Eilea - instructions for use, dose, side effects, contraindications

Active substanceAfleiberceptAfleibercept

Similar drugsTo uncover

Zaltrap®

solution d / infusion in / in

Sanofi-Aventis France France

Eilea®

solution c / cavity

Bayer AG Germany

Dosage form: & nbspintraocular solution

Composition:

1 ml of the preparation contains:

Active substance: aflibercept 40 mg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate heptahydrate, sodium chloride, sucrose, polysorbate 20, water for injection.

One bottle contains 0.1 ml (100 μl) of the solution (extractable volume), which is equivalent to 4 mg of aflibercept. This recoverable volume of solution allows the introduction of a single dose of 2 mg of aflibercept, which is 50 μl of solution.

Description:Transparent or slightly opalescent, colorless or pale yellow liquid.

Pharmacotherapeutic group:Remedies for obstructing neoplasm of vessels

ATX: & nbsp

L.01.X.X Other antineoplastic agents

L.01.X.X.44 Afleibercept

Pharmacodynamics:

Aflicibercept is a recombinant fusion protein consisting of fragments of extracellular domains of human receptors VEGF 1 (VEGFR-1) and 2 (VEGFR-2), connected with Fc-fragment of human immunoglobulin G (IgGl).

Aflibercept is produced by K1 cells of the Chinese hamster ovary (JAX; CHO) using recombinant DNA technology.

Aflibercept acts as a soluble receptor-trap that binds VEGF-A (vascular endothelial growth factor A) and PIGF (placental growth factor) with a higher affinity than their natural receptors, and thus can inhibit the binding and activation of these related VEGF receptors.

Mechanism of action

Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PIGF) are members of the family VEGF angiogenic factors that have a powerful mitogenic, chemotactic effect on endothelial cells and increase vascular permeability. VEGF acts through two types of tyrosine kinase receptors, VEGFR-1 and VEGFR-2, represented on the surface of endothelial cells. PIGF communicates only with VEGFR-1, which are also present on the surface of leukocytes. Over-activation VEGF-And these receptors can lead to pathological neovascularization and excessive vascular permeability. In these processes PIGF can exhibit synergies with VEGF-A, and also stimulates leukocyte infiltration and vascular inflammation.

Pharmacodynamic effects

Neovascular ("wet" form) age-related macular degeneration ("wet" form of AMD)

The "wet" form of AMD is characterized by pathological neovascularization of the choroid. Seepage of blood and fluid from a pathologically neovascularized choroid can cause thickening of the central retina (CP) or edema and / or hemorrhage in the retina / subretinal space, which leads to a decrease in visual acuity.

The safety and efficacy of Eilea ® in the "wet" form of AMD was evaluated in two randomized, multicenter, double-blind, active-control studies VIEW1 and VIEW2. In these studies, 2412 patients were randomized in a ratio of 1: 1: 1: 1 to Eilea ® (1817 patients) or ranibizumab in the following regimens:

1) Eilea® 2 mg every 8 weeks after 3 initial monthly injections (Eilea® 2q8);

2) Eilea® 2 mg every 4 weeks (Eilea® 2q4);

3) Eilea® 0.5 mg every 4 weeks (Eilea® 0,5q4);

4) Ranibizumab 0.5 mg every 4 weeks (ranibizumab 0,5q4).

The study included patients aged 49 to 99 years, the average age was 76 years. About 89% of patients (1616 of 1817) randomized to Eilea® groups were 65 years of age or older, about 63% (1139 of 1817) - aged 75 years or older.

In the second year of the study, patients continued to receive the drugs at the same dose as was prescribed initially,but in the modified dosing regimen, which, according to the protocol, was based on the results of changes in visual acuity and anatomical parameters, with a maximum interval between injections of no more than 12 weeks.

In both studies, the primary endpoint of efficacy was the proportion of patients who met the protocol requirements, which maintained visual acuity, implying a loss of less than 15 letters on a scale ETDRS (Early Treatment Diabetic Retinopathy Study, Study of early treatment of diabetic retinopathy) at 52 weeks compared with baseline.

In the study VIEW1 at the 52nd week achieved improvement in visual acuity 95.1% of patients who received Eilea® 2 mg every 8 weeks after 3 initial monthly injections, compared with 94.4% of patients who received ranibizumab 0.5 mg every 4 weeks.

In the study VIEW2 at the 52nd week achieved improvement in visual acuity was maintained in 95.6% of patients who received Eilea® 2 mg every 8 weeks after 3 initial monthly injections, compared with 94.4% of patients receiving ranibizumab 0.5 mg every 4 weeks.

In both studies it was shown that Eilea® and ranibizumab, used in a dose of 0.5 mg every 4 weeks, are comparable in clinical effectiveness.

A detailed description of the results of the combined data analysis of both studies is given in Table 1.

