Eylea 40 mg/mL solution for injection in pre-filled syringe

PIL File name updated.

PIL File name updated.

PIL File name updated.

Information for guardians of babies born prematurely has been added.

PSUSA/00010020/202211 (REC31695, 31108, 31718)

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2.             What you need to know before you are given Eylea

Pregnancy and breast-feeding

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-         Small amounts of Eylea may pass into human milk. The effects on breast-fed newborns/infants are unknown. Eylea is not recommended during breast-feeding. If you are a breastfeeding woman, discuss this with your doctor before treatment with Eylea. Eylea is not recommended during breast-feeding as it is not known whether Eylea passes into human milk. Ask your doctor for advice before starting Eylea treatment.

6.           Contents of the pack and other information

This leaflet was last revised in 09/2023

PSUSA/00010020/202211 (REC31695, 31108, 31718)

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4.6      Fertility, pregnancy and lactation

Breast-feeding

Based on very limited human data, aflibercept may be excreted in human milk at low levels. Aflibercept is a large protein molecule and the amount of medication absorbed by the infant is expected to be minimal. The effects of aflibercept on a breast-fed newborn/infant are unknown.

As a precautionary measure, breast-feeding is not recommended during the use of Eylea.

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

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

10.      DATE OF REVISION OF THE TEXT

September 2023

Correction (relating to REC20818+20826+ 20947_Var 77)

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REC20818+20826+ 20947_Var 77

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PIL uploaded again to include Summary of Changes:

REC20818+20826+20947_Var 77

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REC20818+20826+20947_Var 77

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REC 30424

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4.2      Posology and method of administration

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Diabetic macular oedema

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

BAfter the first 12 months of treatment with Eylea, and based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may be maintained at 2 months or individualizedextended, such as with a treat-and-extend dosing regimen, where the treatment intervals are usually increased by 2-week increments to maintain stable visual and/or anatomic outcomes. There are limited data for treatment intervals longer than 4 months. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. Treatment intervals shorter than 4 weeks have not been studied (see section 5.1).

The schedule for monitoring should therefore be determined by the treating physician. and may be more frequent than the schedule of injections.

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

Treatment intervals shorter than 4 weeks between injections have not been studied (see section 5.1).

[….]

Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubbles along with excess medicinal product, 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 0.05 mL, i.e. 2 mg aflibercept) (see sections 4.9 and 6.6).

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5.1    Pharmacodynamic properties

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Diabetic macular oedema

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An independent comparative trial (DRCR.net Protocol T) utilised a flexible dosing regimen based on strict OCT and vision re-treatment criteria.

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Ocular and systemic safety profiles (including ATEs) were similar to VIVID^DME and VISTA^DME. 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.

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The changes in BCVA from baseline to week 100 were consistent with the week 52 results: -0.1 ± 9.1 letters in the 2T&E group and 1.8 ± 9.0 letters in the 2PRN group compared to 0.4 ± 6.7 0.1 ± 7.2 letters in the 2Q8 group.

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6.5    Nature and contents of container

Solution in pre-filled syringe (type I glass) marked with a black dosing line, with a plunger stopper (elastomeric rubber) and a Luer lock adaptor with a tip cap (elastomeric rubber).

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6.6    Special precautions for disposal and other handling

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Instructions for use of pre-filled syringe:

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7. Eliminate all bubbles and expel excess medicinal product 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 (equivalent to 0.05 mL, i.e. 2 mg aflibercept).

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10 Date of revision of the text

November 2022

REC 30424

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3. How you will be given Eylea

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Diabetic macular oedema (DME)

Patients with DME will be treated with one injection per month for the first five consecutive doses followed by one injection every two months thereafter. Unless you experience any problems or are advised differently by your doctor, there is no need for you to see your doctor between the injections.

After the first 12 months of treatment with Eylea, the tTreatment interval may be kept at every two months or adjusted to your condition, extended based on your doctor’s examination. Your doctor will decide on the schedule for follow up examinations.

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6. Contents of the pack and other information

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This leaflet was last revised in 11/2022

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The following information is intended for healthcare professionals only:

Instructions for use of pre-filled syringe:

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7. Eliminate all bubbles and expel excess medicinal product 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 (equivalent to 0.05 mL, i.e. 2 mg aflibercept).

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BEC15506

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Section 4:

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects, you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Section 6: Contents of the pack and other information

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Ireland

Bayer Limited

Tel: +353-(0)1-216 3300

Malta

Alfred Gera and Sons Ltd.

