Consumer medicine information

Eylea

Aflibercept

BRAND INFORMATION

Brand name

Eylea

Active ingredient

Aflibercept

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Eylea.

SUMMARY CMI

EYLEA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using EYLEA®?

EYLEA contains the active ingredient aflibercept (rch).

EYLEA® 2 mg is used to treat adults in:1) neovascular (wet) age-related macular degeneration (wet AMD), 2) diabetic macular oedema (DME), 3) visual impairment due to macular oedema after central retinal vein occlusion (also known as CRVO), 4) visual impairment due to macular oedema after branch retinal vein occlusion (also known as BRVO), and 5) visual impairment due to myopic choroidal neovascularisation (myopic CNV).
EYLEA® 8 mg is used to treat adults in:1) neovascular (wet) age-related macular degeneration (wet AMD) and, 2) diabetic macular oedema (DME).

For more information, see Section 1. Why am I using EYLEA®? in the full CMI.

2. What should I know before I use EYLEA®?

Do not use if you have ever had an allergic reaction to aflibercept or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use EYLEA®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with EYLEA® and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given EYLEA®?

EYLEA® is given by an ophthalmologist (eye doctor) as an injection into your eye usually under a local anaesthetic. In adult patients, the usual dose of EYLEA® 2 mg is 0.05 mL or 50 microlitres; and for EYLEA® 8 mg is 0.07 mL or 70 microlitres. More instructions can be found in Section 4. How will I be given EYLEA®? in the full CMI.

5. What should I know while using EYLEA®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using EYLEA®.
  • Tell your doctor if you experience signs of infection, inflammation or you become pregnant.
Driving or using machines
  • Patients may experience temporary visual disturbances after an intravitreal injection with Eylea®. Do not drive or use machinery after your injection as you may experience some temporary problems with vision.
Drinking alcohol
  • There are no known interactions between EYLEA® and alcohol.
Looking after your medicine
  • Your ophthalmologist (eye doctor) will treat you with EYLEA®. There is no need to store this medicine at home.

For more information, see Section 5. What should I know while using EYLEA®? in the full CMI.

6. Are there any side effects?

Common side effects: bloodshot eye (conjunctival haemorrhage), eye pain, clouding of the lens (cataract), intraocular pressure, vitreous detachment, moving spots in vision. Serious side effects: Bleeding in the eye, pus in the eye, inflammation in the eye, damage to the front layer of the eyeball, clouding of the lens, decreased sharpness of vision. For the full list of side effects and for more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

EYLEA® (eye•leah)

Active ingredient(s): Aflibercept (rch)

Consumer Medicine Information (CMI)

This leaflet provides important information about using EYLEA®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using EYLEA®.

Where to find information in this leaflet:

1. Why am I using EYLEA®?
2. What should I know before I use EYLEA®?
3. What if I am taking other medicines?
4. How will I be given EYLEA®?
5. What should I know while using EYLEA®?
6. Are there any side effects?
7. Product details

1. Why am I using EYLEA®?

EYLEA® 2 mg is used to treat adults for the following eye conditions:

  • neovascular (wet) age-related macular degeneration (wet AMD)
  • diabetic macular oedema (DME)
  • visual impairment due to macular oedema after central retinal vein occlusion (CRVO)
  • visual impairment due to macular oedema after branch retinal vein occlusion (BRVO)
  • visual impairment due to myopic choroidal neovascularisation (myopic CNV).

EYLEA® 8 mg is used to treat adults for the following eye conditions:

  • neovascular (wet) age-related macular degeneration (wet AMD)
  • diabetic macular oedema (DME)

EYLEA® contains the active ingredient Aflibercept. Aflibercept, the active substance in EYLEA®, specifically binds to Vascular Endothelial Growth Factor A (VEGF-A) and Placental Growth Factor (PlGF) and blocks the activity of these group of factors, present in the eye which contributes to the progression of wet AMD or myopic CNV and the development of swelling (macular oedema) due to either CRVO, BRVO or DME. By blocking these proteins, EYLEA® can stop the growth and leakage of abnormal blood vessels and swelling of the retina in the eye, which in turn can help improve your eyesight or stop if from getting worse. EYLEA® can help to stabilise, and in many cases, improve the vision loss related to wet AMD, DME, CRVO, BRVO and mCNV.

EYLEA® 2 mg and EYLEA® 8 mg are used in patients with neovascular (wet) age-related macular degeneration (wet AMD), which is a condition in which abnormal blood vessels grow in the back of the eye (retina). These blood vessels can leak blood and fluid into the retina and damage it leading to vision loss.

EYLEA® 2 mg and EYLEA® 8 mg are used to treat diabetic macular oedema (DME) which is a swelling of the retina occurring in patients with diabetes due to leaking of fluid from blood vessels within the macula.

EYLEA® 2 mg is used to treat CRVO which is caused by a blockage in the main blood vessel that transports blood away from the retina, in the back of your eye. The blockage stops blood from flowing in and out of the retina which causes swelling (macular oedema) and can damage your eyesight.

EYLEA® 2 mg is used to treat BRVO which is caused by a blockage in one or more branches of the main blood vessel that transports blood away from the retina, in the back of your eye. The blockage stops blood from flowing in and out of the retina which causes swelling (macular oedema) and can damage your eyesight.

EYLEA® 2 mg is used to treat Myopic CNV which is a severe form of myopia (short sightedness) which leads to extremely elongated eyes with additional defects in some layers in the back of the eye. This triggers the abnormal formation of new blood vessels which can cause bleeding and eventually may lead to loss of vision.

2. What should I know before I use EYLEA®?

Warnings

Do not use EYLEA® if:

  • you are allergic to aflibercept, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

You must not be given this medicine if you have or suspect:

  • an infection in or around the eye
  • severe inflammation of the eye (pain or redness)

If you are not sure whether you should be given this medicine, talk to your doctor.

Do not give this medicine to children under the age of 18 years. There is not enough information to recommend the use of EYLEA for children or adolescents.

Check with your doctor if you:

  • Had any prior issues or problems with injections into your eyes.
  • Have glaucoma (injection with EYLEA® may trigger an increase in eye pressure in some patients within 60 minutes of the injection and your doctor may monitor this after each injection).
  • Have ever had a stroke or experienced transient signs of a stroke (known as a “TIA” or “mini-stroke”).
  • Have previously had or are planning to have an eye surgery within the past or next four weeks.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Eylea 2 mg: It is recommended that you use effective contraception during treatment and for at least 3 months after the last injection of EYLEA®.

Eylea 8 mg: It is recommended that you use effective contraception during treatment and for at least 4 months after the last injection of EYLEA®.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

EYLEA® is not recommended during breastfeeding as it is not known whether it passes into breast milk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect EYLEA®.

4. How will I be given EYLEA®?

How much to use

EYLEA® is given by your ophthalmologist (eye doctor) as an injection into your eye under a local anaesthetic.

How EYLEA® is given

EYLEA® is given as a single injection into your eye.

How much EYLEA® is given

EYLEA® 2 mg:

The recommended dose of EYLEA® 2 mg is 50 microlitres (equivalent to 2 mg aflibercept).

The time between two doses injected into the same eye should not be shorter than one month.

If you are being treated for wet AMD with EYLEA® 2 mg:The injection is given once a month for the first 3 months followed by one injection every 2 months. Your doctor will check the condition of your eye. Depending on how you respond to the treatment, your doctor may decide to gradually increase or adjust the treatment interval for your next injection.

If you are being treated for DME with EYLEA® 2 mg: The injection is given once a month for the first 5 months followed by one injection every 2 months. Treatment interval may be kept at every 2 months or adjusted to your condition, based on your doctor's examination. Your doctor will decide on the schedule for follow up examinations.

If you are being treated for impaired vision due to macular oedema caused by CRVO or BRVO with EYLEA® 2 mg: You will start your treatment with monthly injections. After the first 3 injections, your doctor will determine the most appropriate treatment schedule for you based on your vision and test results at each visit. If considered appropriate, your doctor may decide to gradually increase or adjust the treatment interval for your next injection.

If you are being treated for myopic CNV with EYLEA® 2 mg: You will start your treatment with one injection and you will receive additional injections only if, during subsequent examinations, your doctor finds that your disease persists.

EYLEA® 8 mg:
The recommended dose of EYLEA® 8 mg is 70 microlitres (equivalent to 8 mg aflibercept).

The time between 2 doses injected into the same eye should not be shorter than one month.

If you are being treated for wet AMD or for DME with EYLEA® 8 mg: The treatment is started with one injection of EYLEA® 8 mg per month for the first 3 months. Your doctor will check the condition of your eye. Depending on how you respond to the treatment, your doctor will decide whether and when you need to receive the next injections of EYLEA® 8 mg.

If you forget to use EYLEA®

Your doctor will give you EYLEA® so it is unlikely that you will forget to use this medicine.

If you miss a EYLEA® treatment, you need to contact your doctor to arrange another appointment as soon as possible.