Table 1: Evaluation of efficacy at 52nd and 96th week; combined data research VIEW1 and VIEW2

Efficiency mark	Eilea® 2 mg every 8 weeks after 3 initial monthly injections (N=607)			Ranibizumab 0.5 mg every 4 weeks (N=595)
	Week 52		96 week	Week 52		96 week
Average number of injections	7,6		11,2	12,3		16,5
Average number of injections (weeks 52-96)			4,2			4,7
The proportion of patients with a loss of ≤15 letters with the most corrected visual acuity (IHEC) compared to the baseline	95,33 %		92,42 %	94,42 %		91,60%
The mean change in the maximally corrected visual acuity (IHEC), measured on a scale ETDRS in comparison with the initial state	8,40	7,62		8,74	7,89
The proportion of patients who added ≥15 letters on the scale ETDRS in comparison with the initial state	30,97 %	33,44 %		32,44 %	31,60%

In patients treated with Eilea® (one injection per month for three consecutive months, then one injection every 2 months), the thickness of the central retina (TSZS) and the mean size of the area of pathological neovascularization decreased soon after treatment,which corresponds to the results obtained with ranibizumab at a dose of 0.5 mg every month. The achieved reduction in the size of the zone of pathological neovascularization and TZZS remained stable in the second year of studies to the last evaluation at week 96, with 2-4% of patients requiring all injections on a monthly basis, and one third of patients requiring at least one injection with a treatment interval of one month.

In both studies, there was a decrease in the zone of pathological neovascularization in all groups with different dosing regimens.

Macular edema, which has developed as a result of occlusion of the central vein of the retina (ICVs) or its branches (SABI)

With ICW and DVT, retinal ischemia develops, which is a signal for the release VEGF, which, in turn, leads to destabilization of dense contacts and stimulates the proliferation of endothelial cells. Increased expression VEGF is associated with complications such as a violation of the hemato-ophthalmic barrier, retinal edema due to increased vascular permeability, neovascularization. The safety and efficacy of Eilea® were evaluated in two randomized, multicenter, double-blind, controlledresearch COPERNICUS and GALILEO, including 358 patients with macular edema, which developed as a consequence of ICPV. In both studies, patients were randomized in a 3: 2 ratio to receive 2 mg of Eilea® every 4 weeks (217 patients) (Eilea® group 2q4), or a control group to receive imitations of injections every 4 weeks.

The study included patients aged 22 to 89 years, the average age was 64 years. In the studies of the NSCV, approximately 52% of the patients (112 of 217) randomized to the Eilea® group were 65 years of age or older, and approximately 18% (38 of 217) were aged 75 years or older.

After 6 consecutive monthly injections, patients continued to receive treatment only if they met pre-defined criteria for continuing therapy, except for the control group in the study GALILEO, who continued to receive imitations of injections before the 52nd week. From this point on, all patients were treated if they met pre-defined criteria.

In both studies, the primary endpoint of efficacy was the proportion of patients whose maximally corrected visual acuity (ICDH) increased by at least 15 letters in 24 weeks compared to the baseline condition.The secondary endpoint was a change in visual acuity at 24 weeks compared to the baseline.

Differences between the groups were statistically significant in favor of Eilea's drug in both studies, an improvement in ICDH was achieved after 3 months, followed by stabilization of visual acuity and TSZS until the 6th month. Statistically significant differences persisted until the 52nd week.

A detailed description of the results of the analysis of both studies is given in Table 2 and in Figure 1.

Table 2: Evaluation of effectiveness in studies COPERNICUS and GALILEO on the 24th, 52nd and 76 / 100th week.

Efficiency mark			The proportion of patients who added ≥15 letters compared to the baseline	Average change in the ICDH on a scale ETDRS in comparison with the initial state (CO¹)
COPERNICUS	24 weeks	Control (N = 73)	12%	-4,0(18,0)
	24 weeks	Eilea® 2 mg every 4 weeks (N=114)	56%	17,3(12,8)
	52 weeks	Control² (N = 73)	30%	3,8(17,1)
	52 weeks	Eilea® 2 mg (N = 114)	55 %	16,2(17,4)
	100 weeks	Control^2,3 (N = 73)	23,3 %	1,5(17,7)
	100 weeks	Eilea® ³2 mg (N = 114)	49,1 %	13,0(17,7)
GALILEO	24 weeks	Control (N = 68)	22%	3,3(14,1)
	24 weeks	Eilea® 2 mg every 4 weeks (N=103)	60%	18,0(12,2)
	52 weeks	Control (N = 68)	32%	3,8(18,1)
	52 weeks	Eilea® 2 mg (N = 103)	60%	16,9(14,8)
	76 weeks	Control⁴ (N = 68)	29,4 %	6,2(17,7)
	76 weeks	Eilea® ⁴ 2 mg (N = 103)	57,3 %	13,7(17,8)

1) CO: standard deviation

2) In the study COPERNICUS patients of the control group could receive Eilea® as needed (PRN) every 4 weeks for the period from 24 to 52 weeks, patients visited the doctor every 4 weeks.

3) In the study COPERNICUS and the control group and the Eilea® group of 2 mg received Eilea® 2 mg as needed (PRN) every 4 weeks from 52 to 96 weeks: patients were obliged to visit the doctor every quarter, but if necessary, they could come to the clinic every 4 weeks.

4) In the study GALILEO from 52 to 68 weeks and the control group and the Eilea ® 2 mg group received Eilea ® 2 mg as needed (PRN) every 8 weeks, patients came to the reception without fail every 8 weeks.

The safety and efficacy of Eilea® was evaluated in a randomized, multicenter, double-blind, controlled trial VIBRANT, including 181 patients with macular edema that developed as a result of hemodialysis, including hemiretinal occlusion of the central vein of the retina. In this study, patients were randomized in a 1: 1 ratio to receive Eilea® at a dose of 2 mg every 8 weeks after 6 initial monthly injections (91 patients), or in a group of patients initially receiving laser photocoagulation (active control group).

