibercept therapy, caution should be used in patients with these risk factors for retinal pigmentepithelial tears.

Women of childbearing potential have to use effective contraception during treatment and for at least4 months after the last intravitreal injection with Eylea 114.3 mg/ml (see section 4.6).

There is only limited experience with Eylea treatment in diabetic patients with an HbA1c over 12 % orwith proliferative diabetic retinopathy.

Eylea has not been studied in patients with active systemic infections or in patients with concurrenteye conditions such as retinal detachment or macular hole. There is also no experience of treatmentwith Eylea in diabetic patients with uncontrolled hypertension. This lack of information should beconsidered by the physician when treating such patients.

This medicinal product contains 0.021 mg of polysorbate 20 in each 0.07 ml dose which is equivalentto 0.3 mg/ml. Polysorbates may cause allergic reactions.

No interaction studies have been performed.

Women of childbearing potential have to use effective contraception during treatment and for at least4 months after the last intravitreal injection with Eylea 114.3 mg/ml.

There are limited data on the use of aflibercept in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Eylea 114.3 mg/ml should not be used during pregnancy unless the potential benefit outweighs thepotential risk to the foetus.

Based on very limited human data, aflibercept may be excreted in human milk at low levels.

Aflibercept is a large protein molecule and the amount of medication absorbed by the infant isexpected to be minimal. The effect of aflibercept on a breast-fed newborn/infant is unknown.

As a precautionary measure breast-feeding is not recommended during the use of Eylea 114.3 mg/ml.

There are no fertility data in humans. Results from animal studies with high systemic exposureindicate that aflibercept can impair male and female fertility (see section 5.3).

Injection with Eylea has minor influence on the ability to drive and use machines due to possibletemporary visual disturbance associated either with the injection or eye examination. Patients shouldnot drive or use machines until their visual function has recovered sufficiently.

Serious adverse reactions were cataract (8.2%), retinal haemorrhage (3.6%), intraocular pressureincreased (2.8%), vitreous haemorrhage (1.2%), cataract subcapsular (0.9%), cataract nuclear (0.6%),retinal detachment (0.6%), and retinal tear (0.5%).

The most frequently observed adverse reactions in patients treated with Eylea 114.3 mg/ml werecataract (8.2%), visual acuity reduced (4.4%), vitreous floaters (4.0%), conjunctival haemorrhage(3.8%), vitreous detachment (3.7%), retinal haemorrhage (3.6%), intraocular pressure increased(2.8%), and eye pain (2.0%).

The safety profile observed in the 3 clinical studies was similar in patients treated with

Eylea 114.3 mg/ml (N=1 217) and Eylea 40 mg/ml (N=556), and in patients with nAMD and DME.

A total of 1 217 patients treated with Eylea 114.3 mg/ml up to 96 weeks constituted the safetypopulation in 3 clinical phase II/III studies (CANDELA, PULSAR, PHOTON).

The safety data described below include all adverse reactions with a reasonable possibility of causalityto the injection procedure or medicinal product reported.

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), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: All treatment-emergent adverse reactions reported in patients with nAMD or DMEtreated with Eylea 114.3 mg/ml in phase II/III studies or during post-marketing surveillance

System organ class Frequency Adverse reaction

Immune system

Common Hypersensitivity*disorders

Eye disorders Common Cataract, Intraocular pressure increased, Vitreousfloaters, Vitreous detachment, Vitreoushaemorrhage, Retinal haemorrhage,

Visual acuity reduced, Eye pain, Conjunctivalhaemorrhage, Punctate keratitis, Corneal abrasion

Uncommon Retinal detachment, Retinal tear, Retinal pigmentepithelial tear, Detachment of the retinal pigmentepithelium, Uveitis, Iritis, Iridocyclitis, Vitritis,

Cataract cortical, Cataract nuclear, Cataractsubcapsular, Corneal erosion, Vision blurred,

Injection site pain, Foreign body sensation in eyes,

Lacrimation increased, Injection site haemorrhage,

Conjunctival hyperaemia, Eyelid oedema, Ocularhyperaemia, Injection site irritation

Rare Corneal oedema, Lenticular opacities, Retinaldegeneration, Eyelid irritation

Not known Scleritis**

* Reports of hypersensitivity included rash, pruritus, urticaria.

** From post-marketing reporting.

The following adverse reactions of Eylea 40 mg/ml are also considered expected with

Eylea 114.3 mg/ml: abnormal sensation in eye, corneal epithelium defect, anterior chamber flare,endophthalmitis, blindness, traumatic cataract, hypopyon, severe anaphylactic/anaphylactoid reactions.

Arterial thromboembolic events (ATEs) are adverse reactions potentially related to systemic VEGFinhibition. There is a theoretical risk of ATEs, including stroke and myocardial infarction, followingintravitreal use of VEGF inhibitors. A low incidence rate of ATEs was observed in the afliberceptclinical studies in patients with nAMD and DME. Across indications, no notable difference betweenthe groups treated with Eylea 114.3 mg/ml and the comparator groups treated with Eylea 40 mg/mlwere observed.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case ofoverdose, intraocular pressure should be monitored and, if deemed necessary by the treating physician,adequate treatment should be initiated (see sections 4.4 and 6.6).

Pharmacotherapeutic group: Ophthalmologicals/Antineovascularisation agents, ATC code: S01LA05

Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2extracellular domains fused to the Fc portion of human IgG1.

Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members ofthe VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascularpermeability 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 alsopresent on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result inpathological neovascularisation and excessive vascular permeability. PlGF can act independently toactivate the VEGFR-1 to promote an inflammatory response within the retina, and is known toincrease in pathological states such as nAMD, diabetic retinopathy (DR), DME, and retinal veinocclusion (RVO).

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity thantheir natural receptors, and thereby can inhibit the binding and activation of these cognate VEGFreceptors.