If you stop EYLEA® treatment, your disease may get worse.

If you use too much EYLEA®

If you are given more EYLEA® than you need, your doctor will check the pressure in your eye and treat it if is increased. This is unlikely as your doctor will only give you the recommended dose, they will not give you too much EYLEA®. If you feel unwell after receiving EYLEA® contact your doctor.

5. What should I know while using EYLEA®?

Things you should do

If you experience any problems during the treatment, tell your doctor.

Call your doctor straight away if you:

Tell your doctor immediately if you develop signs of inflammation and/or infection of the eye such as redness of the eye, eye pain, light sensitivity and/or vision changes, seeing flashes of light with moving spots or floaters, progressing to a loss of sight or blurred vision.

A serious eye infection or eye disorder can sometimes develop after an injection into the eye.

If you are treated for visual impairment due to macular oedema in diabetes tell your doctor if you think that the effect of the treatment is being lost.

If you become pregnant while being treated with this medicine, tell your doctor immediately.

Remind any doctor, dentist or pharmacist you visit that you are using EYLEA®.

Things you should not do

Driving or using machines

Patients may experience temporary visual disturbances after an intravitreal injection and the associated eye examinations. Patients should not drive or use machinery until visual function has recovered sufficiently. Be careful before you drive or use any machines or tools until you know how EYLEA® affects you.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Eye disorders:
  • Bloodshot eye (conjunctival haemorrhage)
  • Moving spots in vision (vitreous floaters)
  • Eye irritation or discomfort
  • Sensation of having something in the eye
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Eye disorders
  • Bleeding in the eye
  • Pain at the injection site
  • Swelling or irritated eyelid
  • Redness of the eye
  • Detachment of the gel-like substance inside the eye from the retina (vitreous detachment)
  • Pus in the eye
  • Inflammation in the eye
  • Eye pain
  • Increase in eye pressure (intraocular pressure)
  • Decreased sharpness of vision
  • Damage to the front layer of the eyeball (corneal abrasion, corneal erosion)
  • Blurred vision
  • Certain forms of clouding of the lens (cataract)
  • Flashes of light and floaters (retinal detachment)
Immune system disorders:
  • Hypersensitivity (rash, itching or hives caused by an allergic reaction)
Blood clot related disorders:
  • signs of a stroke, such as weakness or numbness of limbs or face, difficulty speaking or swallowing.
  • signs of heart attack, such as chest pain which may spread to the neck and shoulders
Go straight to the Emergency department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Some side effects (e.g. an increased intraocular pressure in the eye) can only be found when your doctor does tests to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems for Australia or to the Centre for Adverse Reactions Monitoring at pophealth.my.site.com/carmreportnz/s/ for New Zealand. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

This medicine is only available with a doctor's prescription.

What EYLEA® 2 mg contains

Active ingredient
(main ingredient)		Aflibercept (rch)
Other ingredients
(inactive ingredients)		Polysorbate 20
Monobasic sodium phosphate monohydrate
Dibasic sodium phosphate heptahydrate
Sodium chloride
Sucrose
Water for injections

What EYLEA® 8 mg contains

Active ingredient
(main ingredient)		Aflibercept (rch)
Other ingredients
(inactive ingredients)		Polysorbate 20
Arginine hydrochloride
Histidine
Histidine hydrochloride monohydrate
Sucrose
Water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What EYLEA® 2 mg looks like

EYLEA® 2 mg is supplied in a clear, colourless, single-use glass vial. The vial contains approximately 100 µL of extractable volume of a sterile, clear, colourless to pale yellow solution.

Vial: Aust R 180859 (concentration 40 mg/mL).

EYLEA® 2 mg is supplied in a sterile sealed blister pack with a pre-filled syringe. The pre-filled syringe contains approximately 90 µL of extractable volume of a sterile, clear, colourless to pale yellow solution.

Pre-filled syringe: Aust R 180860 (concentration 40 mg/mL).

What EYLEA® 8 mg looks like

EYLEA® 8 mg is supplied in a clear, colourless, single-use glass vial. The vial contains approximately 100 µL of extractable volume of a sterile, clear to slightly opalescent, colourless to pale yellow solution.

Vial: Aust R 405862 (concentration 114.3 mg/mL).

EYLEA® 8 mg is supplied in a sterile sealed blister pack with a pre-filled syringe. The pre-filled syringe contains approximately 100 µL of extractable volume of a sterile, clear to slightly opalescent, colourless to pale yellow solution.

Pre-filled syringe: Aust R 454465 (concentration 114.3 mg/mL).

Not all presentations or strengths may be marketed in Australia and New Zealand.

Who distributes EYLEA®

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073
Website: www.bayer.com.au

Bayer New Zealand Ltd
PO Box 2825
Shortland Street
Auckland 1140
New Zealand
Website: www.bayer.co.nz

This leaflet was prepared in October 2024.

See TGA website (www.ebs.tga.gov.au) in Australia or Medsafe website (www.medsafe.govt.nz) in New Zealand for latest Consumer Medicine Information.

® Registered trademark.

Note: Eylea 40 mg/mL is also referred to as Eylea 2 mg
Eylea 114.3 mg/mL is also referred to as Eylea 8 mg

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Eylea

Active ingredient

Aflibercept

Schedule

S4

 

1 Name of Medicine

Aflibercept (rch).

2 Qualitative and Quantitative Composition

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.
For the full list of excipients, see Section 6.1 List of Excipients.

Eylea 40 mg/mL (vial for 2 mg dosing).

Each 1 mL of Eylea solution contains 40 mg aflibercept. Each vial has a volume of 100 microL solution containing 4 mg aflibercept. This amount is sufficient to deliver a single dose of 50 microL solution for intravitreal injection containing 2 mg aflibercept.

Eylea 40 mg/mL (pre-filled syringe for 2 mg dosing).

Each 1 mL of Eylea solution contains 40 mg aflibercept. Each pre-filled syringe has a volume of 90 microL solution containing 3.6 mg aflibercept. This amount is sufficient to deliver a single dose of 50 microL solution for intravitreal injection containing 2 mg aflibercept.

Eylea 114.3 mg/mL (vial for 8 mg dosing).

Each 1 mL of Eylea solution contains 114.3 mg aflibercept. Each vial has a volume of 0.263 mL (263 microL) solution containing 30.1 mg aflibercept. This amount is sufficient to deliver a single dose of 70 microL solution for intravitreal injection containing 8 mg aflibercept.

Eylea 114.3 mg/mL (pre-filled syringe with OcuClick dosing system for 8 mg dosing).

Each 1 mL of Eylea solution contains 114.3 mg/mL aflibercept. Each pre-filled syringe has a volume of 0.184 mL (184 microL) solution containing 21 mg aflibercept. This amount is sufficient to deliver a single dose of 70 microL solution for intravitreal injection containing 8 mg aflibercept.

3 Pharmaceutical Form

Solution for intravitreal injection.
Eylea 40 mg/mL (for 2 mg dosing) is a sterile, clear, colourless to pale yellow, preservative-free, iso-osmotic aqueous solution.
Eylea 114.3 mg/mL (for 8 mg dosing) is a sterile, clear to slightly opalescent, colourless to pale yellow, preservative-free, iso-osmotic aqueous solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Eylea 2 mg (aflibercept) is indicated in adults for the treatment of:
neovascular (wet) age related macular degeneration (wet AMD);
visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO);
visual impairment due to macular oedema secondary to branch retinal vein occlusion (BRVO);
diabetic macular oedema (DME);
visual impairment due to myopic choroidal neovascularisation (myopic CNV).
Eylea 8 mg (aflibercept) is indicated in adults for the treatment of:
neovascular (wet) age-related macular degeneration (wet AMD);
diabetic macular oedema (DME).

4.2 Dose and Method of Administration

Eylea is for intravitreal injection only.
It must only be administered by a qualified ophthalmologist experienced in administering intravitreal injections.

Dosage for Eylea 2 mg (for all approved indications).

The recommended dose for Eylea 40 mg/mL is 2 mg aflibercept, equivalent to an injection volume of 50 microL. The interval between doses injected into the same eye should not be shorter than one month.
Advice on treatment initiation and maintenance of therapy specific to each patient population is described in the section below. Once optimal visual acuity is achieved and/or there are no signs of disease activity, treatment may then be continued with a treat and extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes. If disease activity persists or recurs, the treatment interval may be shortened accordingly. Monitoring should be done at injection visits. The monitoring and treatment schedule should be determined by the treating ophthalmologist based on the individual patient's response. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea 2 mg should be discontinued.

Treatment of neovascular (wet) age related macular degeneration (wet AMD).