The study included patients aged 42 to 94 years, the average age was 65 years.In a study on PEP, approximately 58% of the patients (53 of 91) randomized to the Eilea® group were aged 65 years or older, and approximately 23% (21 of 91) were aged 75 years or older.

Starting with the 12th week, patients in the active control group could receive additional laser photocoagulation, called "rescue therapy" with a minimum interval of 12 weeks. Since the 24th week, active control group patients who meet pre-defined criteria could receive "rescue therapy" with Eilea® 2 mg every 4 weeks for 3 months, then every 8 weeks.

In the study VIBRANT the primary endpoint of effectiveness was the proportion of patients whose MCHD increased by at least 15 letters in 24 weeks compared with the baseline, this figure in the Eilea group was higher than in the active control group.

In the study VIBRANT the secondary endpoint was an improvement in visual acuity at week 24 compared with the baseline, which was statistically significant in favor of Eilea®. Improvement of vision occurred quickly and reached a maximum value for the 3rd month, with subsequent preservation of the values reached before the 12th month.

Since the 24th week, 67 patients in the active control group received "rescue therapy" with Eilea® (Active Control / Eilea * 2 mg group), which improved the visual acuity by an average of 5 letters from the 24th week of the 52- y week.

Detailed description of the results of the analysis of the study VIBRANT is shown in Table 3 and in Figure 2.

Efficiency mark		The proportion of patients who added ≥15 letters compared to the baseline	Average change in the ICDH on a scale ETDRS in comparison with the initial state (CO¹)
24 weeks	Eilea® 2 mg every 4 weeks (N=91)	52,7 %	17,0(11,9)
24 weeks	Active control (N = 90)	26,7 %	6,9(12,9)
52 weeks	Eilea® 2 mg every 8 weeks (N=91)²	57,1 %	17,1(13,1)
52 weeks	Active control / Eilea® 2 mg (N=90)³	41,1 %	12,2(11,9)

1) CO: standard deviation

2) The treatment interval for all Eilea® patients was increased to 8 weeks during the 24th to 48th week period.

3) Starting at week 24, active control group patients who met at least one of the predefined criteria could receive "rescue therapy" with Eilea® (a total of 67 patients). The fixed mode of "rescue therapy" with Eilea®-Eilea® in a dose of 2 mg every 4 weeks for 3 months, then intravitreal injections every 8 weeks.

Patients who received 6 consecutive monthly injections of 2 mg of Eilea ® received a persistent, rapid and pronounced morphological response (measured by an improvement in the mean values of TCHA). At week 24, the decrease in TSCI was statistically significantly higher than in the control group in all three studies (COPERNICUS (NCSA): -457 microns with respect to -145 microns,

GALILEO (NCVC): -449 microns with respect to -169 microns, VIBRANT (DEWAC): -280 microns with respect to -128 microns). The achieved decrease in TSCA was maintained until the end of each study: up to 100 weeks in the study COPERNICUS, up to 76 weeks in the study GALILEO and up to 52 weeks in the study VIBRANT.

Diabetic macular edema (DMO)

Diabetic macular edema is a consequence of diabetic retinopathy and is characterized by increased vascular permeability and damage to the retinal capillaries, which can lead to loss of visual acuity.

The safety and efficacy of Eilea ® in patients with diabetic macular edema were evaluated in two randomized, multicenter, double-blind, active control studies. A total of 862 patients were randomized.Of these, 576 patients were randomized to Eilea® in two studies (VIVID-DME and VISTA-DME). In each study, patients were randomly assigned to three groups in a ratio of 1: 1: 1:

1) Eilea® 2 mg every 8 weeks for the first 5 months;

2) Eilea® 2 mg every 4 weeks;

3) laser coagulation in the macula (active control).

The study included patients aged 23 to 87 years, the average age was 63 years. In the Phase III studies, the diabetic macular edema of approximately 47% of the patients (268 out of 576) randomized to Eilea® was 65 years of age or older, and approximately 9% (52 of 576) aged 75 years or older. Most patients included in both studies had Type II diabetes.

Since the 24th week, patients who meet predetermined vision loss thresholds could receive additional therapy: patients in Eilea® groups could receive laser coagulation, and patients in the control group receive therapy with Eilea®.

In both studies, the primary endpoint of efficacy was the mean value of the maximum corrected visual acuity (ISCED) at week 52 compared to the baseline,which in the Eilea groups "2 mg every 8 weeks for the first 5 months and Eilea" 2 mg every 4 weeks was statistically significant and exceeded the parameters in the control group. This advantage was maintained until the 100th week.

Detailed description of research results VIVID-DME and VISTA-DME is shown in Table 4 and in Figure 3.

Table 4: Evaluation of efficacy at 52nd and 100th week in studies VIVID-DME and VISTA-DME

In studies VIVID-DME and VISTA-DME 36 (9%) and 197 (43%) patients respectively received the anti--VEGF Therapy, with a washing period of 3 months or more. Effects of treatment in subgroups of patients who received pre-therapy with inhibitors VEGF, were similar to the effects observed in patients who were first treated with inhibitors VEGF.

Patients with bilateral lesions could receive anti--VEGF therapy of another eye, if the attending physician considered it necessary. In the study VISTA-DME 217 (70.7%) patients receiving Eilea ® received Eilea® in both eyes before the 100th week; in the study VIVID-DME 97 (35.8%) patients receiving the preparation Eilea ®, injected various anti--VEGF drugs in the other eye.