In animal studies, aflibercept can prevent pathological neovascularization and vascular leakage in anumber of different models of ocular disease.

nAMDnAMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood andfluid from CNV may cause retinal oedema and/or sub-/intra-retinal haemorrhage, resulting in loss ofvisual acuity.

The pharmacodynamic effects of aflibercept 114.3 mg/ml administered every 12 (8Q12) and every 16(8Q16) weeks are described in comparison with aflibercept 40 mg/ml administered every 8 weeks(2Q8) for the nAMD indication. These effects are shown as the change in CNV size from baseline toweek 12; change in total lesion area from baseline to weeks 48, 60, and 96; and change from baselinein central retinal thickness (CRT).

In the pooled group of patients treated with 8Q12 or 8Q16, reductions in CNV size (LS mean, basedon a mixed model for repeated measurements [MMRM]) at week 12 were -1.63 mm2 comparedto -1.17 mm2 for patients treated with 2Q8.

Pharmacodynamic effects were generally maintained through week 156.

Table 2: Pharmacodynamic parameter (full analysis set) in the PULSAR study

Eylea 8Q12 Eylea 8Q16 Eylea 2Q8

Efficacy outcomes Week(N = 335) (N = 338) (N = 336)

Change in total lesion area from baseline [mm2]

LS mean A 12 -0.55 -0.30

Arithmetic mean (SD), observed -0.4 (2.9) -0.2 (3.1) 0.1 (3.6)

LS mean (SE) A -0.46 (0.19) -0.35 (0.20) 0.09 (0.22)

Difference in LS means -0.55 -0.44(95% CI) A,B (-1.04, -0.06) (-0.94, -0.06)

Arithmetic mean (SD), observed -0.5 (2.8) -0.4 (3.2) -0.3 (3.2)

LS mean (SE) A -0.48 (0.20) -0.54 (0.21) -0.24 (0.20)

Difference in LS means -0.24 -0.29(95% CI) A,B (-0.72, 0.24) (-0.79, 0.20)

Arithmetic mean (SD), observed -0.3 (3.3) -0.3 (3.2) -0.2 (3.4)

LS mean (SE) A -0.43 (0.20) -0.42 (0.20) -0.18 (0.20)

Difference in LS means -0.25 -0.24(95% CI) A,B (-0.72, 0.21) (-0.71, 0.22)

A LS mean, CI and p-value based on an MMRM with baseline measurement as covariate, treatment groupas factor, visit and stratification variables used for randomisation (geographical region, categoricalbaseline BCVA) as fixed factors as well as terms for the interaction between baseline measurement andvisit and for the interaction between treatment and visit.

B Absolute difference is Eylea 8Q12- or 8Q16-groups minus 2Q8-groups, respectively.

CI: Confidence interval

LS: Least square

SD: Standard deviation

SE: Standard error

Figure 1: LS mean change in central retinal thickness (CRT) from baseline through week 96(full analysis set) in the PULSAR study

- 146.82

- 148.75

- 151.97weeks

Diabetic macular oedema is characterised by increased vasopermeability and damage to the retinalcapillaries which may result in loss of visual acuity.

The pharmacodynamic effects of aflibercept 114.3 mg/ml administered every 12 (8Q12) and every 16(8Q16) weeks are described in comparison with aflibercept 40 mg/ml administered every 8 weeks(2Q8) for the DME indication. These effects are shown as the change in the leakage area from baselineto weeks 48, 60, and 96.

Pharmacodynamic effects were generally maintained through week 156.

LS mean change in CRT (microns)

Table 3: Pharmacodynamic parameter (full analysis set) in the PHOTON study

Eylea 8Q12 Eylea 8Q16 Eylea 2Q8

Efficacy Outcomes Week(N = 328) (N = 163) (N = 167)

Change in leakage areaA from baseline [mm2]

Arithmetic mean (SD), observed 48 -13.9 (13.91) -9.4 (11.50) -9.2 (12.11)60 -13.9 (13.54) -12.0 (13.26) -14.4 (12.89)96 -12.8 (10.98) -9.4 (10.61) -11.9 (11.26)

A based on fluorescein angiography measurement

SD: Standard deviation

Figure 2: LS mean change in central retinal thickness (CRT) from baseline through week 96(full analysis set) in the PHOTON study

- 158.39

- 191.26

- 193.99weeks

After dosing with Eylea 114.3 mg/ml for up to 96 weeks treatment-emergent antibodies to

Eylea 114.3 mg/ml were detected in 2.5% to 4.4% of patients treated for DME and nAMD. Noevidence of anti-drug antibodies impact on pharmacokinetics, efficacy or safety was observed.

Clinical efficacy and safetynAMD

Study objectives

The safety and efficacy of Eylea 114.3 mg/ml were assessed in a randomised, multi-centre,double-masked, active-controlled study (PULSAR) in patients with treatment naïve nAMD.

The primary objective was to determine if treatment with Eylea 114.3 mg/ml at intervals of 12 (8Q12)or 16 weeks (8Q16) provides non-inferior best corrected visual acuity (BCVA) change compared to

Eylea 40 mg/ml every 8 weeks in patients with nAMD.

The secondary objectives were to determine the effect of Eylea 114.3 mg/ml versus Eylea 40 mg/mlon anatomic and other visual measures of response, and to evaluate the safety, immunogenicity, andpharmacokinetics of aflibercept.

The primary efficacy endpoint was the change from baseline in BCVA measured by the earlytreatment diabetic retinopathy study (ETDRS) letter score at week 48.

The key secondary endpoints were the change in BCVA from baseline at week 60 and the proportionof patients with no intraretinal fluid (IRF) and no subretinal fluid (SRF) in central subfield at week 16.