Eylea 2 mg treatment is initiated with one Eylea 2 mg injection per month for three consecutive months, followed by one injection every two months.
Based on the ophthalmologist'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, by increasing injection intervals in 2- or 4-weekly increments while maintaining stable visual and/or anatomic outcomes. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened to a minimum of four weeks based on anatomical and/or visual outcomes.
Generally, once optimal visual acuity is achieved and/or there are no signs of disease activity, the treatment interval may be adjusted based on visual and/or anatomic outcomes.
Treatment intervals greater than four months (16 weeks) between injections have not been studied (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Treatment of visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO).

Eylea 2 mg treatment is initiated with one Eylea 2 mg injection per month for three consecutive months. After the first three monthly injections, the treatment interval may be adjusted based on visual and/or anatomic outcomes.

Treatment of visual impairment due to macular oedema secondary to branch retinal vein occlusion (BRVO).

Eylea 2 mg treatment is initiated with one Eylea 2 mg injection per month for three consecutive months. After the first three monthly injections, the treatment interval may be adjusted based on visual and/or anatomic outcomes.

Treatment of diabetic macular oedema (DME).

Eylea 2 mg treatment is initiated with one Eylea 2 mg injection per month for five consecutive months.
Following the initiation period and based on the ophthalmologist's judgement of visual and/or anatomic outcomes, the treatment interval may then be maintained at an injection every two months or further individualised, such as with a treat-and-extend dosing regimen, by increasing injection intervals in 2- or 4-weekly increments while maintaining stable visual and/or anatomic outcomes. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. Treatment intervals shorter than 4 weeks or longer than 4 months have not been studied (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Treatment of visual impairment due to myopic choroidal neovascularisation (myopic CNV).

Eylea 2 mg treatment is initiated with one Eylea 2 mg injection (equivalent to 50 microL).
Additional doses should be administered only if visual and/or anatomic outcomes indicate that the disease persists. Recurrences are treated like a new manifestation of the disease.

Dosage for Eylea 8 mg (for wet AMD and DME indications only).

The recommended dose for Eylea 114.3 mg/mL is 8 mg aflibercept, equivalent to an injection volume of 70 microL. The interval between doses injected into the same eye should not be shorter than one month.
Advice on treatment initiation and maintenance of therapy specific to each patient population is described in the section below. Monitoring should be done at injection visits. The monitoring and treatment schedule should be determined by the treating ophthalmologist based on the individual patient's response. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea 8 mg should be discontinued.

Treatment of neovascular (wet) age-related macular degeneration (wet AMD).

Eylea 8 mg treatment is initiated with one Eylea 8 mg injection per month for three consecutive months, followed by one injection of Eylea 8 mg every 8 to 16 weeks based on the ophthalmologist's judgment of visual and/or anatomic outcomes. Treatment with intervals of one month for more than three consecutive months has not been studied (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Treatment of diabetic macular oedema (DME).

Eylea 8 mg treatment is initiated with one Eylea 8 mg injection per month for three consecutive months, followed by one injection of Eylea 8 mg every 8 to 16 weeks based on the ophthalmologist's judgment of visual and/or anatomic outcomes. Treatment with intervals of one month for more than three consecutive months has not been studied (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Method of administration.

Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualified ophthalmologist experienced in administering intravitreal injections. In general, adequate anaesthesia and asepsis, including topical broad spectrum microbicide, have to be ensured. Surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended.
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, prefilled syringe or pre-filled syringe with OcuClick dosing system should only be used for the treatment of a single eye. The pre-filled syringe or the glass vial contains more than the recommended dose. Therefore, the excess volume must be expelled before injecting (see Instructions for use/ handling). Injecting the entire volume of the glass vial or the pre-filled syringe could result in overdose (see Section 4.9 Overdose).

Eylea 40 mg/mL (vial for 2 mg dosing).

To administer 2 mg aflibercept (equivalent to 50 microL solution for injection), eliminate all bubbles and expel excess drug by slowly depressing the plunger so that the flat plunger edge aligns with the line that marks 0.05 mL (equivalent to 50 microL) on the syringe before injecting.

Eylea 40 mg/mL (pre-filled syringe for 2 mg dosing).

To administer 2 mg aflibercept (equivalent to 50 microL solution for injection), eliminate all bubbles and expel excess drug in the pre-filled syringe by slowly depressing the plunger to align the base of the plunger dome (not the tip of the dome) with the black dosing line on the syringe. This will ensure a delivery equivalent to 50 microL i.e. 2 mg aflibercept.

Eylea 114.3 mg/mL (vial for 8 mg dosing).

To administer 8 mg aflibercept (equivalent to 70 microL solution for injection), eliminate all bubbles and expel excess drug by slowly depressing the plunger so that the flat plunger edge aligns with the line that marks 0.07 mL (equivalent to 70 microL) on the syringe before injecting.

Eylea 114.3 mg/mL (pre-filled syringe with OcuClick dosing system for 8 mg dosing).

To administer 8 mg aflibercept (equivalent to 70 microL solution for injection), eliminate all bubbles and expel excess drug by slowly depressing the plunger rod until it stops. i.e. when the guide on the plunger rod reaches the finger grip. Set the dose to administer 0.07 mL (equivalent to 70 microL). See the detailed description for the preparing and injecting the solution in the section Instructions for use / handling.
After injection any unused product or waste material must be discarded.

Instructions for use/ handling.

The vial and the pre-filled syringe are for single use in one eye only. Extraction of multiple doses from a single vial, pre-filled syringe or pre-filled syringe; with OcuClick dosing system may increase the 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, pre-filled syringe, or pre-filled syringe with OcuClick dosing system to make sure you have the correct Eylea strength.
Prior to administration visually inspect the solution for injection. Do not use the vial or prefilled syringe if particulates, cloudiness, or discolouration are visible. Do not use if any part of the pre-filled syringe is damaged or loose, or if the syringe cap is detached from the Luer-lock.
Prior to usage, the Eylea unopened vial or pre-filled syringe blister pack may be stored at room temperature (25°C) for up to 24 hours. After opening the vial or blister pack, proceed under aseptic conditions.
For the intravitreal injection a 30 G x ½ inch injection needle should be used.
Note for the Filter Needle provided with the vial pack:
Filter (Fill) Needle, is not for skin injection.
Do not autoclave the Filter (Fill) Needle.
The filter needle is non-pyrogenic. Do not use it if individual packaging is damaged.
Discard the used Filter (Fill) Needle in approved sharps collector.
Caution: Re-use of the filter needle may lead to infection or other illness/injury.
Eylea 40 mg/mL vial (for 2 mg dosing). 1. Remove the plastic cap and disinfect the outer part of the rubber stopper of the vial.
2. Attach the 18 G, 5-micron filter needle supplied in the carton to a 1 mL sterile, Luer-lock syringe.
3. Push the filter needle into the centre of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.
4. Using aseptic technique withdraw all of the Eylea vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid.
5. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
6. Remove the filter needle and properly dispose of it.

Note.

Filter needle is not to be used for intravitreal injection.
7. Using aseptic technique, firmly twist a 30 G x ½ inch injection needle to the Luer-lock syringe tip.
8. 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 drug by slowly depressing the plunger so that the flat plunger edge aligns with the line that marks 0.05 mL (equivalent to 50 microL) on the syringe.
10. After injection, any unused product must be discarded.
Eylea 40 mg/mL pre-filled syringe (for 2 mg dosing). 1. When ready to administer Eylea, open the carton and remove the sterilised blister pack. Carefully peel open the blister pack 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 pack.
3. To remove the syringe cap, hold the syringe in one hand while using your other hand to grasp the syringe cap with the thumb and forefinger. Please note: 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.
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. The excess volume must be discarded prior to administration. To eliminate all bubbles and to expel excess drug, slowly depress the plunger to align the base of the plunger dome (not the tip of the dome) with the black dosing line on the syringe (equivalent to 50 microL i.e. 2 mg aflibercept).

Note.

This accurate positioning of the plunger is very important, because incorrect plunger position can lead to delivering more or less than the labelled dose.
8. Inject by pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. Do not administer any residual solution observed in the syringe.
9. The pre-filled syringe is for single use only. After injection any unused product must be discarded.
Eylea 114.3 mg/mL vial (for 8 mg dosing). 1. Prior to administration visually inspect the solution for injection.
Do not use the vial if particulates, cloudiness, or discoloration are visible.
2. Remove the plastic cap and disinfect the outer part of the rubber stopper of the vial.
3. Use aseptic technique to carry out steps 3-10.
Attach the 18 G, 5-micron filter needle supplied in the carton to a 1-mL sterile, Luer-lock syringe.
4. 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.
5. Withdraw all of the Eylea 8 mg 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.
6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. After injection any unused product must be discarded.
7. Remove the filter needle and properly dispose of it.

Note.

Filter needle is not to be used for intravitreal injection.
8. Firmly twist the 30 G x ½ inch injection needle onto the Luer-lock syringe tip.
Use of a smaller size needle (higher gauge) than the recommended 30 G x ½ inch injection needle may result in increased injection forces.
9. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
10. To eliminate all bubbles and to expel excess drug, slowly depress the plunger so that the flat plunger edge aligns with the line that marks 0.07 mL on the syringe.
11. After injection any unused product must be discarded.
Eylea 114.3 mg/mL pre-filled syringe with OcuClick dosing system (for 8 mg dosing).