The parameters of efficiency and safety were comparable with those for the general population.

Shortly after the initiation of therapy, patients who received Eilea® therapy received a rapid and pronounced response from morphological indicators (TSCA, the severity rating scale for diabetic retinopathy (DRSS)). In studies VIVID-DME and VISTA-DME the mean decrease in TSCV compared to baseline at week 52 was statistically significantly higher in the Eilea® group compared to the laser therapy group: -192.4 micron and -183.1 microns in the Eilea® 2 mg group every 8 weeks for the first 5 months and -66.2 microns and -73.3 microns in the laser therapy group, respectively.

In studies VIVID-DME and V1STA-DME improvement of the course of diabetic retinopathy by 2 or more levels on a scale DRSS was assessed in a pre-established manner and was determined in 73.7% of patients in the study VIVID-DME and in 98.3% of patients in the study VISTA-DME.

In an independent comparative study (DRCR.net Protocol T), a dosing regimen based on strict OCT criteria and a change in vision during re-treatment was applied. In the group of treatment with aflibercept (224 patients), the result of this treatment regimen was the patients receiving an average of 9.2 injections,which is similar to the number of doses received in Eilea® 2 mg every 8 weeks for the first 5 months in studies VIVID-DME and VISTA-DME, while the overall efficacy in the aflibercept treatment group in the study Protocol T was comparable to that in Eilea® 2 mg every 8 weeks for the first 5 months in studies VIVID-DME and VISTA-DME. In the study Protocol T, an improvement of 13.3 letters was observed on average, in 42% vision improved by at least 15 letters compared to the initial state. Ophthalmic and system safety profiles (including ATS (arterial thromboembolic events)) were comparable with those in studies VIVID-DME and VISTA-DME.

Myopic choroidal neovascularization (myopic CNV)

Myopic choroidal neovascularization (myopic CNV) is a frequent cause of vision loss in adults with pathological myopia. It is manifested by the appearance of "lacquer cracks", which are a consequence of the ruptures of the Bruch's membrane, and is the most threatening sight in pathological myopia. The safety and efficacy of Eilea® in previously untreated patients with myopic choroidal neovascularization were evaluated in a randomizeda multicenter, double-blind, controlled study MYRROR. Patients were randomized in a 3: 1 ratio to receive 2 mg of Eilea ® drug intravitreal or to receive injection simulations once at the beginning of the study with additional injections if the disease persisted or relapsed before the 24th week. Since the 24th week, patients who received imitations of injections could receive the first dose of Eilea ®. Then patients of both groups could receive additional injections if the disease persisted or relapsed. A total of 121 patients were treated and evaluated for efficacy, of which 90 patients received Eilea ®. Patients aged 27 to 83 years were included in the study, the average age was 58 years. In a study of myopic CNV, approximately 36% (33 of 91) of patients randomized to the Eilea® group were 65 years of age or older, and approximately 10% (9 of 91) were aged 75 years or older. Differences between the groups were statistically significant in favor of Eilea® at the primary endpoint (change in ICDH) and confirming at the secondary endpoint (the proportion of patients with whom MCHO increased by at least 15 letters) at Week 24 compared to baseline .Differences on both endpoints persisted until the 48th week.

Detailed description of the research results MYRROR is shown in Table 5 and in Figure 4.

Table 5: Performance evaluation at week 24 (primary analysis) and 48th week in research MYRROR

Efficiency mark	MYRROR
	Week 24		Week 48
	Eilea® 2 mg (N = 90)	Imitation of injection (N = 31)	Eilea® 2 mg (N = 90)	Simulation of injection / Eilea® 2 mg (N=31)
Average change in the ICDH on a scale ETDRS in comparison with the initial state (CO¹)	12,1 (8,3)	-2,0 (9,7)	13,5 (8,8)	3,9(14,3)
The proportion of patients who added> 15 letters on the scale ETDRS in comparison with the initial state	38,9 %	9,7 %	50,0 %	29,0 %

1) CO: standard deviation

In the study MYRROR in patients treated with Eilea® (one injection at the beginning of the therapy, with additional injections if the disease persisted or relapsed), the TSCS decreased soon after the start of treatment, at week 24 was statistically significantly superior in the Eilea® group (-79 and -4 microns for the Eilea * 2 mg group and the control group, respectively) and was maintained until the 48th week. In addition, the average size of CNV lesion decreased.

Pharmacokinetics:

The drug Eilea ® is injected directly into the vitreous for local exposure.

Suction

After intravitreal administration aflibercept is slowly absorbed into the systemic bloodstream, where it is mainly found in the form of an inactive stable complex with VEGF; while only free aflibercept can bind endogenous VEGF.

In a study of the pharmacokinetics of the frequent sampling in 6 patients with neovascular "wet" form of AMD, the maximum plasma concentration of free aflibercept (System Cmah) within 1-3 days after intravitreal injection of 2 mg doses were low, averaging about 0.02 ug / ml (range of 0 to 0.054), and were indeterminable two weeks after injection in almost all patients. Afleibercept Do not cumulate in blood plasma with intravitreal injection every 4 of the week.