Tel: +356‑21 44 62 05

United Kingdom (Northern Ireland)

Bayer AG

Tel: +44-(0) 118 206 3000

This leaflet was last revised in 02/2022

BEC15506

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Section 4.8:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Section 10. DATE OF REVISION OF THE TEXT

02/2022

(BEC18625)

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2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

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One pre-filled syringe contains an extractable volume of at least 0.09 mL90 microlitres, equivalent to at least 3.6 mg aflibercept. This provides a usable amount to deliver a single dose of 50 microlitres0.05 mL containing 2 mg aflibercept.

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4.2       Posology and method of administration

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Posology

wet AMD

The recommended dose for Eylea is 2 mg aflibercept, equivalent to 0.05 mL50 microlitres.

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

The recommended dose for Eylea is 2 mg aflibercept equivalent to 0.05 mL50 microlitres. 

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Diabetic macular oedema

The recommended dose for Eylea is 2 mg aflibercept equivalent to 0.05 mL50 microlitres.

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Myopic choroidal neovascularisation

The recommended dose for Eylea is a single intravitreal injection of 2 mg aflibercept equivalent to 0.05 mL50 microlitres.

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Method of administration

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The pre-filled syringe contains more than the recommended dose of 2  mg aflibercept (equivalent to 0.05 mL solution for injection). The extractable volume of the syringe (90 microlitres) is not to be used in totalis the amount that can be expelled from the syringe and is not to be used in total. For the Eylea pre-filled syringe, the extractable volume is at least 0.09 mL. The excess volume mustshould be expelled before injecting the recommended dose (see section 6.6).

Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubbles along with excess medicinal product, slowly depress the plunger to align the cylindrical base of the plunger dome (not the tip of the dome)plunger with the black dosing line on the syringe (equivalent to 50 microlitres0.05 mL i.e. 2 mg aflibercept) (see sections 4.9 and 6.6).

4.4     Special warnings and precautions for use

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Intravitreal injection-related reactions

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The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). The excess volume must be expelled prior to administration (see sections 4.2 and 6.6).

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4.9       Overdose

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

6.5     Nature and contents of container

90 microlitres of sSolution in pre-filled syringe (type I glass) marked with a black dosing line, with a plunger stopper (elastomeric rubber) and a Luer lock adaptor with a tip cap (elastomeric rubber). Each pre-filled syringe contains an extractable volume of at least 0.09 mL. Pack size of 1 pre-filled syringe.

6.6     Special precautions for disposal and other handling

The pre-filled syringe is for single use in one eye only.

Do not open the sterile pre-filled syringe blister outside the clean administration room.

Since the pre-filled syringe contains more volume (90 microlitres) than the recommended dose (50 microlitres), a part of the volume contained in the syringe has to be discarded prior to the administration.The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). The excess volume must be discarded prior to administration.

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Instructions for use of pre-filled syringe:

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7. Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger rod to align the cylindrical base of the plunger dome (not the tip of the dome)edge with the black dosing line on the syringe (equivalent to 50 microlitres0.05 mL i.e. 2 mg aflibercept).

Note: This accurate positioning of the plunger is very important, because incorrect plunger positioning can lead to delivering more or less than the labelled dose.

(The 2 images under point 7 were updated: "Plunger Dome Edge" replaced with "Base of the Plunger Dome”)

8. Inject while 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.

8. 9.The pre-filled syringe is for single use only. Extraction of multiple doses from a pre-filled syringe may increase the risk of contamination and subsequent infection.

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

10. DATE OF REVISION OF THE TEXT

June 2021 07/2021

(BEC18625)

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3. How you will be given Eylea

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The recommended dose is 2 mg aflibercept (0.05 mL50 microlitres).

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6.         Contents of the pack and other information

What Eylea contains

• The active substance is: aflibercept. One pre-filled syringe contains an extractable volume of at least 0.09 mL90 microlitres, equivalent to at least 3.6 mg aflibercept. One pre-filled syringe delivers a dose of 2 mg aflibercept in 0.05 mL50 microlitres.

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What Eylea looks like and contents of the pack

Eylea is a solution for injection (injection) in a pre-filled syringe (3.6 mg/90 microlitres). The solution is colourless to pale yellow.

Pack size of 1 pre-filled syringe.

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This leaflet was last revised in 01/202107/2021

The following information is intended for healthcare professionals only:

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

Do not open the sterile pre-filled syringe blister outside the clean administration room.

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). The excess volume must be discarded prior to administration.

[…]

Instructions for use of pre-filled syringe:

[…]

7. Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger rod to align the cylindrical base of the plunger dome (not the tip of the dome)edge with the black dosing line on the syringe (equivalent to 50 microlitres0.05 mL i.e. 2 mg aflibercept).

Note: This accurate positioning of the plunger is very important, because incorrect plunger positioning can lead to delivering more or less than the labelled dose

(The 2 images under point 7 were updated: "Plunger Dome Edge" replaced with "Base of the Plunger Dome”)

8. Inject while 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.

8. 9.The pre-filled syringe is for single use only. Extraction of multiple doses from a pre-filled syringe may increase the risk of contamination and subsequent infection.