Pre-filled syringe with integrated OcuClick dosing system description.

1. Prepare. When ready to administer Eylea 8 mg, open the carton and remove the blister pack. Carefully peel open the blister pack 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 pack.
3. Inspect syringe and solution for injection. Do not use the pre-filled syringe if particulates, cloudiness, or discoloration are visible.
Do not use if any part of the pre-filled syringe with OcuClick system is damaged or loose, or if the syringe cap is detached from the Luer-lock.
4. Snap off syringe cap. Snap off (do not twist off) the syringe cap by holding the syringe in one hand and the syringe cap 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 x 1/2 inch injection needle onto the Luer-lock syringe tip.
Use of a smaller size needle (higher gauge) than the recommended 30G x 1/2 inch injection needle may result in increased injection forces.
6. Dislodge air bubbles. 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. Expel air and excess volume to prime. The syringe does not have a dose line because it is designed to set the dose mechanically as shown in the steps.
Priming and setting the dose must be done using the following steps. To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod until it stops, i.e. when the guide on the plunger rod reaches the finger grip.
8. Set to dose. Turn the end of the plunger rod 90 degrees clockwise or counterclockwise until the guide of the plunger rod aligns with the slot. You may hear a ''click''.

Note.

Now the device is ready to dose. Do not push the plunger rod before insertion into the eye.
9. Administer the injection. Insert the needle into the ocular injection site.
Inject the solution by pushing in the plunger rod until it stops, i.e. until the guide is completely within the slot. Do not apply additional pressure once the guide is within the slot. It is normal to see a small amount of residual solution left in the syringe.
10. The pre-filled syringe is for single dose administration and single use only.
After injection discard the used syringe into a sharps container.

Dosage adjustment.

Patients with hepatic and/or renal impairment.

No specific studies in patients with hepatic and/or renal impairment were conducted with Eylea. Available data do not suggest a need for a dose adjustment with Eylea in these patients (see Section 5.2 Pharmacokinetic Properties).
For Eylea 2 mg, pharmacokinetic analysis of patients with wet AMD in the VIEW 2 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, with DME in the VIVIDDME study and with myopic CNV in the MYRROR study.

Use in elderly.

Available data do not suggest a need for a dose adjustment with Eylea in these patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.3 Contraindications

Known hypersensitivity to aflibercept or to any of the excipients (see Section 6.1 List of Excipients).
Ocular or periocular infection.
Active severe intraocular inflammation.

4.4 Special Warnings and Precautions for Use

Endophthalmitis, retinal vasculitis and/or retinal occlusive vasculitis.

Intravitreal injections, including those with Eylea, have been associated with endophthalmitis and more rarely, with retinal vasculitis and/or retinal occlusive vasculitis (see Section 4.8 Adverse Effects (Undesirable Effects)). Proper aseptic injection technique must always be used when administering Eylea. Patients should be instructed to report any symptoms suggestive of endophthalmitis, retinal vasculitis or retinal occlusive vasculitis without delay and should be managed appropriately.

Retinal detachment.

Intravitreal injections, including those with Eylea, have been associated with retinal detachment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Increase in intraocular pressure.

Transient increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection, including with Eylea (see Section 4.8 Adverse Effects (Undesirable Effects)). Special precaution is needed in patients with poorly controlled glaucoma. 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. 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.

Arterial thromboembolic events.

There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors (see Section 4.8 Adverse Effects (Undesirable Effects)). ATEs include vascular death (e.g. due to stroke or myocardial infarction), nonfatal strokes and nonfatal myocardial infarction.
The risk of stroke may be greater in patients with known risk factors including a history of stroke or transient ischaemic attack (TIA). Patients should be carefully evaluated by their doctor to assess whether the benefits of treatment outweigh the potential risks.

Bilateral treatment.

The safety and efficacy of bilateral treatment with Eylea have not been systematically studied (see Section 5.1 Pharmacodynamic Properties, Clinical trials). 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.

Retinal pigment epithelial tear.

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 anti-VEGF therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Withholding treatment.

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.
In the event of either a decrease in best corrected visual acuity (BCVA) of ≥ 30 letters compared with the last assessment of visual acuity; or 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 and treatment should not be resumed earlier than the next scheduled treatment.
The dose should be withheld in the event of performed or planned intraocular surgery within the previous or next 28 days.
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 with Eylea treatment in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy or Type 1 diabetes. 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 patients with uncontrolled hypertension. 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.
This lack of information should be considered by the ophthalmologist when treating such patients.

Use in the elderly.

Available data do not suggest a need for a dose adjustment with Eylea in these patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There is limited experience in patients with DME aged 75 years and older.

Paediatric use.

The safety and efficacy of Eylea have not been established in children or adolescents.

Effects on laboratory tests.

No relevant effects on laboratory tests are known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed with Eylea.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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 every one to two weeks. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility (considered consequential to male fertility) 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 4900-fold and 1500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg.
the systemic exposures were approximately ~600 and ~180 higher, respectively, than the population PK estimated exposure in humans after an intravitreal dose of 8 mg. All changes were reversible.
(Category D1)
There are limited data on the use of aflibercept in pregnant women.

Eylea 2 mg.

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

Eylea 8 mg.

Women of childbearing potential have to use effective contraception during treatment and for at least 4 months after the last intravitreal injection of aflibercept.
Eylea should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus. The treating ophthalmologist in consultation with the treating obstetrician need to consider the individual benefit-risk balance for each patient. This includes a consideration of timing of treatment, delaying treatment and other potential treatment options.
Population PK modelling estimated that Eylea 8 mg given every 12 or 16 weeks was associated with 9 times the systemic exposure (AUC0-28days) of free aflibercept when compared to Eylea 2 mg given every 8 weeks.
Studies in animals have shown reproductive toxicity, including a series of external, visceral, skeletal malformations, after systemic administration.
Aflibercept produced malformations and other fetal abnormalities in pregnant rabbits with intravenous (3 to 60 mg/kg once every 3 days during the period of organogenesis) and with subcutaneous administration (0.1 to 1 mg/kg on gestational days 1, 7, and 13). A no observed effect level (NOEL) for adverse effects on embryofetal development was not established.
At the lowest dose tested (0.1 mg/kg), the systemic exposures based on Cmax and cumulative AUC for free aflibercept were approximately 13- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the lowest dose tested (0.1 mg/kg), the systemic exposures based on cumulative AUC for free aflibercept were below the corresponding values observed in humans after an intravitreal dose of 8 mg.
1 Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
 It is unknown whether aflibercept is excreted in human milk. A risk to the breastfed 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.

4.7 Effects on Ability to Drive and Use Machines

Patients may experience temporary visual disturbances after an intravitreal injection with Eylea and the associated eye examinations (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should not drive or use machinery until visual function has recovered sufficiently.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Eylea 2 mg.

A total of 3102 patients treated with Eylea constituted the safety population in eight phase III studies. Amongst those, 2501 patients were treated with the recommended dose of 2 mg.
Serious adverse reactions related to the injection procedure have occurred in less than 1 in 2400 intravitreal injections with Eylea and included endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous detachment and intraocular pressure increased (see Section 4.4 Special Warnings and Precautions for Use).
The most frequently observed adverse reactions (in at least 5% of patients treated with Eylea) were conjunctival haemorrhage (25.0%), visual acuity reduced (11.1%), eye pain (10.2%), cataract (7.6%), intraocular pressure increased (7.5%), vitreous detachment (7.4%), and vitreous floaters (6.9%).
In wet AMD, these adverse reactions occurred with a similar incidence in the ranibizumab treatment group.

Eylea 8 mg.

A total of 1,217 patients treated with Eylea 8 mg (n = 726 nAMD, n = 491 DME) and 556 patients treated with Eylea 2 mg constituted the safety population in three Phase II/III studies (CANDELA, PULSAR, PHOTON).
Serious adverse reactions were cataract (4.0%), retinal haemorrhage (2.6%), intraocular pressure increased (2.4%), vitreous haemorrhage (1.0%), cataract subcapsular (0.5%), retinal detachment (0.4%), and retinal tear (0.3%).
Serious adverse reactions related to the injection procedure have occurred in less than 1 in 1,900 intravitreal injections with Eylea 8 mg and included intraocular pressure increased, and retinal tear (see Section 4.4 Special Warnings and Precautions for Use).
The most frequently observed adverse reactions in at least 2% of patients treated with Eylea 8 mg were cataract (4.0%), vitreous floaters (3.5%), visual acuity reduced (3.2%), conjunctival haemorrhage (3.1%), vitreous detachment (2.9%), and intraocular pressure increased (2.4%).

Tabulated list of adverse reactions.

Eylea 2 mg.