Further secondary endpoints were the proportion of patients gaining at least 15 letters in BCVA frombaseline at week 48, the proportion of patients achieving an ETDRS letter score of at least 69(approximate 20/40 Snellen equivalent) at week 48, and the change from baseline in National Eye

Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) total score at week 48, among others.

LS mean change in CRT (microns)

In the PULSAR study a total of 1 009 patients were treated. The patients were assigned in a 1:1:1 ratioto 1 of 3 parallel treatment groups:

1. Eylea 114.3 mg/ml administered every 12 weeks (8Q12)2. Eylea 114.3 mg/ml administered every 16 weeks (8Q16)3. Eylea 40 mg/ml administered every 8 weeks (2Q8)

All patients received 3 initial injections of the assigned dose at 4-week intervals.

Per study protocol the interval of the 8Q12- and 8Q16-groups was to be shortened if both of thefollowing criteria were met:

1. >5 letters loss in BCVA from week 12, and2. >25 microns increase in CRT from week 12 or new foveal haemorrhage or new fovealneovascularisation.

Regardless of whether patient intervals were maintained or shortened in year 1, per study protocol allpatients in the 8Q12- and 8Q16-groups were eligible for interval extension (by 4 weeks increments),beginning at week 52, if the following criteria were met:

1. <5 letters loss in BCVA from week 12, and2. no fluid in the central subfield on optical coherence tomography (OCT), and3. no new onset of foveal haemorrhage or foveal neovascularisation.

For patients who did not meet the criteria for shortening or extension of the interval, the dosinginterval was maintained. The minimum interval between injections was 8 weeks in all groups.

Patients with bilateral disease were eligible to receive Eylea 40 mg/ml treatment or another anti-VEGFmedicinal product in their fellow eye.

Patient characteristics at baseline

Patient ages ranged from 50 to 96 years with a mean of 74.5 years.

Approximately 92% (309/335) and 87% (295/338) of the patients randomised to the 8Q12- and8Q16-groups, respectively, were 65 years of age or older and approximately 51% (172/335) and 51%(171/338) were 75 years of age or older.

Patients in the 8Q12-, 8Q16- and 2Q8-groups who completed week 48 received a median (mean) of6.0 (6.1), 5.0 (5.2) and 7.0 (6.9) injections, respectively.

At week 48, in the 8Q12-group, 79.4% of patients maintained Q12 intervals while in the 8Q16-group76.6% of patients maintained Q16 intervals.

Patients in the 8Q12-, 8Q16- and 2Q8-groups who completed week 60 received a median (mean) of7.0 (7.1), 6.0 (6.2) and 9.0 (8.8) injections, respectively.

At week 60, 43.1% of patients in the 8Q12-group were extended to a treatment interval of 16 weeks,and 38.5% of patients in the 8Q16-group were extended to a treatment interval of 20 weeks.

Patients in the 8Q12-, 8Q16- and 2Q8-groups who completed week 96 received a median (mean) of9.0 (9.7), 8.0 (8.2) and 13.0 (12.8) injections, respectively.

At week 96, in the pooled 8Q12- and 8Q16-groups 71.0% of patients had attained treatment intervalsof ≥16 weeks, 46.8% of patients had attained treatment intervals of ≥20 weeks, and 27.8% of patientshad attained treatment intervals of 24 weeks, while maintaining visual and anatomic outcomes.

Treatment with 8Q12 and 8Q16 was shown to be non-inferior and clinically equivalent to treatmentwith 2Q8 in terms of the primary efficacy endpoint ‘mean change in BCVA at week 48’ and the keysecondary efficacy endpoint ‘mean change in BCVA at week 60’. The treatment effect with

Eylea 114.3 mg/ml in mean change in BCVA was maintained through week 96.

Furthermore, treatment with Eylea (pooled 8Q12- and 8Q16-groups) was shown to be superior totreatment with 2Q8 in terms of the key secondary efficacy endpoint ‘proportion of patients with nointraretinal fluid (IRF) and no subretinal fluid (SRF) in the central subfield at week 16’ (see table 4).

Table 4: Efficacy outcomes from the PULSAR study

Eylea 8Q12 Eylea 8Q16 Eylea 2Q8

Efficacy outcomes Week(N = 335) (N = 338) (N = 336)

Change in BCVA from baseline as measured by ETDRS letter score D

Arithmetic mean (SD), observed 6.7 (12.6) 6.2 (11.7) 7.6 (12.2)

LS mean (SE) A 6.06 (0.77) 5.89 (0.72) 7.03 (0.74)

Difference in LS means -0.97 -1.14(95% CI) A,B 48(-2.87, 0.92) (-2.97, 0.69)p-value (one-sided non-inferiority test

A,B 0.0009 0.0011at a margin of 4 letters)

Arithmetic mean (SD), observed 6.6 (13.6) 6.6 (11.7) 7.8 (12.6)

LS mean (SE) A 6.37 (0.74) 6.31 (0.66) 7.23 (0.68)

Difference in LS means -0.86 -0.92

A,B 60(95% CI) (-2.57, 0.84) (-2.51, 0.66)p-value (one-sided non-inferiority test0.0002 <0.0001at a margin of 4 letters) A,B

Arithmetic mean (SD), observed 5.9 (14.2) 5.6 (13.7) 7.4 (13.8)

LS mean (SE) A 5.59 (0.77) 5.52 (0.75) 6.60 (0.73)

Difference in LS means -1.01 -1.08(95% CI) A,B (-2.82, 0.80) (-2.87, 0.71)

Patients with no IRF and no SRF in the central subfield D

Proportion (LOCF) 63.3% 51.6%

Adjusted difference in proportion

B,C 16 11.7% (5.3%, 18.2%)(95% CI)p-value (one-sided superiority test) B, C 0.0002

Proportion (LOCF) 71.1% 66.8% 59.4%

Adjusted difference in proportion 48 11.7% 7.5%(95% CI) B,C (4.5%, 18.9%) (0.1%, 14.8%)