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

BEC18548 (v0069)

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4.2 Posology and method of administration

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After the first 12 months of treatment with Eylea, and based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually usually increased by 2-week increments to maintain stable visual and/or anatomic outcomes. There are limited data for treatment intervals longer than 4 months.; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections.

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

Treatment intervals shorter than 4 weeks between injections have not been studied (see section 5.1).

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5.1 Pharmacodynamic properties

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The VIOLET study compared three different dosing 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. At week 52 and week 100 of the study, i.e. second and third year of treatment, the mean changes in CRT were clinically similar for treat-and-extend (2T&E), pro re nata (2PRN) and 2Q8, respectively, -2.1, 2.2 and -18.8 microns at week 52, and 2.3,

-13.9 and -15.5 microns at week 100.

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VIOLET, a 100-week multicentre, randomised, open-label, active controlled study in patients with DME compared three different dosing 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 (2T&E where injections intervals were kept at a minimum of 8 weeks and gradually extended based onclinical and anatomical outcomes) 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) for the second and third year of treatment.

The primary efficacy endpoint (change in BCVA from baseline to week 52) was 0.5 ± 6.7 letters in the 2T&E 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 (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 2T&E group and 1.8 ± 9.0 letters in the 2PRN group compared to 0.4 ± 6.7 letters in the 2Q8 group. The mean number of injections over 100 weeks were 12.3, 10.0 and 11.5 for 2Q8fix, 2T&E and 2PRN, respectively.

Ocular and systemic safety profiles in all 3 treatment groups were similar to those observed in the pivotal studies VIVID and VISTA.

In the 2T&E group, the increments and decrements for the injection intervals were at the investigator’s discretion; increments of 2 weeks were recommended in the study.

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Section 10 Date of revision of the text

June 2021

Reason for Change

• To introduce ARIES data in the Eylea pre filled syringe PIL (section 3) to allow a more frequent than Q8 treatment for the wAMD indication for a sub-group of patients that might need it.

3. How you will be given Eylea

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wet AMD

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If your condition worsens, the interval between injections can be shortened, but to not less than every two months in the first year of treatment.

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6. Contents of the pack and other information

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This leaflet was last revised in 01/2021

Reason for Change

• To introduce ARIES data in the Eylea pre-filled syringe SmPC (section 4.2 and 5.1) to allow a more frequent than Q8 treatment for the wAMD indication for a sub-group of patients that might need it.

4.2 Posology and method of administration

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Posology

wet AMD

[…]

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly to a minimum of two months during the first 12 months of treatment.

[…]

Treatment intervals greater than four months or shorter than 4 weeks between injections have not been studied (see Section 5.1).

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5.1 Pharmacodynamic properties

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Pharmacodynamic effects

wet AMD

[…]

The ARIES study was designed to explore the non-inferiority of an Eylea 2 mg treat-and-extend dosing regimen initiated immediately after administration of 3 initial monthly injections and one additional injection after 2 months vs. a treat-and-extend dosing regimen initiated after one year of treatment. For patients requiring a more frequent than Q8 dosing at least once over the course of the study, CRT remained higher, but the mean decrease in CRT from baseline to week 104 was -160.4 microns, similar to the patients treated at Q8 or less frequent intervals.

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Clinical efficacy and safety

wet AMD

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ARIES was a 104-week multicentre, randomised, open-label, active-controlled study in 269 patients with treatment naïve wet AMD, designed to assess the non-inferiority in terms of efficacy as well as the safety of a treat-and-extend dosing regimen initiated after 3 consecutive monthly doses followed by extension to a 2 monthly treatment interval vs. a treat-and-extend dosing regimen initiated after the first year of treatment.

The ARIES study also explored the percentage of patients that required more frequent treatment than every 8 weeks based on the investigator’s decision. Out of the 269 patients 62 patients received more frequent dosing at least once during the course of the study. Such patients remained in the study and received treatment according to the investigator’s best clinical judgement but not more frequently than every 4 weeks and their treatment intervals could be extended again afterwards. The average treatment interval after the decision to treat more frequently was 6.1 weeks. Week 104 BCVA was lower in patients requiring more intensive treatment at least once over the course of the study compared with patients who did not and the mean change in BCVA from baseline to end of the study was +2.3 ± 15.6 letters. Among the patients treated more frequently, 85.5% maintained vision, i.e. lost less than15 letters, and 19.4% gained 15 letters or more. The safety profile of patients treated more frequently than every 8 weeks was comparable to the safety data in VIEW 1 and VIEW 2.

[…]

10. DATE OF REVISION OF THE TEXT

January 2021