The safety data described in Table 1 include all adverse reactions (serious and nonserious) from eight phase III studies with a reasonable possibility of causality to the injection procedure or medicinal product over the 96 weeks study duration for wet AMD, over 100 weeks for CRVO, over 100 weeks for DME, over 52 weeks for BRVO and over 48 weeks for myopic CNV.
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 patients). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Eylea 8 mg.

The safety data described in Table 2 include all adverse reactions (serious and non-serious) with a reasonable possibility of causality to the injection procedure or medicinal product reported from Eylea 8 mg phase II/III studies up to 60 weeks for the indications wet AMD and DME.
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 patients). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Post-marketing experience.

In addition, the following adverse reactions have also been reported during the postmarketing period of Eylea 2 mg, for which a frequency could not be estimated.

Immune system disorders.

Hypersensitivity (including rash, pruritus, urticaria, and isolated cases of severe anaphylactic/ anaphylactoid reactions).

Eye disorders.

Retinal vasculitis and retinal occlusive vasculitis, scleritis.
The following adverse reactions have also been reported during the postmarketing period of Eylea 8 mg, for which a frequency could not be estimated.

Eye disorders.

Retinal vasculitis and retinal occlusive vasculitis, scleritis.

Description of selected adverse reactions.

The following adverse reactions of Eylea 2 mg strength are also considered expected with Eylea 8 mg but have not been reported in the studies with Eylea 8 mg:
Anterior chamber flare, corneal epithelium defect, lenticular opacities, ocular hyperaemia, endophthalmitis, hypopyon, cataract traumatic, severe anaphylactic/anaphylactoid reactions.
Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors.
ATEs, as defined by Antiplatelet Trialists' Collaboration (APTC) criteria, include nonfatal myocardial infarction, nonfatal stroke, or vascular death (including deaths of unknown cause).

Eylea 2 mg.

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.
The incidence of adjudicated APTC ATEs in the VIEW 1 and VIEW 2 wet AMD studies during the 96 weeks study period was 3.3% (60 out of 1824) in the combined group of patients treated with Eylea (2.4% in the Eylea 2Q4 arm and 3.6% in the Eylea 2Q8 arm), compared to 3.2% (19 out of 595) in patients treated with ranibizumab.
The incidence of adjudicated APTC ATEs in the CRVO studies (GALILEO and COPERNICUS) during the 76/100 weeks study duration was 0.6% (2 out of 317) in patients treated with at least one dose of Eylea compared to 1.4% (2 out of 142) in the group of patients receiving only sham treatment.
The incidence of adjudicated APTC ATEs in the DME studies (VIVIDDME and VISTADME) during the 100 weeks study duration was 6.4% (37 out of 578) in the combined group of patients treated with Eylea compared with 4.2% (12 out of 287) in the control group.
The incidence of APTC ATEs in the BRVO study (VIBRANT) during the 52 week study duration was 0% (0 out of 91) in patients treated with Eylea compared with 2.2% (2 out of 92) in the control group.
The incidence of APTC ATEs in the myopic CNV study (MYRROR) during the 48 week study duration was 1.1% (1 out of 91) in the group of patients treated with Eylea compared to 0% (0 out of 31) in the group of patients in the control group.
As with all therapeutic proteins, there is a potential for immunogenicity with Eylea.

Eylea 8 mg.

The pooled incidence of APTC ATEs in the phase II/III nAMD studies CANDELA (through Week 44) and PULSAR (through Week 60) studies was 2.1% (8 out of 389) in the 2Q8 arm, 0.3% (1 out of 388) in 8Q12 arm, 0.6% (2 out of 338) in 8Q16 arm, all 0.4% (3 out of 726) in the pooled 8 mg arms (combined 8Q12 and 8Q16 arms).
The incidence of APTC ATEs in the DME study PHOTON (through Week 60) was 3.6% (6 out of 167) in the 2Q8 arm, 4.0% (13 out of 328) in the 8Q12 arm, 5.5% (9 out of 163) in the 8Q16 arm, and 4.5% (22 out of 491) in the pooled 8 mg arms (combined 8Q12 and 8Q16 arms).
As with all therapeutic proteins, there is a potential for immunogenicity with Eylea.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage intraocular pressure should be monitored and if deemed necessary by the treating ophthalmologist, adequate treatment should be initiated (see Section 4.2, Instructions for use/ handling).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ophthalmologicals/ antineovascularization agents.
ATC code: S01LA05.

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 leukocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can synergise with VEGF-A in these processes, and is also known to promote leukocyte infiltration and vascular inflammation. A variety of ocular diseases is associated with pathologic neovascularisation and vascular leakage, and/or can result in thickening and oedema of the retina, which is thought to contribute to vision loss.
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. The equilibrium dissociation constant (KD) for aflibercept binding to human VEGF-A165 is 0.5 picoM and to human VEGF-A121 is 0.36 picoM. The KD for binding to human PlGF-2 is 39 picoM.

Pharmacodynamic effects.

Neovascular (wet) age related macular degeneration (wet AMD).

Wet AMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal oedema and/or sub/intraretinal haemorrhage, resulting in loss of visual acuity.
In patients treated with Eylea 2 mg (one injection per month for three consecutive months, followed by one injection every 2 months), retinal thickness decreased soon after treatment initiation, and the mean CNV lesion size was reduced, consistent with the results seen with ranibizumab 0.5 mg every month.
In pivotal phase III clinical studies, VIEW 1 and VIEW 2, there were mean decreases in retinal thickness on time domain optical coherence tomography (OCT) at week 52: -130 and -129 microns for the Eylea 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively, in VIEW 1; -149 and -139 microns for the Eylea 2 mg every two months, and ranibizumab 0.5 mg every month study groups, respectively, in VIEW 2.
The reduction of CNV size and reduction in retinal thickness were generally maintained in the second year of the studies.
The supportive study, ALTAIR, enrolled Japanese patients with treatment naive wet AMD, using 3 initial monthly Eylea 2 mg injections, followed by one injection after 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 spectral domain 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 retinal thickness was generally maintained in both treatment arms in the second year of the ALTAIR study.
In the PULSAR study with Eylea 8 mg, at week 48, central retinal thickness (CRT) was reduced in patients treated with 8Q12, 8Q16 and 2Q8, and total lesion area was reduced in patients treated with 8Q12 and 8Q16 and showed minimal increase in patients treated with 2Q8. See Table 3.

Diabetic macular oedema (DME).

Diabetic macular oedema is characterised by increased vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.
In patients treated with Eylea 2 mg, rapid and robust response in morphology (CRT) as assessed by OCT was seen soon after treatment initiation. The mean change in CRT from baseline to week 52 was statistically significant favouring Eylea and was maintained through week 100. See Table 4.
The VIOLET study compared three different dosing regimens of Eylea 2 mg for treatment of DME. Following 5 consecutive monthly doses and treatment at fixed 8 week intervals for at least 1 year, patients continued treatment with Eylea 2 mg according to one of the dosing regimens:
treat-and-extend (2TandE) where treatment intervals were maintained at a minimum of 8 weeks and gradually extended based on clinical and anatomical outcomes;
pro re nata (2PRN) where patients were observed every 4 weeks and injected when needed based on clinical and anatomical outcomes; and
dosed every 8 weeks (2Q8) for the second and third year of treatment.
At week 52 of the study, i.e. after at least two years of treatment, the mean changes in CRT from baseline were -2.1, 2.2 and -18.8 microns for 2TandE, 2PRN, and 2Q8 respectively. At week 100, i.e. after at least three years of treatment, the mean changes in CRT from baseline were 2.3, -13.9 and -15.5 microns, respectively (see Clinical trials).
In the PHOTON study with Eylea 8 mg, at week 48, central retinal thickness (CRT) was reduced in patients treated with 8Q12, 8Q16 and 2Q8. See Table 5.

Macular oedema following central retinal vein occlusion (CRVO).

In CRVO, retinal ischaemia occurs and signals the release of VEGF which in turn destabilises the tight junctions and promotes endothelial cell proliferation. Up-regulation of VEGF is associated with the breakdown of the blood retina barrier and this increased vascular permeability results in retinal oedema, stimulation of endothelial cell growth and neovascularisation.
In patients treated with Eylea (one injection every month for six months), there was consistent, rapid and robust response in morphology (CRT as assessed by OCT). Improvements in mean CRT were maintained through week 24.
Retinal thickness on OCT at week 24 compared to baseline was a secondary efficacy endpoint in both the COPERNICUS and GALILEO studies. In both studies, the mean change in CRT from baseline to week 24 statistically significantly favoured Eylea. See Table 6.

Macular oedema following branch retinal vein occlusion (BRVO).

