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

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.

Solution for injection (injection)

The solution is a clear, colourless to pale yellow and iso-osmotic solution.

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).

Eylea is for intravitreal injection only.

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

Posology

wet AMD

The recommended dose for Eylea is 2 mg aflibercept, equivalent to 50 microlitres.

Eylea treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections.

After the first 12 months of treatment with Eylea, the treatment interval may be extended based on visual and/or anatomic outcomes. In this case the schedule for monitoring should be determined by the treating physician and may be more frequent than the schedule of injections.

Macular oedema secondary to RVO (branch RVO or central RVO)

The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres.

After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month.

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

Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed.

Treatment may then be continued with a treat and extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

The monitoring and treatment schedule should be determined by the treating physician based on the individual patient's response.

Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).

Diabetic macular oedema

The recommended dose for Eylea is 2 mg aflibercept equivalent to 50 microlitres.

Eylea treatment is initiated with one injection per month for five consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections.

After the first 12 months of treatment with Eylea, the treatment interval may be extended based on visual and/or anatomic outcomes. The schedule for monitoring should be determined by the treating physician.

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

Myopic choroidal neovascularisation

The recommended dose for Eylea is a single intravitreal injection of 2 mg aflibercept equivalent to 50 microlitres.

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

Safety and efficacy have not been established in children and adolescents. There is no relevant use of Eylea in the paediatric population in the indications wet AMD, CRVO, BRVO, 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.

The vial contains more than the recommended dose of 2 mg aflibercept. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting.

Injecting the entire volume of the vial could result in overdose. To expel the air bubble along with excess medicinal product, slowly depress the plunger to align the cylindrical base of the dome plunger with the black dosing line on the syringe (equivalent to 50 microlitres i.e. 2 mg aflibercept).

After injection any unused product must be discarded.

For handling of the medicinal product, see section 6.6.

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.

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.

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

 • a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity;
• a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area

• The dose should be withheld within the previous or next 28 days in the event of a performed or planned intraocular surgery.

• Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus (see section 4.6).

• Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept (see section 4.6).

• There is limited experience with treatment of patients with ischaemic CRVO and BRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended.

Populations with limited data

There is only limited experience in the treatment of subjects with DME due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy.

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

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.

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.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept (see section 4.4).

Pregnancy

There are no data on the use of aflibercept in pregnant women.

Studies in animals have shown embryo-foetal toxicity (see section 5.3).

Although the systemic exposure after ocular administration is very low, Eylea should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breastfeeding

It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed child cannot be excluded.

Eylea is not recommended during breastfeeding. A decision must be made whether to discontinue breastfeeding or to abstain from Eylea therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility (see section 5.3). Such effects are not expected after ocular administration with very low systemic exposure.

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.