Эйлеа

Эйлеа is indicated for adults for the treatment of

- neovascular (wet) age-related macular degeneration (AMD) ,

- visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO) ,

- visual impairment due to diabetic macular oedema (DME) ,

- visual impairment due to myopic choroidal neovascularisation (myopic CNV).

Эйлеа is for intravitreal injection only.

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

Posology

wet AMD

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

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

After the first 12 months of treatment with Эйлеа, 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.

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

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

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

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

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

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

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

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

Diabetic macular oedema

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

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

After the first 12 months of treatment with Эйлеа, 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.

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

Myopic choroidal neovascularisation

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

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

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

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

Special populations

Hepatic and/or renal impairment

No specific studies in patients with hepatic and/or renal impairment have been conducted with Эйлеа.

Available data do not suggest a need for a dose adjustment with Эйлеа in these patients.

Elderly population

No special considerations are needed. There is limited experience in patients older than 75 years with DME.

Paediatric population

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

Method of administration

Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. In general, adequate anaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine applied to the periocular skin, eyelid and ocular surface), have to be ensured. Surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, sterile equipment for paracentesis should be available.

Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g. eye pain, redness of the eye, photophobia, blurring of vision) without delay.

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

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

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

After injection any unused product must be discarded.

Active or suspected ocular or periocular infection.

Active severe intraocular inflammation.

Intravitreal injection-related reactions

Intravitreal injections, including those with Эйлеа, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Proper aseptic injection techniques must always be used when administering Эйлеа. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay.

Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including those with Эйлеа. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Эйлеа while the intraocular pressure is > 30 mmHg). In all cases, both the intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with Эйлеа. Patients should be instructed to report any signs or symptoms of intraocular inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign attributable to hypersensitivity.

Systemic effects

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with CRVO, BRVO, DME or myopic CNV with a history of stroke or transient ischaemic attacks or myocardial infarction within the last 6 months. Caution should be exercised when treating such patients.

Other

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

- The safety and efficacy of Эйлеа therapy administered to both eyes concurrently have not been systematically studied. If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events.

- Concomitant use of other anti-VEGF (vascular endothelial growth factor)

- There is no data available on the concomitant use of Эйлеа with other anti-VEGF medicinal products (systemic or ocular).

- Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinal detachment. When initiating Эйлеа therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

- Treatment should be withheld in patients with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

- In the event of a retinal break the dose should be withheld and treatment should not be resumed until the break is adequately repaired.

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

â–ª a decrease in best-corrected visual acuity (BCVA) of >30 letters compared with the last assessment of visual acuity;

â–ª a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is >50%, of the total lesion area.

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

- Эйлеа should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus.

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

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

Populations with limited data

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

Эйлеа 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 Эйлеа in diabetic patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

In myopic CNV there is no experience with Эйлеа in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.

Injection with Эйлеа has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances associated either with the injection or the eye examination. Patients should not drive or use machines until their visual function has recovered sufficiently.

Summary of the safety profile

A total of 3,102 patients constituted the safety population in the eight phase III studies. Among those, 2,501 patients were treated with the recommended dose of 2 mg.

Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in less than 1 in 1,900 intravitreal injections with Эйлеа and included blindness, endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, and intraocular pressure increased.

The most frequently observed adverse reactions (in at least 5% of patients treated with Эйлеа) were conjunctival haemorrhage (25%), visual acuity reduced (11%), eye pain (10%), cataract (8%), intraocular pressure increased (8%), vitreous detachment (7%), and vitreous floaters (7%).

Tabulated list of adverse reactions

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

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)

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

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, DME and myopic CNV) or during post-marketing surveillance

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

** Culture positive and culture negative endophthalmitis

*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases of severe anaphylactic/anaphylactoid reactions.

Description of selected adverse reactions

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 Эйлеа.

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 Эйлеа 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.

As with all therapeutic proteins, there is a potential for immunogenicity with Эйлеа.

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

In clinical trials, doses of up to 4 mg in monthly intervals have been used and isolated cases of overdoses with 8 mg occurred.

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.