In BRVO, retinal ischaemia occurs and signals the release of VEGF, which in turn destabilises the tight junctions and promotes endothelial cell proliferation. Up-regulation of VEGF is associated with the breakdown of the blood retina barrier and this increased vascular permeability results in retinal oedema, stimulation of endothelial cell growth and neovascularisation.
In patients treated with Eylea 2 mg (one injection every month for six months) in the VIBRANT study, there was consistent, rapid and robust response in retinal morphology (CRT as assessed by OCT). There was a statistically significant improvement in the Eylea 2 mg group in comparison to the active control group treated with laser photocoagulation at week 24 (-280 microns vs. -128 microns). At week 24, the dosing interval was extended to every 2 months, and anatomic outcomes were maintained.
Retinal thickness on OCT at week 24 compared to baseline was a secondary efficacy variable in the VIBRANT study. This decrease from baseline was maintained to week 52, favouring Eylea (see Table 7).

Myopic choroidal neovascularisation (myopic CNV).

Myopic CNV is a frequent cause of vision loss in adults with pathologic myopia. Eyes with pathologic myopia are elongated, often excessively, and have, in addition, pathologic tissue alterations such as retinal pigment epithelial thinning and defects, lacquer cracks and Bruch's membrane ruptures, choroidal neovascularisation, subretinal haemorrhage and choroidal atrophy. As a consequence of ruptures of Bruch's membrane, myopic CNV develops as a wound healing mechanism and at the same time represents the most vision threatening event in pathologic myopia.
In patients treated with Eylea (one injection given at the start of therapy, additional injection given in case of disease persistence or recurrence) retinal thickness assessed by OCT decreased soon after treatment initiation and the mean CNV lesion size was reduced. The mean change in CRT from baseline to week 24 was statistically significant favouring Eylea. See Table 8.

Clinical trials.

Neovascular (wet) age related macular degeneration (wet AMD).

Eylea 2 mg.

The safety and efficacy of Eylea were assessed in two pivotal phase III randomised, multicentre, double masked, active controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with Eylea) in the two studies (VIEW 1 and VIEW 2). 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).
4. Ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).
Patient ages ranged from 49 to 99 years with a mean of 76 years. Approximately 89% (1616/1817) of the patients randomised to treatment with Eylea were 65 years of age or older and approximately 63% (1139/1817) were 75 years of age or older.
In the follow-up exploratory phase of the studies (i.e. from week 52 onwards to week 96), patients continued to receive the dosage strength to which they were initially randomised but on a modified dosing schedule. Injections were given as frequently as every 4 weeks, but no less frequently than every 12 weeks based upon prespecified retreatment criteria guided by assessment of visual and/or anatomic outcomes. After the first year of the studies, 90% of patients originally treated with Eylea 2Q8 received 6 doses or less and 72% received 4 doses or less among the patients completing the follow-up exploratory phase of the studies.
In both studies, the primary efficacy endpoint was the proportion of patients in the per protocol set who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. The studies were intended to test for noninferiority against ranibizumab 0.5 mg given every 4 weeks.
In the VIEW 1 study, at week 52, 95.1% of patients in the Eylea 2Q8 treatment group maintained vision compared to 94.4% of patients in the ranibizumab 0.5Q4 group. Eylea treatment was shown to be non-inferior to the ranibizumab 0.5Q4 group.
In the VIEW 2 study, at week 52, 95.6% of patients in the Eylea 2Q8 treatment group maintained vision compared to 94.4% of patients in the ranibizumab 0.5Q4 group. Eylea treatment was shown to be non-inferior to the ranibizumab 0.5Q4 group.
The VIEW 1 and VIEW 2 studies included four secondary efficacy endpoints: mean change in Best Corrected Visual Acuity (BCVA), proportion of patients who gained ≥ 15 letters, change in the total National Eye Institute Visual Function Questionnaire (NEI VFQ-25) score, and change in CNV area.
Detailed results from the combined analysis of both studies (primary* and secondary# endpoints) are shown in Table 9 and Figure 1.
While there were small differences between Eylea and ranibizumab, no clinically relevant differences were seen between the treatment groups across all four secondary efficacy endpoints, based on the confidence intervals for the differences between Eylea and ranibizumab. All statistical tests on secondary efficacy endpoints were considered to be exploratory in the combined analysis of both studies. All secondary endpoint analyses supported the comparability of the efficacy of all 3 Eylea treatment schedules and ranibizumab.
In combined data analysis of the VIEW 1 and VIEW 2 studies Eylea demonstrated clinically meaningful changes from baseline in NEI VFQ-25 scores and subscales (near activities, distance activities, and vision specific dependency). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15 letter gain in BCVA.
After the first year of the studies, efficacy was generally maintained through the last assessment at week 96. Over the 96 weeks period, patients in the Eylea 2Q8 group received an average of 11.2 doses and patients in the ranibizumab group received an average of 16.5 doses.
Exploratory analyses of 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.
The supportive study, ALTAIR, is a 96 week Phase IV multicentre, randomised, open-label study in 247 Japanese patients with treatment naive 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 3 monthly doses of Eylea 2 mg, 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 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 and 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. Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2. There are no data directly comparing Eylea administered in a treat-and-extend dosing regimen with Eylea administered every 8 weeks following 3 initial monthly doses during the first 12 months of treatment of wet AMD.
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.
Between week 16 and 96, 43.1% (n = 53) and 54.5% (n = 67) of the patients (2-week and 4-week adjustment groups respectively) were extended to a maximum treatment interval of 16 weeks at least once. Of these patients, 96.2% (n = 51 of 53) patients in the 2-week adjustment group and 77.6% (n = 52 of 67) patients in the 4-week adjustment group maintained a 16-week treatment interval until the end of the study. During the 96 week study period, 41.5% (n=51) and 46.3% (n=57) of patients in the 2-week and 4-week adjustment groups respectively had a final treatment interval of 16 weeks.
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. Over the 2-year treatment period patients received an average of 10.4 injections.

Eylea 8 mg.

The safety and efficacy of Eylea 8 mg were assessed in a randomised, multi-centre, double- masked, active-controlled study (PULSAR) in patients with treatment naïve nAMD. The patients were assigned in a 1:1:1 ratio to 1 of 3 parallel treatment groups:
1. Eylea 8 mg administered at 8 mg every 12 weeks (8Q12), after 3 initial injections at 4-week intervals;
2. Eylea 8 mg administered at 8 mg every 16 weeks (8Q16), after 3 initial injections at 4-week intervals;
3. Eylea 2 mg administered at 2 mg every 8 weeks (2Q8), after 3 initial injections at 4- week intervals.
Patients in the 8Q12 and 8Q16 groups could move to a more frequent dosing regimen based on visual and anatomic outcomes. Per study protocol the interval of the 8Q12- and 8Q16-groups was to be shortened if both of the following criteria were met:
1. > 5 letters loss in BCVA from week 12; and
2. > 25 microns increase in CRT from week 12 or new foveal haemorrhage or new foveal neovascularisation.
The minimum interval between injections was 8 weeks in all groups.
Patients with bilateral disease were eligible to receive Eylea 2 mg treatment or another anti-VEGF medicinal product in their fellow eye.
The study population was aged from 50 to 96 years with a mean of 74.5 years. There were approximately 90% (604/673) and 51% (343/673) patients randomised to the 8Q12 and 8Q16 groups aged 65 years of age or older and 75 years of age or older respectively. The mean best corrected visual acuity (BCVA) at baseline (measured by the Early Treatment Diabetic Retinopathy Study [ETDRS] letter score) was 59.9, 60.0 and 58.9 in the 8Q12, 8Q16 and 2Q8 groups, respectively.
Patients in the 8Q12, 8Q16 and 2Q8 groups received a median (mean) of 6.0 (6.1), 5.0 (5.2) and 7.0 (6.9) injections, respectively, through week 48.
Patients in the 8Q12, 8Q16- and 2Q8-groups who completed week 60 received a median (mean) of 7.0 (7.1), 6.0 (6.2) and 9.0 (8.8) injections, respectively.
The primary efficacy endpoint was the mean change from baseline in BCVA at week 48.
Treatment with 8Q12 and 8Q16 was shown to be non-inferior to treatment with 2Q8 in terms of the primary efficacy endpoint mean change in BCVA at week 48 and the key secondary efficacy endpoint mean change in BCVA at week 60.
For the key secondary efficacy endpoint proportion of participants with no intraretinal fluid (IRF) and no subretinal fluid (SRF) in the central subfield at week 16, treatment with Eylea 8 mg (pooled 8Q12 and 8Q16 groups) was shown to be superior to treatment with Eylea 2 mg (2Q8). See Table 10 and Figure 2.
No clinically meaningful differences were found between the 8Q12-, 8Q16- and 2Q8 groups in changes of NEI VFQ-25 total score at week 48 from baseline.
Efficacy for the primary endpoint 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.
Diabetic macular oedema (DME).

Eylea 2 mg.