Proportion (LOCF) 74.6% 72.2% 74.6%

Adjusted difference in proportion 60 0.0% -2.2%(95% CI) B,C (-6.6%, 6.7%) (-8.9%, pct. 4.4%)

Proportion (LOCF) 69.6% 63.6% 66.5%

Adjusted difference in proportion 96 3.0% -3.0%(95% CI) B,C (-4.1%, 10.1%) (-10.2%, 4.2%)

Eylea 8Q12 Eylea 8Q16 Eylea 2Q8

Efficacy outcomes Week(N = 335) (N = 338) (N = 336)

Patients achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) D

Proportion (LOCF) 56.9% 54.3% 57.9%

Adjusted difference in proportion 48 -0.2% -2.2%(95% CI) B,C (-6.6%, 6.2%) (-8.4%, 4.0%)

Proportion (LOCF) 56.3% 54.6% 58.2%

Adjusted difference in proportion 60 -1.1% -2.3%(95% CI) B,C (-7.5%, 5.3%) (-8.7%, 4.1%)

Proportion (LOCF) 53.3% 53.1% 56.7%

Adjusted difference in proportion 96 -2.7% -2.4%(95% CI) B,C (-9.4%, 4.0%) (-9.1%, 4.2%)

Patients who gained at least 15 letters in BCVA from baseline D

Proportion (LOCF) 20.7% 21.7% 22.1%

Adjusted difference in proportion 48 -1.7% -0.9%(95% CI) B,C (-7.8%, pct. 4.3%) (-7.0%, 5.1%)

Proportion (LOCF) 23.7% 23.1% 23.3%

Adjusted difference in proportion 60 0.1% -0.7%(95% CI) B,C (-6.2%, 6.3%) (-6.9%, 5.5%)

Proportion (LOCF) 22.2% 22.8% 24.2%

Adjusted difference in proportion 96 -2.4% -2.0%(95% CI) B,C (-8.4%, 3.6%) (-8.0%, 4.1%)

Last intended treatment intervals

Patients at ≥Q12 treatment interval E

Proportion (pooled 8Q12- and87.8% n/a8Q16-groups) 96

Proportion 86.6% 89.0% n/a

Patients at ≥Q16 treatment interval E

Proportion (pooled 8Q12- and71.0% n/a8Q16-groups) 96

Proportion 63.6% 78.4% n/a

Patients at ≥Q20 treatment interval E

Proportion (pooled 8Q12- and46.8% n/a8Q16-groups) 96

Proportion 40.5% 53.1% n/a

Patients at Q24 treatment interval E

Proportion (pooled 8Q12- and27.8% n/a8Q16-groups) 96

Proportion 24.7% 30.8% n/a

A LS mean, CI and p-value based on an MMRM with baseline best corrected visual acuity (BCVA)measurement as covariate, treatment group as factor, visit and stratification variables used forrandomisation (geographical region, categorical baseline BCVA) as fixed factors as well as terms for theinteraction between baseline BCVA and visit and for the interaction between treatment and visit.

B Absolute difference is Eylea 8Q12- or 8Q16-groups minus 2Q8-groups, respectively.

C Mantel-Haenszel weighted treatment difference with stratification variables used for randomization(geographical region, categorical baseline BCVA) and CI calculated using normal approximation.

D Full analysis set

E Safety analysis set; patients considered as completer for the respective timepoint

CI: Confidence interval

LOCF: Last observation carried forward

LS: Least square

SD: Standard deviation

SE: Standard error

Treatment intervals were analysed in a pre-specified exploratory manner.

Figure 3: LS mean change in BCVA as measured by ETDRS letter score from baseline throughweek 96 (full analysis set) in the PULSAR study+6.60+5.59+5.52weeks

Figure 4: Last intended treatment interval at week 96pooled 8Q12- and 8Q16-groups27.8% Q2446.8%≥Q2071.0%19.0% Q20 ≥Q1687.8%≥Q1224.2% Q1616.8% Q1212.2% Q8

Aflibercept at all doses (8Q12, 8Q16, 2Q8) demonstrated meaningful increase from baseline in thepre-specified secondary efficacy endpoint national eye institute visual function questionnaire (NEI

VFQ-25).

No clinically meaningful differences were found between the 8Q12-, 8Q16- and 2Q8-groups inchanges of NEI VFQ-25 total score at week 48 and week 96 from baseline.

Efficacy results in evaluable subgroups for age, gender, geographic region, ethnicity, race, baseline

BCVA, and lesion type were consistent with the results in the overall population.

Efficacy was generally maintained through week 96.

LS mean change visual acuity(letters)

Results - PULSAR extension phase

At the end of the main phase of the study at week 96, patients could enrol into the 60 week, open-labelextension phase. 417 patients originally assigned to 8Q12 and 8Q16 continued on Eylea 114.3 mg/mlwhile maintaining their latest intervals. 208 patients originally assigned to 2Q8 at the beginning of thestudy were switched to Eylea 114.3 mg/ml starting at 12-week intervals. Treatment intervals could befurther adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

In those patients originally assigned to 8Q12 and 8Q16, the treatment effect with Eylea 114.3 mg/mlwas generally maintained throughout 3 years (week 156). The LS mean change from baseline in thepooled 8Q12- and 8Q16-groups in BCVA was +3.41 letters and in CRT was -148.05 microns atweek 156.

In those patients originally assigned to 2Q8, the treatment effect with Eylea 114.3 mg/ml was similar.

The LS mean change from baseline in BCVA was +4.58 letters and in CRT was -145.21 microns atweek 156.

Patients in the 8Q12- and 8Q16-groups who completed week 156 received a median (mean) of 13.0(13.5) and 11.0 (12.2) injections, respectively.

