Section 4

Addition of retinal haemorrhage as a very common side effect.

Section 6

Date of revision changed to September 2020.

Correct version of document uploaded.

Section 4

Addition of retinal haemorrhage as a very common side effect.

Section 6

Revision date changed to September 2020.

Section 4.8

Addition of retinal haemorrhage as a very common adverse event.

Section 10

Revision to September 2020.

• Reduction of text to improve readability
• Alignment with QRD template 10.01
• Update of excipient information for sodium, in line with the European Commission guideline on Excipients in the labelling and package leaflet of medicinal products for human use.
• Update of the phone number for Bayer Limited Ireland.

Throughout the document “ml” has been changed to “mL”.

Heading:

[…]

AAaflibercept

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

You will not be given Eylea::

[...]

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

[...]

Important information about some of the ingredients of Eylea

This medicine contains less than 1 mmol (23 mg) of (23 mg) of sodium (23 mg) per dosage unitee, that is to say which means it is which means it is essentially ““’sodium-free”’”.

[...]

4.         Possible side effects

[...]

Reporting of side effects

[...]

<HPRA reporting details updated>

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

5.       How to store Eylea

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton and label after EXP. The expiry date refers to the last day of that month.

• Store in a refrigerator (2°C -toto 8°C). Do not freeze.
• Prior to usage, tPrior to usage, tThe unopened vial may be stored outside the refrigerator at room temperature (at room temperature(below 25°C)) for up to 24  hours.

• Store in the original package Keep the vial in its outer cartonKeep the vial in its outer carton in order to protect from light.
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away any medicines you no longer use. These measures will help protect the environment.

6.         Contents of the pack and other information

What Eylea contains

• The active substance is: aflibercept. One vial contains 100 microlitres, equivalent to 4 mg aflibercept. One vial delivers a dose of 2 mg aflibercept in 50 microlitres.

• The other ingredients are: polysorbate 20 (E 432), sodium dihydrogen phosphate monohydrate (for pH adjustment), disodium hydrogen phosphate heptahydrate (for pH adjustment), sodium chloride, sucrose, water for injection.

[…]

Ireland

Bayer Limited

Tel: +353-(0)1-216 33002999 313 2999 313

[…]

This leaflet was last revised in 06/2020

The following information is intended for healthcare professionals only:

Each Each The vial should only be used for the treatment of a single eye.

The solution should be inspected visually for any foreign particulate matter and/or discolouration or any variation in physical appearance prior to administration. In the event of either being observed, discard the medicinal product.

Prior to usage, tPrior to usage, tThe unopened vial of Eylea of Eylea may be stored outside the refrigerator at room temperature at room temperature ((below 25° C)) for up to 24 hours. After opening the vial, proceed under aseptic conditions.

For the intravitreal injection, a 30 G x ½ inch injection needle should be used.

• Reduction of text to improve readability
• Alignment with QRD template 10.01
• Update of excipient information for sodium, in line with the European Commission guideline on Excipients in the labelling and package leaflet of medicinal products for human use.
• Update of the phone number for Bayer Limited Ireland.

Throughout the document “ml” has been changed to “mL”.

4.2       Posology and method of administration

[….]

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

[….]

4.4     Special warnings and precautions for use

[….]

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

[….]

[….]

Information about excipients

This medicine contains less than 1 mmol  sodium (23 mg) per dosage unit, that is to say essentially ’sodium-free’.

[….]

4.8       Undesirable effects

<HPRA reporting details updated>

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

5.1     Pharmacodynamic properties

[….]

Clinical efficacy and safety

[….]

At the last visit   up to week 52, 56. 8% and 57.8% 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

[….]

6.1     List of excipients

Polysorbate 20 (E 432)

Sodium dihydrogen phosphate, monohydrate (for pH adjustment)

Disodium hydrogen phosphate, heptahydrate (for pH adjustment)

Sodium chloride

Sucrose

Water for injections

6.4       Special precautions for storage

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original packageKeep the vial in the outer carton in order to protect from light.

Prior to usage, tThe unopened vial of Eylea may be stored outside the refrigerator at room temperature (below 25°C) for up to 24 hours. After opening the vial, proceed under aseptic conditions.