Distribution

The average maximum plasma concentrations of free aflibercept are approximately 50-500 times lower than the concentrations necessary to inhibit biological activity VEGF in the systemic circulation by 50% on animal models in which the blood pressure changes were observed after the free aflibercept concentration in the systemic circulation of about 10 ug / ml, the pressure was returned to normal values at lower concentrations of less than 1 ug / ml.It is expected that the average plasma concentration of free afiberceptse after intravitreal injection of 2 mg of aflibercept to patients will be more than 100 times lower than the concentration of aflibercept necessary for binding half of the systemic VEGF (2.91 μg / ml) in healthy volunteers. Thus, the development of systemic pharmacodynamic effects, such as changes in blood pressure, is unlikely.

The value of the average Cmfree aflibercept in the plasma according to the results of pharmacokinetic supplementary studies with the participation of patients with ICVs, SABI, DMO and myopic XHB was in the range from 0.03 to 0.05 μg / ml, individual values did not exceed 0.14 μg / ml. Subsequently, the plasma concentrations of free afiberbertsept decreased to values below or close to the lower limit of quantitation, usually within one week. At the end of 4 weeks, before the next use in all patients, concentrations were undetectable.

Metabolism

Since Eilea® is a protein preparation, no studies of its metabolism have been conducted.

Excretion

Free aflibercept communicates with VEGF with the formation of a stable inert complex. It is expected that, like other large proteins, both free and bound aflibercept will be excreted from the body by proteolytic catabolism.

Pharmacokinetics in different patient groups

Elderly patients

Observance of any special conditions is not required. The experience of using in patients with DMO is older than 75 years is limited.

Children

Eilea ® is not used in this group of patients as indicated by the "wet" form of AMD, ICPV, SABI, DMO, and myopic KNV.

Patients with impaired renal function

No special studies have been conducted with patients with impaired renal function receiving Eilea ®.

Analysis of pharmacokinetic data of the study VIEW2 showed that 40% of patients with impaired renal function (24% mild, 15% moderate and 1% severe) after intravitreal administration every 4 or 8 weeks had no difference in plasma concentrations of the active substance.

Similar results were obtained in patients with ICPV in the study GALILEO, in patients with DME in the study VIVID-DME and in patients with myopic CNV in the study MYRROR.

Indications:

Eilea ® is indicated to adults for treatment:

- neovascular ("wet" form) age-related macular degeneration ("wet" form of AMD);

- Reducing visual acuity caused by macular edema due to retinal vein occlusion (central vein (ICVs) or its branches (SABI));

- reduction of visual acuity caused by diabetic macular edema (DMO);

- reduction in visual acuity caused by myopic choroidal neovascularization (myopic CNV).

Contraindications:

- Hypersensitivity to aflibercept or any other component included in the preparation;

- active or suspected intra- or periocular infection;

active severe intraocular inflammation;

- pregnancy and the period of breastfeeding, except when the potential benefit to the mother exceeds the potential risk to the fetus (see section "Application during pregnancy and during breast-feeding");

- age to 18 years.

Carefully:

- In the treatment of patients with poorly controlled glaucoma (do not administer Eilea ® with intraocular pressure ≥ 30 mm Hg) (see section "Special instructions");

- in patients who underwent a stroke, transient ischemic attack, or myocardial infarction within the last 6 months (in the treatment of ICVs, SABs, DMOs, or myopic KNV)section "Special instructions");

- in patients with risk factors, the integrity of retinal pigment epithelium (see section "Special instructions").

Pregnancy and lactation:

Women of reproductive age

Women of reproductive age should use effective contraception during the treatment period and, at least, within 3 months after the last intravitreal injection of aflibercept (see section "Special instructions").

Pregnancy

Data on the use of aflibercept in pregnant women are absent. In animal studies, embryo-fetotoxicity (see section "Special instructions").

Despite the fact that the systemic exposure after intraocular administration of Eilea® is very small, the drug should not be used during pregnancy, except when the potential benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

It is not known whether the aflibercept in breast milk. The risk to the child during breastfeeding can not be ruled out.

Eilea ® is not recommended for breastfeeding (see section "Special instructions"). It is necessary to decide whether to interrupt breastfeeding or to abstain from Eilea® therapy, taking into account the benefits of breastfeeding for the baby and the benefits of treatment for the mother.

Fertility

The results of studies on animals with a high system exposure of the drug show that aflibercept can violate the fertility of individuals male and female. Such effects are unlikely after intraocular administration of the drug taking into account a very low system exposure.

Dosing and Administration:

The drug Eilea ® is intended only for administration to the vitreous.

The contents of the vial should be used for only one injection.

The drug Eilea ® should be administered only by a doctor who has the appropriate qualifications and experience of intravitreal injections.

Neovascular ("wet" form) age-related macular degeneration ("wet" form of AMD)

The recommended dose of Eilea® is 2 mg of aflibercept, which is equivalent to 50 μl of the solution.

Treatment with Eilea ® begins with the introduction of three consecutive monthly injections, then perform one injection every two months.Control between injections is not required.

After 12 months of treatment with Eilea®, the interval between injections can be increased based on changes in visual acuity and anatomical parameters; In treatment in the "treat and increase the interval" mode, the intervals between doses administration gradually increase to maintain the achieved stable visual acuity and / or anatomical parameters, but the data for establishing the length of such intervals is not sufficient. In the case of deterioration of visual acuity and anatomical parameters, the intervals between injections should be correspondingly reduced. In this case, the attending physician should draw up a schedule of control examinations that may be more frequent than injections.

Macular edema, developed due to the occlusion of the veins of the retina (central vein (ICVs) or its branches (SABI))

The recommended dose of Eilea® is 2 mg of aflibercept, which is equivalent to 50 μl of the solution.