Patients who switched to Eylea 114.3 mg/ml and completed week 156 received a total median (mean)of 18.0 (17.7) injections, of which 5.0 (4.9) injections were administered after the switch to

Eylea 114.3 mg/ml within the 60 weeks of the study extension phase.

The overall safety profile in the extension phase was similar to that observed in the main phase.

Table 5: Efficacy outcomes from the PULSAR extension phase at week 1568Q12 continued on 8Q16 continued on 2Q8 switched to

Efficacy outcomes Eylea 114.3 mg/ml Eylea 114.3 mg/ml Eylea 114.3 mg/ml(N = 185) (N = 190) (N = 208)

Change in BCVA from baseline (LS mean) +3.57 letters +3.23 letters +4.58 letters

Change in CRT from baseline (LS mean) -148.42 microns -147.54 microns -145.21 microns

Last intended treatment interval A≥12 weeks 76.2% 78.4% 78.5%≥16 weeks 53.5% 62.1% 42.5%≥20 weeks 37.8% 42.6% 16.1%24 weeks 23.8% 24.2% NA B

A based on patients completing week 156

B NA for patients originally randomised to 2Q8, due to study design/length of study

Study objectives

The safety and efficacy of Eylea 114.3 mg/ml were assessed in a randomised, multi-centre,double-masked, active-controlled study (PHOTON) in patients with DME.

The primary objective was to determine if treatment with Eylea 114.3 mg/ml at intervals of 12 (8Q12)or 16 weeks (8Q16) provides non-inferior BCVA change compared to Eylea 40 mg/ml every 8 weeks.

The secondary objectives were to determine the effect of Eylea 114.3 mg/ml versus Eylea 40 mg/mlon anatomic and other visual measures of response, and to evaluate the safety, immunogenicity, andpharmacokinetics of aflibercept.

The primary efficacy endpoint was the change from baseline in BCVA measured by the earlytreatment diabetic retinopathy study (ETDRS) letter score at week 48.

One key secondary endpoint was the change in BCVA from baseline at week 60.

Further secondary endpoints were the proportion of patients gaining at least 15 letters in BCVA frombaseline at week 48, the proportion of patients achieving an ETDRS letter score of at least 69(approximate 20/40 Snellen equivalent) at week 48, and the change from baseline in National Eye

Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) total score at week 48, among others.

In the PHOTON study a total of 658 patients were treated. The patients were assigned in a 2:1:1 ratioto 1 of 3 parallel treatment groups:

1. Eylea 114.3 mg/ml administered every 12 weeks (8Q12)2. Eylea 114.3 mg/ml administered every 16 weeks (8Q16)3. Eylea 40 mg/ml administered every 8 weeks (2Q8)

Patients who were switched from other anti-VEGF medicinal products to Eylea 114.3 mg/ml receivedthe last injection of the previous treatment at least 12 weeks prior to initiating the Eylea 114.3 mg/mltreatment.

All patients in the 8Q12- and 8Q16-groups received 3 initial injections and all patients in the2Q8-group received 5 initial injections at 4-week intervals.

Per study protocol the interval of the 8Q12- and 8Q16-groups was to be shortened if both of thefollowing criteria were met:

1. >10 letter loss in BCVA from week 12 in association with persistent or worsening DME, and2. >50 microns increase in CRT from week 12.

Regardless of whether patient intervals were maintained or shortened in year 1, per study protocol allpatients in the 8Q12- and 8Q16-groups were eligible for interval extension (by 4 weeks increments),beginning at week 52, if the following criteria were met:

1. <5 letter loss in BCVA from week 12, and2. CRT <300 microns on SD-OCT (or <320 microns if measured including RPE).

For patients who did not meet the criteria for shortening or extension of the interval, the dosinginterval was maintained. The minimum interval between injections was 8 weeks in all groups.

Patients with bilateral disease were eligible to receive Eylea 40 mg/ml treatment in their fellow eye.

Patient characteristics at baseline

Patient ages ranged from 24 to 90 years with a mean of 62.3 years.

Approximately 44% (143/328) and 44% (71/163) of the patients randomised to the 8Q12- and8Q16-groups, respectively, were 65 years of age or older and approximately 11% (36/328) and 14%(14/163) were 75 years of age or older.

The proportion of patients who were treated previously for DME was balanced between the treatmentgroups (43.6% in 8Q12-, 43.6% in 8Q16-, 44.3% in 2Q8-group).

Patients in the 8Q12-, 8Q16- and 2Q8-groups who completed week 48 received a median (mean) of6.0 (6.0), 5.0 (5.0) and 8.0 (7.9) injections, respectively.

At week 48, in the 8Q12-group, 91.0% of patients maintained Q12 intervals while in the 8Q16-group89.1% of patients maintained Q16 intervals.

Patients in the 8Q12-, 8Q16- and 2Q8-groups who completed week 60 received a median (mean) of7.0 (7.0), 6.0 (6.0) and 10.0 (9.8) injections, respectively. At week 60, 42.6% of patients in the8Q12-group were extended to a treatment interval of 16 weeks, and 34.2% of patients in the8Q16-group were extended to a treatment interval of 20 weeks.

Patients in the 8Q12-, 8Q16- and 2Q8-groups who completed week 96 received a median (mean) of9.0 (9.5), 8.0 (7.8) and 14.0 (13.8) injections, respectively.

At week 96, in the pooled 8Q12- and 8Q16-groups 72.4% of patients had attained treatment intervalsof ≥16 weeks, 44.3% of patients had attained treatment intervals of ≥20 weeks, and 26.8% of patientshad attained treatment intervals of 24 weeks, while maintaining visual and anatomic outcomes.

Treatment with Eylea (both 8Q12- and 8Q16-groups) was shown to be non-inferior and clinicallyequivalent to treatment with 2Q8 in terms of the primary efficacy endpoint ‘mean change in BCVA atweek 48’ and the key secondary efficacy endpoint ‘mean change in BCVA at week 60’. The treatmenteffect with Eylea 114.3 mg/ml in mean change in BCVA was maintained through week 96.