10.     DATE OF REVISION OF THE TEXT

June 2020

Update of section 5.1 of the SmPC in order to reflect the final results from ALTAIR (SN17668) study; this is a randomized, open-label phase 4 study evaluating the efficacy and safety of repeated doses of intravitreal aflibercept with variable treatment intervals in Japanese subjects with neovascular age-related macular degeneration. In addition, the Marketing authorisation holder (MAH) took the opportunity to include minor editorial changes in section 5.1 of the SmPC.

Addition of Malta to reporting of side effects

In Section 4.2 - The posology for neovascular (wet) age-related macular degeneration (AMD) has been updated and the treatment duration extended.

In the section "Method of Administration" - Addition of "Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection.

In section 5.1 - Addition of: The ALTAIR study was conducted in Japanese patients with treatment naïve wet AMD, showing similar outcomes to the VIEW studies using 3 initial monthly Eylea 2 mg injections, followed by one injection after a further 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 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.

......

ALTAIR is a multicentre, randomised, open-label study in 247 Japanese patients with treatment naïve 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 monthly doses of Eylea 2 mg for 3 months, 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. At the last visit prior to week 52, 56.7% and 57.8% of patients in the 2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 12 weeks or more. Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2.

In the section "Information for Healthcare Professionals", addition of: "Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection. "

Posology

wet AMD

After the first 12 months of treatment with Eylea, and based on 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 increased to maintain  stable visual and/or anatomic outcomes;however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

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

Under: Diabetic macular oedema

After the first 12 months of treatment with Eylea, and based on 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 increased to maintain  stable visual and/or anatomic outcomes; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

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

Under: Paediatric population

The safety and efficacy of Eylea have not been established in children and adolescents. There is no relevant use of Eylea in the paediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV -was inserted.

Under: Method of administration

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

In Section: 4.8 Undesirable effects

Description of selected adverse reactions

Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors.

A low incidence rate of arterial thromboembolic events was observed in the Eylea clinical trials in patients with AMD, DME, RVO and myopic CNV. Across indications no notable difference between the groups treated with aflibercept and the respective comparator groups were observed -was inserted.

ATEs, as defined by Antiplatelet Trialists’ Collaboration (APTC) criteria, include nonfatal myocardial infarction, nonfatal stroke, or vascular death (including deaths of unknown cause).
The incidence of ATEs in the phase III wet AMD studies during the 96 weeks study duration was 3.3% (60 out of 1,824) in the combined group of patients treated with Eylea compared to 3.2% (19 out of 595) in patients treated with ranibizumab (see section 5.1) The corresponding numbers in the DME studies during the first 100 weeks were 6.4% (37 out of 578) (Eylea) and 4.2% (12 out of 287) (control group) (see section 5.1).
The incidence of ATEs in the phase III CRVO studies 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 (see section 5.1) whilst for the Phase III BRVO study during the 52 weeks study duration it was 0% (0 out of 91) in patients treated with Eylea compared with 2.2% (2 out of 92) in the control group (see section 5.1). One of these patients in the control group had received Eylea rescue treatment.
The incidence of ATEs in the myopic CNV study during the 48 weeks study duration was 1.1% (1 out of 91) (Eylea) compared to 0% (0 out of 31) (control group). -was deleted.

Under:  5.1     Pharmacodynamic properties

In patients treated with 6 consecutive monthly injections of Eylea 2mg, there was a consistent, rapid and robust morphologic response (as measured by improvements in mean CRT) observed. At week 24, the reduction in CRT was statistically superior versus control in all three studies (COPERNICUS in CRVO: -457 vs. -145 microns; GALILEO in CRVO: -449 vs. -169 microns; VIBRANT in BRVO: -280 vs. -128 microns) -was inserted.

In the COPERNICUS and GALILEO studies (CRVO) the mean decrease from baseline in CRT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-457 microns vs. -145 microns in COPERNICUS, and -449 microns vs. -169 microns in GALILEO).
In the VIBRANT study (BRVO) the mean decrease from baseline in CRT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-280 microns vs. -128 microns). This decrease from baseline in CRT was maintained to the end of each study, week 100 in COPERNICUS, week 76 in GALILEO, and week 52 in VIBRANT. -was deleted.