After the initial injection, the treatment is carried out monthly. The interval between the two injections should be at least one month.

If there is no improvement in visual acuity and anatomical indicators after continuous treatment, treatment with Eilea® should be discontinued.Monthly injections continue until the greatest possible visual acuity is achieved in the absence of signs of disease activity. To do this, it is necessary to carry out a sin and more consistent monthly injections.

Therapy can be continued in the "treat and increase the interval" mode with a gradual increase in the interval between injections to maintain the achieved stable visual acuity and anatomical indicators, however, data that allow setting the duration of intervals is not enough. In the case of deterioration of visual acuity and anatomical parameters, the intervals between injections should be correspondingly reduced.

Monitoring and selection of the treatment regimen are carried out by the attending physician on the basis of the patient's individual response.

Monitoring of manifestations of disease activity may include a standard ophthalmologic examination, functional diagnostics or visual methods of investigation (optical coherence tomography or fluorescent angiography).

Diabetic macular edema (DMO)

The recommended dose of Eilea® is 2 mg of aflibercept, which is equivalent to 50 μl of the solution.

Eilea® therapy is started with a single monthly injection for the first five months, after which the injections are given every two months. Monitoring between injections is not required.

After 12 months of treatment with Eilea®, the interval between injections can be increased based on the results of changes in visual acuity and anatomical parameters, for example, in the treatment and interval treatment mode, in which the intervals between dose administration gradually increase to maintain the achieved stable acuity vision and / or anatomical indicators, but there is not enough data to establish the length of such intervals. In the case of deterioration of visual acuity and anatomical parameters, the intervals between injections should be correspondingly reduced. In this case, the attending physician should draw up a schedule of control examinations that may be more frequent than injections. If the results of visual acuity and anatomical indicators indicate a lack of effect from the treatment, Eilea® therapy should be discontinued.

Myopic choroidal neovascularization (myopic CNV)

The recommended dose of Eilea ® is a single intravitreal injection of 2 mg of aflibercept, which is equivalent to 50 μl of the solution.

If the results of visual acuity and anatomical indicators indicate the preservation of the disease, it is possible to introduce additional doses. Relapses should be treated as a new manifestation of the disease.

The schedule of control examinations is compiled by the attending physician.

The interval between the two doses should be at least one month.

Special patient groups

Patients with impaired hepatic and / or renal function

No special studies involving patients with hepatic and / or renal failure receiving Eilea ® were carried out.

Based on the available data, dose adjustment in such patients is not required (see section "Pharmacokinetics").

Elderly patients

Observance of any special conditions is not required. The experience of treating patients older than 75 years with DMO is limited.

Children

The safety and efficacy of Eilea® have not been studied in children and adolescents. Eilea® is not indicated for use in this group of patients.

Method of administration

Intravitreal injections should be performed in accordance with medical standards and current recommendations by a qualified physician experienced in the conduct of such injections. In general necessary to ensure adequate anesthesia and aseptic conditions, including the use of antibacterial agents include a broad spectrum of action (e.g., povidone-iodine applied to the skin around the eye lid and the eye surface). Recommended disinfection of hand surgery, use sterile gloves and sterile wipes and expander age (or its equivalent).

An injection needle to be administered to 3.5-4.0 mm posterior to the limbus in the vitreous cavity, avoiding the horizontal meridian and aiming the needle into the center of the eyeball. The volume of the introduced solution was 0.05 ml (50 μl). The next injection is carried out to another site of the sclera.

Immediately after intravitreal injection, the patient should be monitored for increased intraocular pressure. Adequate monitoring may include checking the optic nerve perfusion or ophthalmotonometry. If necessary, ensure the availability of sterile equipment for paracentesis.

After intravitreal injection, the patient should be warned to immediately report any symptoms that may indicate the development of endophthalmitis (eg, eye pain, conjunctival or pericorneal injection, photophobia, blurred vision).

Each vial should be used for only one intravitreal injection. The bottle contains a dose of afiberceptsept, exceeding the recommended dose of 2 mg. The volume of the bottle is not used completely. Excess volume should be removed prior to injection. The introduction of the full volume of the vial may lead to an overdose. To remove air bubbles and excess volume of medicament, slowly push the syringe piston and move the cylindrical base of the piston dome to a black mark on the syringe (equivalent to 50 μl, ie 2 mg of aflibercept).

After the injection, all unused medication should be disposed of.

Before use, carefully inspect the vial. If the integrity of the bottle is violated, a significant change in color, clouding, the detection of visible particles, the drug should not be used.

Instructions for using the bottle:

1) Remove the plastic cap and disinfect the outer part of the vial of the vial.

2) Attach the filter needle 18 G, 5-micron, enclosed in a cardboard bundle, to a 1 ml sterile syringe with a luer tip.

3) The filter needle is inserted through the center of the vial plug until it completely enters the vial and its end does not touch the bottom or the bottom edge of the vial.

4) Observing the rules of aseptic, extract the contents of the bottle with Eilea® in a syringe, holding the bottle vertically, tilting it slightly to completely remove the drug. To prevent air from entering, ensure that the chamfered end of the needle is immersed in the liquid. When selecting a solution, continue to tilt the bottle, making sure that the tip of the needle is immersed in the liquid.

5) After making sure that the piston rod is sufficiently pulled back when the solution is taken from the vial, the filter needle is completely emptied.