Table 6: Efficacy outcomes from the PHOTON study

Eylea 8Q12 Eylea 8Q16 Eylea 2Q8

Efficacy outcomes Week(N = 328) (N = 163) (N = 167)

Change in BCVA from baseline as measured by ETDRS letter score D

Arithmetic mean (SD), observed 8.77 (8.95) 7.86 (8.38) 9.21 (8.99)

LS mean (SE) A 8.10 (0.61) 7.23 (0.71) 8.67 (0.73)

Difference in LS means -0.57 -1.44(95% CI) A,B (-2.26, 1.13) (-3.27, 0.39)p-value (one-sided non-inferiority test<0.0001 0.0031at a margin of 4 letters) A,B

Arithmetic mean (SD), observed 9.05 (9.27) 7.96 (9.14) 9.62 (9.58)

LS mean (SE) A 8.52 (0.63) 7.64 (0.75) 9.40 (0.77)

Difference in LS means -0.88 -1.76(95% CI) A,B (-2.67, 0.91) (-3.71, 0.19)p-value (one-sided non-inferiority test0.0003 0.0122at a margin of 4 letters) A,B

Arithmetic mean (SD), observed 8.82 (9.93) 7.50 (9.86) 8.41 (11.10)

LS mean (SE) A 8.15 (0.63) 6.59 (0.77) 7.70 (0.89)

Difference in LS means 0.45 -1.11(95% CI) A,B(-1.55, 2.45) (-3.27, 1.05)

Patients achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) D

Proportion (LOCF) 65.3% 62.6% 63.0%

Adjusted difference in proportion 48 2.45% -0.67%(95% CI) B,C (-6.47%, 11.36%) (-11.16%, 9.82%)

Proportion (LOCF) 64.7% 62.0% 60.6%

Adjusted difference in proportion 60 4.34% 1.63%(95% CI) B,C (-4.72%, 13.40%) (-8.91%, 12.17%)

Proportion (LOCF) 66.9% 61.3% 63.0%

Adjusted difference in proportion 96 4.01% -1.51%(95% CI) B,C (-4.99%, 13.01%) (-11.91%, 8.89%)

Patients who gained at least 15 letters in BCVA from baseline D

Proportion (LOCF) 18.7% 16.6% 23.0%

Adjusted difference in proportion 48 -4.64% -7.14%(95% CI) B,C (-12.30%, 3.02%) (-15.45%, 1.17%)

Proportion (LOCF) 21.5% 16.0% 26.1%

Adjusted difference in proportion 60 -5.01% -10.78%(95% CI) B,C (-13.04%, 3.02%) (-19.27%, -2.29%)

Proportion (LOCF) 24.5% 19.6% 26.1%

Adjusted difference in proportion 96 -1.88% -7.07%(95% CI) B,C (-10.03%, 6.28%) (-15.94%, 1.80%)

Last intended treatment intervals

Patients at ≥Q12 treatment interval E

Proportion (pooled 8Q12- and92.9% n/a8Q16-groups) 96

Proportion 91.8% 95.0% n/a

Patients at ≥Q16 treatment interval E

Proportion (pooled 8Q12- and72.4% n/a8Q16-groups) 96

Proportion 64.1% 87.8% n/a

Patients at ≥Q20 treatment interval E

Proportion (pooled 8Q12- and44.3% n/a8Q16-groups) 96

Proportion 43.0% 46.8% n/a

Patients at Q24 treatment interval E

Proportion (pooled 8Q12- and26.8% n/a8Q16-groups) 96

Proportion 23.8% 32.4% n/a

A LS mean, CI and p-value based on an MMRM with baseline best corrected visual acuity (BCVA)measurement as covariate, treatment group as factor, visit and stratification variables used forrandomisation (geographical region, categorical baseline BCVA) as fixed factors as well as terms for theinteraction between baseline BCVA and visit and for the interaction between treatment and visit.

B Absolute difference is Eylea 8Q12- or 8Q16-groups minus 2Q8-groups, respectively.

C Mantel-Haenszel weighted treatment difference with stratification variables used for randomization(geographical region, categorical baseline BCVA) and CI calculated using normal approximation.

D Full analysis set

E Safety analysis set; patients considered as completer for the respective timepoint

CI: Confidence interval

LOCF: Last observation carried forward

LS: Least square

SD: Standard deviation

SE: Standard error

Treatment intervals were analysed in a pre-specified exploratory manner.

Figure 5: LS mean change in BCVA as measured by ETDRS letter score from baseline throughweek 96 (full analysis set) in the PHOTON study+8.15+7.70+6.59weeks

Figure 6: Last intended treatment interval at week 96pooled 8Q12- and 8Q16-groups26.8% Q2444.3%≥Q2072.4%17.5% Q20≥Q1692.9%≥Q1228.1% Q1620.5% Q127.1% Q8

LS mean change visual acuity(letters)

Eylea at all doses (8Q12, 8Q16, 2Q8) demonstrated meaningful increase from baseline in thepre-specified secondary efficacy endpoint national eye institute visual function questionnaire (NEI

VFQ-25).

No clinically meaningful differences were found between the 8Q12-, 8Q16- and 2Q8-groups inchanges of NEI VFQ-25 total score at week 48 and week 96 from baseline.

Efficacy results in evaluable subgroups for age, gender, geographic region, ethnicity, race, baseline

BCVA and baseline CRT and prior DME treatment were consistent with the results in the overallpopulation.

Efficacy was generally maintained through week 96.

Treatment effects in the sub-group of previously treated patients were similar to those seen in patientswho were treatment naïve.