In patients treated with Eylea in the MYRROR study (one injection given at start of therapy, with additional injections given in case of disease persistence or recurrence), CRT decreased soon after treatment initiation favouring Eylea at week 24 (-79 microns and -4 microns for the Eylea 2 mg treatment group and the control group, respectively), which was maintained through week 48. In addition, the mean CNV lesion size decreased.The mean change in CRT from baseline to week 24 was statistically significant favouring Eylea (-79 microns and -4 microns for the Eylea 2 mg treatment group and the control group, respectively). The decrease from baseline in retinal thickness in the Eylea 2 mg group was maintained through week 48.-was deleted.

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD(VIEW 1 and VIEW 2) with a. A total of 2,412 patients were treated and evaluable for efficacy (1,817 with Eylea) in the two studies (VIEW1 and VIEW2). Patient ages ranged from 49 to 99 years with a mean of 76 years. In these clinical studies, approximately 89% (1,616/1,817) of the patients randomised to treatment with Eylea were 65 years of age or older and approximately 63% (1,139/1,817) were 75 years of age or older. In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: -was deleted.

Figure 4:          Mean change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52100 in VIVID^DME and VISTA^DME Studies

The VISTA^DME second year outcomes are in line with the results from the primary and secondary endpoints obtained at week 52.

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 VIVID^DME and VISTA^DME studies, 36 (9%) and 197 (43%) 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 naïve prior to study participation.

Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if determined to be necessary by the physician. In the VISTA^DME study, 198 217(6570.7%) of Eylea patients received bilateral Eylea injections until week 100; in the VIVID^DME study, 70 97(2635.8%) of Eylea patients received a different anti-VEGF treatment in their fellow eye.

Elderly population

In the DME phase III studies, 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.

…

5.2     Pharmacokinetic properties

…

Absorption / Distribution

…

In a pharmacokinetic sub-study in 6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic C_max) were low, with a mean of approximately 0.02 microgram/ml (range 0 to 0.054) within 1 to 3 days after a 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.

…

10.     DATE OF REVISION OF THE TEXT

110/2015

In section 4.1 Therapeutic indications, the following bullet point has been added:

Visual impairment due to myopic choroidal neovascularisation (myopic CNV) (see section 5.1).

In section 4.2 Posology and method of administration, the following text has been added:

Myopic choroidal neovascularisation

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

Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease.

The schedule for monitoring should be determined by the treating physician.

The interval between two doses should not be shorter than one month.

In the same section, myopic CNV has been added:

There is no relevant use of Eylea in the paediatric population in the indications wet AMD, CRVO, BRVO, and DME and myopic CNV

In section 4.3 Contraindications, the following text has been altered to include:

There are limited data on safety in the treatment of patients with CRVO, BRVO, or DME or myopic CNV

As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, and DME and myopic CNV the following also applies:

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.

In section 4.8 Undesirable effects, the following text has been added:

A total of 2,957 3,073 patients constituted the safety population in the seven eight phase III studies. Among those, 2,356 2,472 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 2,200 intravitreal injections with Eylea and included blindness, endophthalmitis, retinal detachment, cataract traumatic, vitreous haemorrhage, cataract, vitreous detachment, and intraocular pressure increased (see section 4.4).

The most frequently observed adverse reactions (in at least 5% of patients treated with Eylea) were conjunctival haemorrhage (24.924%), visual acuity reduced (10.710%), eye pain (9.910%), intraocular pressure increased (7.17%), vitreous detachment (6.87%), vitreous floaters (6.66%) and cataract (6.66%).

Tabulated list of adverse reactions

The safety data described below include all adverse reactions from the seven eight phase III studies in the indications wet AMD, CRVO, BRVO, and DME and myopic CNV with a reasonable possibility of causality to the injection procedure or medicinal product.

 Table 1: All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications  wet AMD, CRVO, BRVO, and DME and myopic CNV)