6) The filter needle is removed and disposed of.

Note: the filter needle is not used for intravitreal injection.

7) Following the rules of asepsis, the needle for injection 30 G x 1/2 inch tightly attached to the tip of the syringe with luerovsky tip.

8) Holding the syringe with the needle up, check the solution for bubbles. If they are available, gently shake the syringe with your finger until all the bubbles rise up.

9) Slowly pressing the piston so that its edge reaches the mark of 0.05 ml on the syringe, remove all bubbles and excess volume of the preparation.

10) The bottle is intended for single use only. Any unused volume of medicinal product or waste must be disposed of.

Side effects:

3102 patients who participated in eight phase III studies made up the safety assessment population. Of these, 2501 patients received the recommended dose of 2 mg.

Serious ocular adverse reactions that occurred in the eye under study and associated with the administration procedure were noted in less than 1 case for 1,900 intra-viral injections of Eilea® and included blindness, endophthalmitis, retinal detachment, iatrogenic traumatic cataract, cataracts, vitreous hemorrhage, body and increased intraocular pressure (see section "Special instructions").

The most common adverse reactions (at least in 5% of patients,receiving therapy with Eylea®) include subconjunctival hemorrhage (25%), reduction of visual acuity (11%), eye pain (10%), cataract (8%), increased Intraocular pressure (8%), detachment of the vitreous body (7%) and floating vitreous opacities (7%).

Safety data below include all adverse reactions noted in the eight trials III phase in the treatment of indications "wet" form of AMD, CRVO, OVTSVS, DME and myopic CNV, indicating the possibility of having a causal connection with the process of administration or drug .

The undesirable reactions presented below are listed according to the frequency of occurrence in clinical trials and with the system-organ class. Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1000), rarely (< 1/10 000).

Within each group, adverse reactions are presented in order of decreasing severity.

Immune system disorders

Infrequently: hypersensitivity * * *

Disturbances on the part of the organ of sight

Often: reduction of visual acuity, subconjunctival hemorrhage, pain in the eye.

Often: rupture of retinal pigment epithelium *, retinal pigment epithelial retinal detachment, retinal degeneration, vitreous hemorrhage, cataracts, cortical cataracts, nuclear cataracts, subcapsular cataracts, corneal erosion, corneal erosion, increased intraocular pressure, blurred vision, floating opacities, vitreous humor body, pain at the injection site, foreign body sensation in the eye, lacrimation, eyelid edema, hemorrhages at the injection site, acupuncture, conjunctival eyelid injection, and conjunctival injection of the eyeball.

Infrequently: endofalmitis **, retinal detachment, retinal rupture, iritis, uveitis, iridocyclitis, lens opacity, corneal epithelial defect, irritation at the site of injection, abnormal sensitivity of eye tissues, eyelid irritation, suspended blood cells in the anterior chamber, corneal edema.

Rarely: blindness, iatrogenic traumatic cataract, inflammatory reaction from vitreous body (Vitreit), hypopion.

* The states associated, as is known, with the "wet" form of AMD. Observed only in studies with a "wet" form of AMD.

** Endophthalmitis with sowing and non-sowing culture.

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

Description of individual adverse reactions

In Phase III studies, in the "wet" form of AMD, there was an increase in the incidence of subconjunctival hemorrhage in patients receiving antithrombotic drugs. An increase in the incidence of this phenomenon was comparable in patients receiving ranibizumab and Eilea® preparation. Arterial thromboembolic events (ATS) are undesirable phenomena potentially associated with systemic inhibition VEGF. Theoretically, there is a risk of ATS, including stroke and myocardial infarction, after intravitreal administration of inhibitors VEGF.

In clinical studies of Eilea ® in patients with a "wet" form of AMD, DMO, ICPV, DVVC and myopic CNV, a low incidence of ATS was observed. For each of the indications, there was no significant difference between the groups of patients receiving aflibercept, and patients of appropriate control groups.

Like all therapeutic proteins, Eilea ® has an immunogenic potential.

Overdose:

Symptoms

In clinical studies, doses up to 4 mg were applied at an interval of 1 month, there were individual cases of overdose with a dose of 8 mg.

Overdosing with the introduction of a larger volume of solution may lead to an increase in intraocular pressure.

Treatment

In case of an overdose, intraocular pressure should be monitored, if necessary, the treating physician should begin adequate therapy to correct it.

Interaction:

There were no studies on drug interactions.

The combined use of photodynamic therapy (PDT) with verteporfin and Eilea ® was not studied, therefore, the safety profile is unknown.

Special instructions:

Reactions, due to intravitreal administration

The relationship between intravitreal injections, including injections of aflibercept, with the development of endophthalmitis, an inflammatory response from the vitreous humor, rheumatogenic retinal detachment, rupture of the retina, iatrogenic traumatic cataract (see section "Side effect"). When administering Eilea ®, always follow the appropriate technique for aseptic injection. In addition, patients should be monitored within a week after the injection to identify the first signs of inflammation and promptly prescribe the necessary therapy. Patients should be informed of the need to immediately inform the doctor of any symptoms that indicate the development of endophthalmitis or any other reaction indicated above.

There have been cases of increased intraocular pressure in the first 60 minutes after intravitreal injections, including injections of Eilea® (see section "Side effect"). In the treatment of patients with poorly controlled glaucoma, special precautions are necessary (do not administer Eilea ® with intraocular pressure ≥ 30 mmHg). In all cases, monitoring of intraocular pressure and perfusion of the optic nerve disk is necessary with the appointment of an appropriate therapy condition.