The safety and efficacy of Eylea 2 mg were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME. A total of 862 randomised and treated patients were evaluable for efficacy. Of those, 576 were randomised to the Eylea groups in two studies (VIVIDDME and VISTADME). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens:
1. Eylea administered at 2 mg every 8 weeks following 5 initial monthly injections (Eylea 2Q8);
2. Eylea administered at 2 mg every 4 weeks (Eylea 2Q4); and
3. macular laser photocoagulation (active control).
Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the Eylea groups could receive laser and patients in the laser group could receive Eylea.
Patient ages ranged from 23 to 87 years with a mean of 63 years. Approximately 47% (268/576) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. Efficacy and safety outcomes were consistent with the outcomes of the overall population.
In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at Week 52 as measured by ETDRS letter score. Both Eylea 2Q8 and Eylea 2Q4 groups were shown to have efficacy that was statistically significantly superior to the laser control group. This benefit was maintained through week 100.
Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 11 and Figure 3.
At week 52, 33.3% and 33.8% of 2Q4 patients, 27.7% and 29.1% of 2Q8 patients, and 7.5% and 14.3% of laser control patients in the VIVIDDME and VISTADME studies, respectively experienced an improvement in the severity of diabetic retinopathy, as measured by a ≥ 2 step improvement in the diabetic retinopathy severity scale (DRSS). This improvement was maintained through week 100 (see Table 11).
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 (8.9%) and 197 (42.9%) patients received prior anti-VEGF therapy, respectively, with a 3-month or longer washout period. Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naive prior to study participation.
Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye. In the VISTADME study, 217 (70.7%) of Eylea patients received bilateral Eylea injections until week 100; in the VIVIDDME study, 97 (35.8%) of EYLEA patients received a different anti-VEGF treatment in their fellow eye until week 100.
An independent comparative trial (DRCR.net Protocol T) utilised a flexible 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 and mean gain of 13.3 letters, which was similar to the Eylea 2Q8 group in VIVIDDME and VISTADME. (Mean number of injections: 8.7 and 8.4. Mean vision acquity improvement 10.7 letters). 42% of patients gained at least 15 letters in vision from baseline which also comparable to VIVIDDME and VISTADME (33.3% and 31.1% respectively). Safety outcomes demonstrated that overall incidence of ocular and non-ocular adverse events (including ATEs) were comparable across all treatment groups in each of the studies and between the studies.
A propensity score matching methodology (PSM) analysis compared the flexible aflibercept treatment group in Protocol T with the combined 2Q8 treatment groups in VIVID and VISTA.
This PSM identified, subsets of 179 matched patients from pooled VIVIDDME and VISTADME (utilising a fixed aflibercept dosing regimen) and Protocol T (utilising a flexible dosing regimen based on strict OCT and vision re-treatment criteria).
The PSM analysis showed that mean change in BCVA from baseline at week 52 was 10.9 letters in the 2 mg aflibercept 2Q8 fixed dosing regimen (VIVIDDME and VISTADME) and 13.7 letters in the 2 mg aflibercept flexible dosing regimen (Protocol T).
VIOLET was a 100-week multicentre, randomised, open-label, active controlled study in 463 patients with DME. Patients were randomised in a 1:1:1 ratio to three regimens of Eylea 2 mg for treatment of DME after at least one year of treatment at fixed intervals, where treatment was initiated with 5 consecutive monthly doses followed by dosing every 2 months. The study evaluated non-inferiority of:
Eylea 2 mg dosed according to a treat-and-extend regimen (2TandE) where treatment intervals were maintained at a minimum of 8 weeks and gradually extended based on clinical and anatomical outcomes. The increments and decrements for the treatment intervals were at the investigator's discretion; increments of 2 weeks were recommended in the study; and
Eylea 2 mg dosed as needed (2PRN) where patients were observed every 4 weeks and injected when needed based on clinical and anatomical outcomes, compared to Eylea 2 mg dosed every 8 weeks (2Q8).
The primary efficacy endpoint (change in BCVA from baseline to week 52) was 0.5 ± 6.7 letters in the 2TandE group and 1.7 ± 6.8 letters in the 2PRN group compared to 0.4 ± 6.7 letters in the 2Q8 group, achieving statistical non-inferiority (NI) (p < 0.0001 for both comparisons; NI margin 4 letters). The changes in BCVA from baseline to week 100 were consistent with the week 52 results: -0.1 ± 9.1 letters in the 2TandE group and 1.8 ± 9.0 letters in the 2PRN group compared to 0.1 ± 7.2 letters in the 2Q8 group. The mean number of injections over 100 weeks were 10.0, 11.5 and 12.3 for 2TandE, 2PRN and 2Q8, respectively.
Ocular and systemic safety profiles in all 3 treatment groups were similar to those observed in the pivotal studies VIVID and VISTA.

Eylea 8 mg.

The safety and efficacy of Eylea 8 mg were assessed in a randomised, multi-centre, double-masked, active-controlled study (PHOTON) in patients with DME. The patients were assigned in a 2:1:1 ratio to 1 of 3 parallel treatment groups:
1. Eylea 8 mg administered at 8 mg every 12 weeks (8Q12), after 3 initial injections at 4-week intervals;
2. Eylea 8 mg administered at 8 mg every 16 weeks (8Q16), after 3 initial injections at 4-week intervals;
3. Eylea 2 mg administered at 2 mg every 8 weeks (2Q8), after 5 initial injections at 4week intervals.
Patients in the 8Q12 and 8Q16 groups could move to a more frequent dosing regimen based on visual and anatomic outcomes. Per study protocol the interval of the 8Q12- and 8Q16-groups was to be shortened if both of the following criteria were met:
1. > 10 letter loss in BCVA from week 12 in association with persistent or worsening DME; and
2. > 50 microns increase in CRT from week 12.
The minimum interval between injections was 8 weeks in all groups.
Patients with bilateral disease were eligible to receive Eylea 2 mg treatment in their fellow eye.
The study population was aged from 24 to 90 years with a mean of 62.3 years. [i] There were approximately 44% (214/491) and 10% (50/491) patients randomised to the 8Q12 and 8Q16 groups aged 65 years of age or older and 75 years of age or older respectively.
The study population included treatment-naïve patients (56.4%) and patients previously treated for DME (43.6%).
Patients in the 8Q12, 8Q16 and 2Q8 groups received a median (mean) of 6.0 (6.0), 5.0 (5.0) and 8.0 (7.9) injections, respectively, through week 48.
The mean best corrected visual acuity (BCVA) at baseline (measured by the Early Treatment Diabetic Retinopathy Study [ETDRS] letter score) was 63.6, 61.4 and 61.5 in the 8Q12-, 8Q16- and 2Q8-groups, respectively.
The primary efficacy endpoint was the mean change from baseline in BCVA at week 48.
Treatment with Eylea 8 mg (both 8Q12 and 8Q16 groups) was shown to be non-inferior to treatment with Eylea 2 mg (2Q8), in terms of the primary efficacy endpoint mean change in BCVA at week 48.
For the key secondary efficacy endpoint proportion of participants with ≥ 2-step improvement in DRSS score at Week 48, Eylea 8Q12 was non-inferior to Eylea 2Q8. Non-inferiority of Eylea 8Q16 to Eylea 2Q8 was not shown. See Table 12 and Figure 4.
No clinically meaningful differences were found between the 8Q12-, 8Q16- and 2Q8-groups in changes of NEI VFQ-25 total score at week 48 from baseline.
Efficacy for the primary endpoint 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 overall population.
For the pre-specified exploratory endpoint 'proportion of patients maintaining treatment intervals through week 48', there were 92.8% of patients in the pooled 8Q12- and 8Q16- groups maintained on their original randomised dosing intervals of ≥ 12 weeks and 89.1% of patients in the 8Q16 group maintained on dosing intervals of 16 weeks, while maintaining visual and anatomic outcomes.
Macular oedema secondary to central retinal vein occlusion (CRVO).

Eylea 2 mg.

The safety and efficacy of Eylea 2 mg were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with Eylea) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks (2Q4) or the control group receiving sham injections every 4 weeks for a total of 6 injections.
After 6 monthly injections, patients received treatment only if they met prespecified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. Starting from this time point, all patients were offered treatment if they met prespecified criteria.
Patient ages ranged from 22 to 89 years with a mean of 64 years. 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, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. The studies were designed to evaluate superiority against the control group (receiving sham injections).
Change in visual acuity at week 24 compared to baseline was an important secondary endpoint in both COPERNICUS and GALILEO studies.
The difference between treatment groups was statistically significant in favour of Eylea in both studies, for the proportion of patients who gained at least 15 letters in BCVA and for mean change in visual acuity, at week 24 compared to baseline. In both pivotal studies, the maximal improvement in visual acuity was achieved at month 3 with subsequent stabilisation of the effect on visual acuity and central retinal thickness until month 6. The statistically significant difference was maintained through week 52. A difference was maintained through week 76/100.
Three other secondary endpoints were included in the studies: change in CRT, as assessed by OCT, at week 24 compared to baseline (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects); proportion of patients progressing to neovascularisation (anterior segment neovascularisation, neovascularisation of the optic disk, or neovascularisation of the retina elsewhere) at week 24; and change in the NEI VFQ-25 total score at week 24 compared to baseline.
Detailed results from the analysis of both studies (primary* and secondary# endpoints) are shown in Table 2 (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects), Table 13 and Figure 5.
Exploratory analyses of efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, retinal perfusion status, CRVO duration) in each study were in general consistent with the results in the overall populations.
Macular oedema secondary to branch retinal vein occlusion (BRVO).