Results - PHOTON extension phase

At the end of the main phase of the study at week 96, patients could enrol into the 60 week, open-labelextension phase. 195 patients originally assigned to 8Q12 and 8Q16 continued on Eylea 114.3 mg/mlwhile maintaining their latest intervals. 70 patients originally assigned to 2Q8 at the beginning of thestudy were switched to Eylea 114.3 mg/ml starting at 12-week intervals. Treatment intervals could befurther adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

In those patients originally assigned to 8Q12 and 8Q16, the treatment effect with Eylea 114.3 mg/mlwas generally maintained throughout 3 years (week 156). The LS mean change from baseline in thepooled 8Q12- and 8Q16-groups in BCVA was +7.2 letters and in CRT was -192.4 microns atweek 156.

In those patients originally assigned to 2Q8, the treatment effect with Eylea 114.3 mg/ml was similar.

The LS mean change from baseline in BCVA was +6.5 letters and in CRT was -197.4 microns atweek 156.

Patients in the 8Q12- and 8Q16-groups who completed week 156 received a median (mean) of 13.0(13.2) and 11.0 (11.4) injections, respectively.

Patients who switched to Eylea 114.3 mg/ml and completed week 156 received a total median (mean)of 19.0 (18.6) injections, of which 5.0 (4.8) injections were administered after the switch to

Eylea 114.3 mg/ml within the 60 weeks of the study extension phase.

The overall safety profile in the extension phase was similar to that observed in the main phase.

Table 7: Efficacy outcomes from the PHOTON extension phase at week 1568Q12 continued on 8Q16 continued on 2Q8 switched to

Efficacy outcomes Eylea 114.3 mg/ml Eylea 114.3 mg/ml Eylea 114.3 mg/ml(N = 103) (N = 49) (N = 70)

Change in BCVA from baseline (LS mean) +6.8 letters +8.1 letters +6.5 letters

Change in CRT from baseline (LS mean) -190.3 microns -198.1 microns -197.4 microns

Last intended treatment interval A≥12 weeks 85.4% 91.8% 82.8%≥16 weeks 62.1% 81.6% 50.0%≥20 weeks 40.8% 63.3% 19.0%24 weeks 20.4% 42.9% NA B

A based on patients completing week 156

B NA for patients originally randomised to 2Q8, due to study design/length of study

The European Medicines Agency has waived the obligation to submit the results of studies withaflibercept in all subsets of the paediatric population in nAMD and DME (see section 4.2 forinformation on paediatric use).

Absorption/Distribution

Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitrealadministration and is predominately observed in the systemic circulation as an inactive, stablecomplex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF.

Following unilateral intravitreal administration of 8 mg aflibercept, the mean (SD) Cmax of freeaflibercept in plasma was 0.25 (0.21) mg/l, and the median time to maximal concentration in plasmawas 1 day, in the nAMD and DME population combined. The accumulation of free aflibercept inplasma following 3 initial monthly doses was minimal. Subsequently, no further accumulation wasobserved. These data are also supported by population pharmacokinetic analyses.

Aflibercept is a protein-based therapeutic and no metabolism studies have been conducted.

Aflibercept is expected to undergo elimination through both target-mediated disposition via binding tofree endogenous VEGF and metabolism via proteolysis. The median time to reach the last quantifiableconcentration of free aflibercept in plasma for 8 mg administered intravitreally was 3 weeks.

No special studies in patients with renal or hepatic impairment have been conducted with

Eylea 114.3 mg/ml.

The systemic exposures to aflibercept in patients with mild to severe renal impairment were similar tothose with normal renal function. Limited available data in patients with mild hepatic impairment donot indicate an influence on systemic exposures to aflibercept compared to patients with normalhepatic function.

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated withaflibercept intravitreally were observed at systemic exposures in excess of the maximum humanexposure. The systemic exposure for free aflibercept was approximately 26- and 33-fold higher basedon Cmax and AUC when compared to corresponding values in adult patients after an intravitreal dose of8 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemicexposure was 3.2- and 3.8-fold higher based on Cmax and AUC when compared to correspondingvalues in adult patients.

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 studiesin 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. Adevelopmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposure for freeaflibercept was approximately 1.0- and 1.0-fold based on Cmax and cumulative AUC when comparedto corresponding values in adult patients after an intravitreal dose of 8 mg.

Effects on male and female fertility were assessed as part of a 6-month study in monkeys withintravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregularmenses associated with alterations in female reproductive hormone levels and changes in spermmorphology and motility were observed at all dose levels. Based on Cmax and AUC for free afliberceptobserved at the 3 mg/kg intravenous dose, the systemic exposures were approximately 377-fold and104-fold higher, respectively, than the exposure in humans after an intravitreal dose of 8 mg. Allchanges were reversible.

Sucrose

Arginine hydrochloride

Histidine hydrochloride monohydrate

Histidine

Polysorbate 20

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years

Eylea 114.3 mg/ml solution for injection

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Prior to usage, the unopened vial may be stored outside the refrigerator below 25 °C for up to24 hours.

Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

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 may be stored outside the refrigerator below 25 °C for up to24 hours.

Eylea 114.3 mg/ml solution for injection

Vial (type I glass) with a grey rubber stopper (chlorobutyl) sealed with an aluminium cap with whitelid, and a 18 G, 5-micron filter needle.

Each vial contains 0.263 ml solution.

Pack size of 1 vial and 1 filter needle.

Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Pre-filled syringe (type I glass) with a grey plunger stopper (elastomeric rubber), a white Luer-lockadaptor with a grey tip cap (elastomeric rubber) and a blue OcuClick dosing system (PC/ABS plastic).

Each pre-filled syringe contains 0.184 ml solution.

Pack size of 1 pre-filled syringe.

Eylea 114.3 mg/ml solution for injection

The vial is for single use in one eye only. Extraction of multiple doses from a single vial may increasethe risk of contamination and subsequent infection.