Immunogenicity

Since Eilea® is a protein with therapeutic properties, there is a possibility of manifestation of immunogenicity (see section "Side effect"). Patients should be informed of the need to inform the physician of any signs or symptoms of intraocular inflammation such as pain, photophobia or conjunctival or pericorneal injection, which may be clinical manifestations of hypersensitivity to the drug.

System Effects

After intravitreal injections of inhibitors VEGF Systemic adverse events were noted, including hemorrhages outside the visual organ and thromboembolism arteries. There is a theoretical risk of linking these phenomena with inhibition VEGF. There are limited data on the safety of the use of aflibercept in patients with ICVs, SABs, DMOs, or myopic KNV with anamnestic data on stroke, transient ischemic attack, or myocardial infarction for a period of 6 months before the start of therapy. Care should be taken when treating such patients.

Other

As in the case of intravitreal administration of other anti--VEGF drugs with AMD, ICPV, PEP, DMO and myopic CNV, the following should be taken into account:

- The safety and effectiveness of Eilea ® when administered simultaneously into both eyes has not been systematically studied (cm.section "Pharmacodynamics"). Simultaneous bilateral administration may lead to an increase in the system exposure of the drug, which in turn increases the risk of systemic adverse events.

- There is no information on the simultaneous use of Eilea ® with other anti-inflammatory drugs-VEGF drugs (systemic or ocular).

- Risk factors associated with impairment of the integrity of the pigment cell layer after anti--VEGF therapy for the "wet" form of AMD, include an extensive and / or pronounced detachment of retinal pigment epithelium. At the beginning of therapy with Eilea ®, caution should be exercised when prescribing the drug to patients with risk factors for the development of retinal pigment epithelial ruptures.

- Patients with rheumatogenic retinal detachment or with macular tears of stage 3 or 4 from treatment should refrain.

- In case of a retinal rupture, the injection should be canceled, the treatment should not be resumed until an adequate recovery of the gap is achieved.

- The injection should be abstained until the next scheduled injection schedule in the event of:

· decrease in ICDH ≥30 letters compared with the latest assessment of visual acuity;

· subretinal hemorrhages affecting the central fossa, or if the hemorrhage size is ≥ 50% of the total lesion area.

- The injection should be abstained for a period of 28 days before the planned and 28 days after intraocular surgery.

- Eilea ® should not be used during pregnancy, unless the potential benefit to the mother exceeds the potential risk to the fetus (see section "Application during pregnancy and during breast-feeding").

- Women of reproductive age should use effective contraception during the treatment period and, at least 3 months after the last intravitreal injection of aflibercept (see section "Application during pregnancy and during breast-feeding").

- The experience of treatment of patients with ischemic WSCA and DEFIC is limited. If patients have clinical signs of irreversible changes in visual function against ischemia, therapy with aflibercept is not recommended.

Populations with limited data

The experience of treatment of DME in patients with type 1 diabetes, in patients with a glycated hemoglobin level of more than 12%, in patients with proliferative diabetic retinopathy is limited.

The use of Eilea ® in patients with active systemic infections or in patients with concomitant eye diseases, such as retinal detachment or the rupture of the macula, has not been studied. The experience of Eilea® treatment of patients with diabetes mellitus and uncontrolled hypertension is absent. This should be taken into account by the attending physician in the management of such patients.

The experience of using Eilea ® for the treatment of myopic CNV in patients of the non-Asian population, in patients previously treated with myopic KNV, as well as in patients with extrafoveal injuries is absent.

Data obtained from preclinical studies

In preclinical studies in the study of repeated dose toxicity, the effects of the drug were observed only in systemic exposures significantly exceeding the maximum exposure in a person after intravitreal administration at a dose intended for clinical use, which indicates the low significance of these results in clinical practice.

Studies to study the mutagenic or carcinogenic potential of aflibercept were not conducted.

Effect on the ability to drive transp. cf. and fur:

The use of Eilea ® has a minimal effect on the ability to drive vehicles and use mechanisms due to possible temporary visual impairment, related both to injection and to the examination procedure. If, after the injection, the patient experienced temporary visual impairment, then the patient is not advised to drive or work with the machines until the visual clarity is restored.

Form release / dosage:Solution for intraocular administration 40 mg / ml.

Packaging:

For 0.1 ml (100 μl) of recoverable volume * preparation in a bottle of colorless glass type I, sealed with a plug of butyl rubber with a fluoropolymer coating, with a crimping aluminum cap and a polypropylene lid. For 1 bottle and 1 filter needle with instructions for use are placed in a cardboard box.

* The drug is produced with an excess of filling in order to provide a recoverable volume of not less than 0.1 ml (100 μl).

Storage conditions:

Store at a temperature of 2 to 8 ° C, in a place protected from light.

Do not freeze.

Keep out of the reach of children.

Before use, the unopened vial can be stored at a temperature of no higher than 25 ° C for up to 24 hours.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003544

Date of registration:29.03.2016 / 19.09.2017

Expiration Date:29.03.2021

The owner of the registration certificate:Bayer AGBayer AG Germany

Manufacturer: & nbsp

Regeneron Pharmaceutical, Inc. USA

BAYER PHARMA, AG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp18.02.2018

Illustrated instructions

Instructions

Eilea® (Eylea®)