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)

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.

**  Culture positive and culture negative endophthalmitis

*** including allergic reactions

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).

In section 5.1 Pharmacodynamic properties, the following text has been added

Retinal thickness on OCT at week 24 compared to baseline was a secondary efficacy variable in the COPERNICUS and GALILEO studies (CRVO) and the VIBRANT study (BRVO). In all three studies, the mean change in CRT from baseline to week 24 was statistically significant, favouring Eylea.

In the COPERNICUS and GALILEO studies (CRVO) the mean decrease from baseline in CRTretinal thickness on OCT 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). The decrease from baseline in retinal thickness was maintained to the end of study, week 100 in COPERNICUS, and to week 76 in GALILEO.

In the VIBRANT study (BRVO) the mean decrease from baseline in CRTretinal thickness on OCT 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 was maintained to end of study, week 100 in COPERNICUS, week 76 in GALILEO, and to week 52 in VIBRANT.

Diabetic macular oedema

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, rapid and robust response in morphology (central retinal thickness [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.

In the VIVID-DME study there were mean decreases in CRT retinal thickness on optical coherence tomography (OCT) (of -192.4 and -66.2 microns at week 52 for the Eylea 2Q8 and laser group, respectively). Likewise,Also at the 52 week time point, in the VISTA-DME study there were mean decreases in CRTretinal thickness on OCT ( of -183.1 and -73.3 microns at week 52 for the Eylea 2Q8 and laser group, respectively).

Myopic choroidal neovascularisation

Myopic choroidal neovascularisation (myopic CNV) is a frequent cause of vision loss in adults with pathologic myopia. It develops as a wound healing mechanism consequent to Bruch’s membrane ruptures and represents the most vision-threatening event in pathologic myopia.

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), 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 (-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.

The following text has been added to the same section:

Myopic choroidal neovascularisation

The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, sham-controlled study in treatment-naïve, Asian patients with myopic CNV. Patients were randomly assigned in a 3:1 ratio to receive either 2 mg Eylea intravitreally or sham injections administered once at study start with additional injections given monthly in case of disease persistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patients initially randomised to sham were eligible to receive the first dose of Eylea. Following this, patients in both groups continued to be eligible for additional injections in case of disease persistence or recurrence.

A total of 121 patients were treated and evaluable for efficacy (90 with Eylea). Their age ranged from 27 to 83 years with a mean of 58 years.

The difference between treatment groups was statistically significant in favour of Eylea for the primary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion of patients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for both endpoints were maintained through week 48.

Detailed results from the analysis of the MYRROR study are shown in Table 6 and Figure 5 below.

Table 6:             Efficacy outcomes at week 24 (primary analysis) and week 48 in MYRROR study (Full Analysis Set with LOCF^A))

^A)                LOCF: Last Observation Carried Forward

^{B)         &n}