Pharmacotherapeutic group: Ophthalmologicals / Antineovascularisation agents

ATC code: S01LA05

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.

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.

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 leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can synergize with VEGF-A in these processes, and is also known to promote leucocyte infiltration and vascular inflammation.

Pharmacodynamic effects

wet AMD

Wet AMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or sub-/intra-retinal haemorrhage, resulting in loss of visual acuity.

In patients treated with Эйлеа (one injection per month for three consecutive months, followed by one injection every 2 months), central retinal thickness [CRT] 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 the VIEW1 study there were mean decreases in CRT on optical coherence tomography (OCT) (-130 and -129 microns at week 52 for the Эйлеа 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively). Also at the 52 week time point, in the VIEW2 study there were mean decreases in CRT on OCT (-149 and -139 microns for the Эйлеа 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively).

The reduction of CNV size and reduction in CRT were generally maintained in the second year of the studies.

Macular oedema secondary to CRVO and BRVO

In CRVO and 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, increased vascular permeability, retinal oedema, and neovascularisation complications.

In patients treated with 6 consecutive monthly injections of Эйлеа 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).

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.

Diabetic macular oedema

Diabetic macular oedema is a consequence of diabetic retinopathy and is characterised by increased vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.

In patients treated with Эйлеа, the majority of whom were classified as having Type II diabetes, a rapid and robust response in morphology (CRT, DRSS level) was observed.

In the VIVID^DME and the VISTA^DME studies, a statistically significant greater mean decrease in CRT from baseline to week 52 was observed in patients treated with Эйлеа than with the laser control, -192.4 and -183.1 microns for the 2Q8 Эйлеа groups and -66.2 and -73.3 microns for the control groups, respectively. At week 100 the decrease was maintained with -195.8 and -191.1 microns for the 2Q8 Эйлеа groups and -85.7 and -83.9 microns for the control groups, in the VIVID^DME and VISTA^DME studies, respectively.

A > 2 step improvement in DRSS was assessed in a pre-specified manner in VIVID^DME and VISTA^DME. The DRSS score was gradable in 73.7% of the patients in VIVID-^DME and 98.3% of the patients in VISTA^DME. At week 52, 27.7% and 29.1% of the Эйлеа 2Q8 groups, and 7.5% and 14.3% of the control groups experienced a >2 step improvement in the DRSS. At week 100, the respective percentages were 32.6% and 37.1% of the Эйлеа 2Q8 groups and 8.2% and 15.6% of the control groups.

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 Эйлеа 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 Эйлеа at week 24 (-79 microns and -4 microns for the Эйлеа 2 mg treatment group and the control group, respectively), which was maintained through week 48. In addition, the mean CNV lesion size decreased.

Clinical efficacy and safety

wet AMD

The safety and efficacy of Эйлеа were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD (VIEW1 and VIEW2) with a total of 2,412 patients treated and evaluable for efficacy (1,817 with Эйлеа). 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 Эйлеа 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:

1) Эйлеа administered at 2 mg every 8 weeks following 3 initial monthly doses (Эйлеа 2Q8);

2) Эйлеа administered at 2 mg every 4 weeks (Эйлеа 2Q4);

3) Эйлеа administered at 0.5 mg every 4 weeks (Эйлеа 0.5Q4); and

4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).

In the second year of the studies, patients continued to receive the initially randomised dosage but on a modified dosing schedule guided by assessment of visual and anatomic outcomes with a protocol-defined maximum dosing interval of 12 weeks.

In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Set who maintained vision, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline.

In the VIEW1 study, at week 52, 95.1% of patients in the Эйлеа 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% of patients in the Эйлеа 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In both studies Эйлеа was shown to be non-inferior and clinically equivalent to the ranibizumab 0.5Q4 group.

Detailed results from the combined analysis of both studies are shown in Table 2 and Figure 1 below.

Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined data from the VIEW1 and VIEW2 studies^B)

^A) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LS: Least square means derived from ANCOVA

PPS: Per Protocol Set

^B) Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) for all analyses except proportion of patients with maintained visual acuity at week 52 which is PPS

^C) The difference is the value of the Эйлеа group minus the value of the ranibizumab group. A positive value favours Эйлеа.