Eylea 2 mg.

The safety and efficacy of Eylea 2 mg were assessed in a randomised, multicentre, double masked, active controlled study in patients with macular oedema secondary to BRVO, which included hemiretinal vein occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with Eylea) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg Eylea administered every 4 weeks, with a total of 6 injections, or laser photocoagulation administered at baseline (laser control group). Patients in the laser control group could receive additional laser photocoagulation (called "rescue laser treatment") beginning at week 12, if at least one prespecified rescue treatment criterion was met. The minimum interval between laser photocoagulation treatments was 12 weeks. After week 24, patients in the Eylea group received 2 mg every 8 weeks through week 48, and patients in the control group could receive treatment with Eylea 2 mg, if at least one prespecified rescue criterion was met. Eylea rescue treatment consisted of a fixed regimen with 2 mg Eylea administered every 4 weeks for 3 injections, followed by intravitreal injections every 8 weeks through week 48.
Patient ages ranged from 42 to 94 years with a mean of 65 years. 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 VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the Eylea group was superior to laser control for the primary endpoint.
Change in visual acuity at week 24 compared to baseline was a secondary efficacy variable in the VIBRANT study. The difference between treatment groups was statistically significant in favour of Eylea. The course of visual improvement was rapid and maximal improvement was achieved at week 12, with subsequent stabilisation of the effect on visual acuity and central retinal thickness until week 24 and subsequent maintenance of the effect until week 52.
In the laser group 67 patients (74%) received rescue treatment with Eylea beginning at week 24. In this treatment group, visual acuity improved by about 5 letters from week 24 to 52.
Detailed results from the analysis of the VIBRANT study are shown in Table 14 and Figure 6.
The proportion of retinal perfused patients in the Eylea group at baseline was 60.4% (n = 55). At week 24, this proportion increased to 80.2% (n = 65) and was sustained at week 52 (77.9%, n = 67). The proportion of perfused patients that started on grid laser photocoagulation was 68.9% (n = 62) at baseline. Perfusion at the week 24 primary endpoint in the laser group was 67.1% (n = 55). Patients in the laser group were eligible for rescue treatment with Eylea beginning at week 24 according to prespecified criteria. At week 52, 78.0% (n = 64) were perfused at this time.
The beneficial effect of Eylea treatment on visual function was similar in the baseline groups with perfused and nonperfused patients.
Treatment effects in evaluable subgroups (e.g. age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations.
Myopic choroidal neovascularisation (myopic CNV).

Eylea 2 mg.

The safety and efficacy of Eylea 2 mg were assessed in a randomised, multicentre, double masked, sham controlled study (MYRROR) in patients with myopic CNV. A total of 121 patients were treated and evaluable for efficacy (90 with Eylea). Patients were randomly assigned in a 3:1 ratio to either 2 mg Eylea administered once at study start (with additional injections given in the case of disease persistence or reoccurrence) or sham injections. In total 6 injections was possible until the week 24 primary endpoint assessment in the study.
After the first 6 months, patients initially randomised to sham were eligible to receive the first dose of Eylea at week 24. Following this, patients in this former sham arm and also patients in the arm initially randomised to active treatment continued to be eligible for additional injections in case of disease persistence or recurrence.
Patient ages ranged from 27 to 83 years with a mean of 58 years. 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.
The primary efficacy endpoint was the change in visual acuity at week 24 compared to baseline. The confirmatory secondary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline.
The difference between treatment groups was statistically significant in favour of Eylea for the primary and confirmatory secondary efficacy endpoints at week 24. Differences for both endpoints were maintained through week 48.
Detailed results from the analyses are shown in Table 15 and Figure 7.
Treatment effects in all evaluable subgroups were in general, consistent with the results in the overall populations.

5.2 Pharmacokinetic Properties

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.

Eylea 2 mg.

In a pharmacokinetic substudy with frequent sampling in patients with wet AMD, 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 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.
These pharmacokinetic results were consistent in pharmacokinetic substudies in patients with CRVO, BRVO, DME or myopic CNV, with mean Cmax of free aflibercept in plasma 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. See Table 16.
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. 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. Therefore, systemic pharmacodynamic effects are unlikely.

Eylea 8 mg.

As no relevant differences in pharmacokinetics between the nAMD and DME populations were observed based on a population pharmacokinetic analysis of the data, population pharmacokinetic estimated parameters are presented for the two populations combined. Following unilateral intravitreal administration of 8 mg aflibercept, the mean (SD) Cmax of free aflibercept in plasma was 0.30 (0.27) mg/L, and the median time to maximal plasma concentration in plasma was 2.89 days. The accumulation of free aflibercept in plasma following three initial monthly intravitreal doses was minimal (mean accumulation ratio 1.2); subsequently, no further accumulation was observed.

Metabolism.

As Eylea is a protein based therapeutic, no metabolism studies have been conducted.

Excretion.

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. The median time to reach non-quantifiable concentrations of free aflibercept in plasma for 8 mg administered intravitreally was 3.5 weeks.

Patients with renal/hepatic impairment.

No special studies in patients with renal impairment or hepatic impairment have been conducted with Eylea.
Population pharmacokinetic analysis revealed that systemic exposures to aflibercept in patients with mild to severe renal impairment were similar to those with normal renal function. Mild hepatic impairment had no influence on systemic exposures to aflibercept compared to patients with normal hepatic function.
Also see Section 4.2, Dosage adjustment, Patients with hepatic and/or renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been conducted on the mutagenic or clastogenic potential of aflibercept. As a large protein molecule, aflibercept is not expected to interact directly with DNA or other chromosomal material.

Carcinogenicity.

No studies have been conducted on the carcinogenic potential of aflibercept.

6 Pharmaceutical Particulars

6.1 List of Excipients

Eylea 40 mg/mL (Eylea 2 mg).

Polysorbate 20, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, sodium chloride, sucrose, water for injections.

Eylea 114.3 mg/mL (Eylea 8 mg).

Polysorbate 20, arginine hydrochloride, histidine, histidine hydrochloride monohydrate, sucrose, water for injections.

6.2 Incompatibilities

Eylea must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze). Protect from light.
Keep the vial in its carton in order to protect from light.
Keep the pre-filled syringe in its blister pack and carton in order to protect from light.

6.5 Nature and Contents of Container

Eylea is supplied in a single-use vial or pre-filled syringe.
Not all presentations are being distributed in Australia.

Eylea 40 mg/mL (Eylea 2 mg) vial.

Each carton includes a type I glass vial containing approximately 100 microL of extractable volume, with an elastomeric rubber stopper, and an 18 G filter needle.

Eylea 40 mg/mL (Eylea 2 mg) pre-filled syringe.

Each carton includes a sealed blister pack with a sterile pre-filled type I glass syringe, containing approximately 90 microL of extractable volume, sealed with an elastomeric plunger stopper and an elastomeric tip cap that is part of a closure system with Luer lock adaptor. The syringe has a pre-attached plunger rod and a finger plate.

Eylea 114.3 mg/mL (Eylea 8 mg) vial.

Eylea 8 mg is supplied in a single-use vial. Each carton includes a type I glass vial containing approximately 100 microL of extractable volume, with an elastomeric rubber stopper, and an 18 G filter needle.

Eylea 114.3 mg/mL (Eylea 8 mg) pre-filled syringe with OcuClick dosing system.

Each carton includes a sealed blister pack with a sterile pre-filled type I glass syringe containing 184 microL fill volume, sealed with an elastomeric plunger stopper and an elastomeric tip cap. The prefilled syringe comes with a customised integrated OcuClick dosing system consisting of finger flange and plunger rod.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The secondary and tertiary structures of aflibercept as well as the amino acid structure are shown.
Chemical name: Vascular endothelial growth factor receptor type VEGFR-1 (synthetic human immunoglobulin domain 2 fragment) fusion protein with vascular endothelial growth factor receptor type VEGFR-2 (synthetic human immunoglobulin domain 3 fragment) fusion protein with immunoglobulin G1 (synthetic Fc fragment), dimer. Des-432-lysine-[human vascular endothelial growth factor receptor 1-(103-204)-peptide (containing Ig-like C2-type 2 domain) fusion protein with human vascular endothelial growth factor receptor 2-(206-308)-peptide (containing Ig-like C2-type 3 domain fragment) fusion protein with human immunoglobulin G1-(227 C-terminal residues)-peptide (Fc fragment)], (211-211':214-214')-bisdisulfide dimer.
Molecular weight: 97 kDa (protein molecular weight), 115 kDa (total molecular weight).

CAS number.

862111-32-8.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes