4.1. Therapeutic indications

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 (DMO) (see section 5.1)

- visual impairment due to macular oedema secondary to retinal vein occlusion (branch, central and hemiretinal RVO) (see section 5.1).

4.2. Posology and method of administration

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

Posology

nAMD and DMO

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

For patients who are initiating treatment, Eylea is administered with 1 injection per month for 3 consecutive doses. Injection intervals may then be extended up to every 4 months based on the physician's judgement of visual and/or anatomic outcomes. Subsequently, the treatment intervals may be further extended up to 6 months, such as with a treat‑and‑extend dosing regimen, while maintaining stable 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 medicinal products and are switching to Eylea 114.3 mg/ml, the treatment regimen can differ from that used for treatment-naïve patients. Treatment intervals should be determined based on visual and/or anatomic outcomes (see section 5.1).

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

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

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly based on the physician's discretion. The interval between 2 injections should not be shorter than 1 month.

If visual and/or anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea 114.3 mg/ml should be discontinued.

Eylea at monthly doses of 8 mg has not been studied for more than 3 consecutive doses in the PULSAR (nAMD) and PHOTON (DMO) studies. Available data support the administration of more than 3 consecutive monthly doses for certain patients, however the data are currently limited.

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

RVO

The recommended dose is 8 mg aflibercept, equivalent to 0.07 ml solution. 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 for 3 consecutive doses. Injection intervals may then be extended based on the physician's judgement of 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 medicinal products and are switching to Eylea 114.3 mg/ml, the treatment regimen can differ from that used for treatment-naïve patients. Treatment intervals should be determined based on visual and/or anatomic outcomes (see section 5.1).

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

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

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly based on the physician's discretion (see section 5.1). The interval between 2 injections should not be shorter than 1 month.

If visual and/or anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea 114.3 mg/ml should be discontinued.

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

Special populations

Renal or hepatic impairment

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 (see section 5.2).

Elderly

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

Paediatric population

The safety and efficacy of Eylea 114.3 mg/ml in children and adolescents below 18 years have not been established. There is no relevant use of Eylea 114.3 mg/ml in the paediatric population in the nAMD, DMO and RVO indications.

Method of administration

Eylea is for intravitreal injection only.

Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualified healthcare professional 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 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 of 0.07 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 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.

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.

4.3. Contraindications

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

- Ocular or periocular infection.

- Active severe intraocular inflammation.

4.4. Special warnings and precautions for use

Traceability

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

Intravitreal injection‑related reactions

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 be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay and should be managed appropriately.

Intraocular pressure increased

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

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with aflibercept (see section 5.1). 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 (see section 4.8).

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

Bilateral treatment

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 increased systemic exposure, which could increase the risk of systemic adverse events.

Concomitant use of other anti-VEGF

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

Withholding treatment

Treatment should be withheld in the event of:

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

Retinal pigment epithelial tear

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

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and for at least 4 months after the last intravitreal injection with Eylea 114.3 mg/ml (see section 4.6).

Populations with limited data

There is only limited experience with Eylea treatment 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.

Information about excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

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 4 months after the last intravitreal injection with Eylea 114.3 mg/ml.

Pregnancy

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 the potential risk to the foetus.

Breast-feeding

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 is expected 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.

Fertility

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

4.7. Effects on ability to drive and use machines

Injection with Eylea has minor influence on the ability to drive and use machines due to possible temporary visual disturbance associated either with the injection or 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

Serious adverse reactions were cataract (7.1%), intraocular pressure increased (3.8%), retinal haemorrhage (2.8%), vitreous haemorrhage (1.1%), cataract subcapsular (0.6%), retinal tear (0.5%), cataract nuclear (0.4%) and retinal detachment (0.4%).

The most frequently observed adverse reactions in patients treated with Eylea 114.3 mg/ml were cataract (7.1%), visual acuity reduced (4.3%), conjunctival haemorrhage (4.0%), intraocular pressure increased (3.8%), vitreous detachment (3.5%), vitreous floaters (3.2%) and retinal haemorrhage (2.8%).

The safety profile observed in the 4 clinical studies was similar in patients treated with Eylea 114.3 mg/ml (N=1 808) and Eylea 40 mg/ml (N=857), and in patients with nAMD, DMO and RVO.

Tabulated list of adverse reactions

A total of 1 808 patients treated with Eylea 114.3 mg/ml up to 96 weeks constituted the safety population in 4 clinical phase II/III studies (CANDELA, PULSAR, PHOTON, QUASAR).

The safety data described below include all adverse reactions with a reasonable possibility of causality to 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, DMO or RVO treated with Eylea 114.3 mg/ml in phase II/III studies or during post‑marketing surveillance

System organ class

Frequency

Adverse reaction

Immune system disorders

Common

Hypersensitivity*

Eye disorders

Common

Cataract, Intraocular pressure increased, Vitreous floaters, Vitreous detachment, Vitreous haemorrhage, Retinal haemorrhage, Visual acuity reduced, Eye pain, Conjunctival haemorrhage, Punctate keratitis, Corneal abrasion

Uncommon

Retinal detachment, Retinal tear, Retinal pigment epithelial tear, Detachment of the retinal pigment epithelium, Uveitis, Iritis, Iridocyclitis, Vitritis, Cataract cortical, Cataract nuclear, Cataract subcapsular, Corneal erosion, Vision blurred, Injection site pain, Foreign body sensation in eyes, Lacrimation increased, Injection site haemorrhage, Conjunctival hyperaemia, Lenticular opacities, Eyelid oedema, Ocular hyperaemia, Injection site irritation, Retinal degeneration, Corneal oedema

Rare

Blindness, Endophthalmitis, 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, traumatic cataract, hypopyon, severe anaphylactic/anaphylactoid reactions.

Description of selected adverse reactions

Product‑class‑related adverse reactions

Arterial thromboembolic events (ATEs) are adverse reactions potentially related to systemic VEGF inhibition. There is a theoretical risk of ATEs, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of ATEs was observed in the aflibercept clinical studies in patients with nAMD, DMO and RVO. Across indications, no notable difference between the groups treated with Eylea 114.3 mg/ml and the comparator groups treated with Eylea 40 mg/ml were observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 (see sections 4.4 and 6.6).