^D) Confidence interval (CI) calculated by normal approximation

^E) After treatment initiation with three monthly doses

^F) A confidence interval lying entirely above -10% indicates a non-inferiority of Эйлеа to ranibizumab

Figure 1. Mean Change in Visual Acuity from Baseline to Week 96 for the Combined Data from the View1 and View2 Studies

In combined data analysis of VIEW1 and VIEW2 Эйлеа demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

In the second year of the studies, efficacy was generally maintained through the last assessment at week 96, and 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month.

Decreases in mean CNV area were evident in all dose groups in both studies.

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.

Macular oedema secondary to CRVO

The safety and efficacy of Эйлеа were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO (COPERNICUS and GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with Эйлеа). Patient ages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with Эйлеа were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Эйлеа administered every 4 weeks (2Q4), or the control group receiving sham injections every 4 weeks for a total of 6 injections.

After 6 consecutive monthly injections, patients received treatment only if they met pre-specified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. From this timepoint all patients were treated if pre-specified criteria were met.

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. A secondary efficacy variable was change in visual acuity at week 24 compared to baseline.

The difference between treatment groups was statistically significant in favour of Эйлеа in both studies. The maximal improvement in visual acuity was achieved at month 3 with subsequent stabilisation of visual acuity and CRT until month 6. The statistically significant difference was maintained through week 52.

Detailed results from the analysis of both studies are shown in Table 3 and Figure 2 below.

Table 3: Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCF^C)) in COPERNICUS and GALILEO studies

^A) Difference is Эйлеа 2 mg Q4 weeks minus control

^B) Difference and confidence interval (CI) are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

^C) BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

LOCF: Last Observation Carried Forward

SD: Standard deviation

LS: Least square means derived from ANCOVA

^D) LS mean difference and confidence interval based on an ANCOVA model with factors treatment group, region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

^E) In COPERNICUS study, control group patients could receive Эйлеа on an as-needed basis as frequently as every 4 weeks during week 24 to week 52; patients had visits every 4 weeks.

^F) In COPERNICUS study, both control group and Эйлеа 2mg patients received Эйлеа 2 mg on an as-needed basis as frequently as every 4 weeks starting from week 52 to week 96; patients had mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary.

^G) In GALILEO study, both control group and Эйлеа 2mg patients received Эйлеа 2 mg on an as-needed basis every 8 weeks starting from week 52 to week 68; patients had mandatory visits every 8 weeks.

Figure 2: Mean Change from Baseline to Week 76/100 in Visual Acuity by Treatment Group for the COPERNICUS and GALILEO Studies (Full Analysis Set)

In GALILEO, 86.4% (n=89) of the Эйлеа group and 79.4% (n=54) of the sham group had perfused CRVO at baseline. At week 24, this was 91.8% (n=89) in the Эйлеа group and 85.5% (n=47) in the sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the Эйлеа group and 84.0% (n=42) in the sham group.

In COPERNICUS, 67.5% (n = 77) of the Эйлеа group and 68.5% (n = 50) of the sham group had perfused CRVO at baseline. At week 24, this was 87.4% (n = 90) in the Эйлеа group and 58.6% (n = 34) in the sham group. These proportions were maintained at week 100 with 76.8 % (n = 76) in the Эйлеа group and 78% (n = 39) in the sham group. Patients in the sham group were eligible to receive Эйлеа from week 24.

The beneficial effect of Эйлеа treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g. age, gender, race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results in the overall populations.

In combined data analysis of GALILEO and COPERNICUS, Эйлеа demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

Macular oedema secondary to BRVO

The safety and efficacy of Эйлеа were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) which included Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with Эйлеа). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with Эйлеа were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg Эйлеа administered every 8 weeks following 6 initial monthly 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 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients in the laser group could receive rescue treatment with Эйлеа 2mg from week 24, administered every 4 weeks for 3 months followed by every 8 weeks.

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 and the Эйлеа group was superior to laser control.