Do not use if the package or its components are expired, damaged, or have been tampered with.

Check the label on the vial to make sure you have the strength of Eylea that you intended to use. The8 mg dose requires use of the Eylea 114.3 mg/ml vial.

18 G, 5-micron filter needle:

- blunt filter (fill) needle, not for skin injection.

- Do not autoclave blunt filter (fill) needle.

- The filter needle is non-pyrogenic. Do not use it if individual packaging is damaged.

- Discard the used blunt filter (fill) needle in approved sharps collector.

- Caution: Re-use of the filter needle may lead to infection or other illness/injury.

The intravitreal injection should be performed with a 30 G × ½ inch injection needle (not included).

Use of a smaller size needle (higher gauge) than the recommended 30 G × ½ inch injection needlemay result in increased injection forces.

1. Prior to administration visually inspect the solution for injection.

Do not use the vial if particulates, cloudiness, or discolouration are visible.

2. Remove the plastic cap and disinfect theouter part of the rubber stopper of the vial.

3. Use aseptic technique to carry out steps 3-10.

Attach the filter needle supplied in the cartonto a 1-ml sterile, Luer-lock syringe.

4. Push the filter needle into the centre of the vial stopper until the needle is completely insertedinto the vial and the tip touches the bottom or bottom edge of the vial.

5. Withdraw all of the Eylea vial content into the syringe, keeping the vial in an upright position,slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure thebevel of the filter needle is submerged into the liquid. Continue to tilt the vial duringwithdrawal keeping the bevel of the filter needle submerged in the liquid.

needle bevelsolution pointing down6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial to completelyempty the filter needle. After injection any unused product must be discarded.

7. Remove the filter needle and properly dispose of it.

Note: The filter needle is not to be used for the intravitreal injection.

8. Firmly twist the 30 G × ½ inch injectionneedle onto the Luer-lock syringe tip.

9. Holding the syringe with the needle pointingup, check the syringe for bubbles. If there arebubbles, gently tap the syringe with yourfinger until the bubbles rise to the top.

10. To eliminate all bubbles and to expel excess medicinal product, slowly depress the plunger sothat the flat plunger edge aligns with the line that marks 0.07 ml on the syringe.

solution after expelling air bubblesand excess medicinal productdose line for0.07 mlflat plungeredge

Eylea 114.3 mg/ml solution for injection in pre-filled syringe

The pre-filled syringe with OcuClick dosing system is for single use in one eye only. Extraction ofmultiple doses from a single pre-filled syringe with OcuClick dosing system may increase the risk ofcontamination and subsequent infection.

Do not use if the package or its components are expired, damaged, or have been tampered with.

Check the label on the pre-filled syringe with OcuClick dosing system to make sure you have thestrength of Eylea that you intended to use. The 8 mg dose requires use of the Eylea 114.3 mg/mlpre-filled syringe.

The intravitreal injection should be performed with a 30 G × ½ inch injection needle (not included).

Use of a smaller size needle (higher gauge) than the recommended 30 G × ½ inch injection needlemay result in increased injection forces.

Pre-filled syringe with integrated OcuClick dosing system descriptionsyringe cap

Luer-lockplunger stopper90° viewfinger grip

OcuClickdosingsystemplunger rodguideslot1. Prepare

When ready to administer Eylea 114.3mg/ml, open the carton and remove the sterile blister.

Carefully peel open the blister ensuring the sterility of its contents.

Keep the syringe in the sterile tray until you are ready to attach the injection needle.

Use aseptic technique to carry out steps 2-9.

2. Remove syringe

Remove the syringe from the sterilised blister.

3. Inspect syringe and solution for injection

Do not use the pre-filled syringe if

- particulates, cloudiness, or discolouration are visible

- any part of the pre-filled syringe with OcuClick dosing system is damaged or loose

- the syringe cap is detached from the Luer-lock.

4. Snap off syringe cap

To snap off (do not twist off) the syringe cap,hold the syringe in one hand and the syringe cap

SNAP!with the thumb and forefinger of the other hand.

Note: Do not pull back on the plunger rod.

5. Attach needle

Firmly twist the 30 G × ½ inch injection needleonto the Luer-lock syringe tip.

Luer-lock6. Dislodge air bubbles

Holding the syringe with the needle pointing up,check the syringe for bubbles. If there arebubbles, gently tap the syringe with your fingeruntil the bubbles rise to the top.

TAP!7. Expel air and excess volume to prime

The syringe does not have a dose line because it is designed to set the dose mechanically asexplained in the steps below.

Priming and setting the dose must be done using the following steps.

To eliminate all bubbles and to expel excess medicinal product, slowly depress the plunger rod(left picture below) until it stops, i.e. when the guide on the plunger rod reaches the finger grip(right picture below).

Ensure bubbles airare at the top bubbleso they can beexpelled.plunger rodsolutionfinger gripfinger grip fullydepressedplunger rod plungerguide guide8. Set the dose

Turn the end of the plunger rod 90 degreesclockwise or counter clockwise until the guide CLICK!of the plunger rod aligns with the slot. You mayhear a ‘click’.

Note: Now the device is ready to dose. Do notpush the plunger rod before insertion into theeye. slotguideplungerrod9. Administer the injection

Insert the needle into the ocular injection site.

Inject the solution by pushing in the plunger roduntil it stops, i.e. until the guide is completelywithin the slot. guideslot

Do not apply additional pressure once the guideis within the slot. It is normal to see a smallamount of residual solution left in the syringe.

plungerrod10. The pre-filled syringe is for single dose administration and single use only.

After injection discard the used syringe into a sharps container.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bayer AG51368 Leverkusen

Germany

EU/1/12/797/003 - Eylea 114.3 mg/ml solution for injection

EU/1/12/797/004 - Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Date of first authorisation: 22 November 2012

Date of latest renewal: 13 July 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.