A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, which was statistically significant in favour of Эйлеа in the VIBRANT study. The course of visual improvement was rapid and peaked at 3 months with maintenance of the effect until month 12.

In the laser group 67 patients received rescue treatment with Эйлеа beginning at week 24 (Active Control/ Эйлеа 2mg group), which resulted in improvement of visual acuity by about 5 letters from week 24 to 52.

Detailed results from the analysis of the VIBRANT study are shown in Table 4 and Figure 3 below.

Table 4: Efficacy outcomes at week 24 and week 52 (Full Analysis Set with LOCF) in VIBRANT study

^A) Difference is Эйлеа 2 mg Q4 weeks minus Laser Control

^B) Difference and 95% CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200)

^C) LS mean difference and 95% CI based on an ANCOVA model with treatment group, baseline BCVA category (> 20/200 and ≤ 20/200) and region (North America vs. Japan) as fixed effects, and baseline BCVA as covariate

^D) From week 24 on the treatment interval in the Эйлеа treatment group was extended for all subjects from 4 weeks to 8 weeks through week 48.

^E) Beginning at week 24 subjects in the Laser Group could receive rescue treatment with Эйлеа, if they met at least one pre-specified eligibility criterion. At total of 67 subjects in this group received Эйлеа rescue treatment. The fixed regimen for Эйлеа rescue was three times Эйлеа 2mg every 4 weeks followed by injections every 8 weeks.

^F) Nominal p-value

Figure 3: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in VIBRANT Study

At baseline, the proportion of perfused patients in the Эйлеа and laser groups was 60% and 68%, respectively. At week 24 these proportions were 80% and 67%, respectively. In the Эйлеа group the proportion of perfused patients was maintained through week 52. In the laser group, where patients were eligible for rescue treatment with Эйлеа from week 24, the proportion of perfused patients increased to 78% by week 52.

Diabetic macular oedema

The safety and efficacy of Эйлеа were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME (VIVID^DME and VISTA^DME). A total of 862 patients were treated and evaluable for efficacy, 576 with Эйлеа. Patient ages ranged from 23 to 87 years with a mean of 63 years. In the DME studies, approximately 47% (268/576) of the patients randomised to treatment with Эйлеа were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. The majority of patients in both studies had Type II diabetes.

In both studies, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens:

1) Эйлеа administered 2 mg every 8 weeks following 5 initial monthly injections (Эйлеа 2Q8);

2) Эйлеа administered 2 mg every 4 weeks (Эйлеа 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 Эйлеа groups could receive laser and patients in the control group could receive Эйлеа.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 and both Эйлеа 2Q8 and Эйлеа 2Q4 groups demonstrated statistical significance and were superior to the control group. This

Эйлеа is administered directly into the vitreous to exert local effects in the eye.

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.

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.

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, in which blood pressure changes were observed after circulating levels of free aflibercept attained approximately 10 microgram/ml and returned to baseline when levels fell below approximately 1 microgram/ml. 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 (2.91 microgram/ml) in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely.

In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean C_max of free aflibercept in plasma were similar with values 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.

Elimination

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

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.

Renal impairment

No special studies in patients with renal impairment have been conducted with Эйлеа.

Pharmacokinetic analysis of patients in the VIEW2 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, in patients with DME in the VIVID^DME study, and in patients with myopic CNV in the MYRROR study.

Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures considered substantially in excess of the maximum human exposure after intravitreal administration at the intended clinical dose indicating little relevance to clinical use.

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at systemic exposures in excess of the maximum human exposure. The systemic exposure based on C_max and AUC for free aflibercept were approximately 200- and 700-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold higher based on C_max and AUC, respectively.

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

An effect of aflibercept on intrauterine development was shown in embryo-foetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on C_max and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg.

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. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. Based on C_max and AUC for free aflibercept observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4,900-fold and 1,500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

The vial is for single use in one eye only.

Since the vial contains more volume (100 microlitres) than the recommended dose (50 microlitres), a part of the volume contained in the vial has to be discarded prior to the administration.

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.

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

Instructions for use of vial: