Eylea

Generic Name: aflibercept
Dosage Form: injection, solution

Indications and Usage for Eylea

Eylea is indicated for the treatment of patients with:

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

1.3 Diabetic Macular Edema (DME)

Eylea Dosage and Administration

General Dosing Information

FOR OPHTHALMIC INTRAVITREAL INJECTION. Eylea must only be administered by a qualified physician.

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The recommended dose for Eylea is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although Eylea may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when Eylea was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.1)].

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The recommended dose for Eylea is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly) [see Clinical Studies (14.2)].

Diabetic Macular Edema (DME)

The recommended dose for Eylea is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although Eylea may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when Eylea was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.3)].

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Preparation for Administration

Eylea should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used.

Using aseptic technique, the intravitreal injection should be performed with a 30-gauge × ½-inch injection needle.

Vial

The glass vial is for single use only.

  1. Remove the protective plastic cap from the vial (see Figure 1).

  2. Clean the top of the vial with an alcohol wipe (see Figure 2).

  3. Remove the 19-gauge × 1½-inch, 5-micron, filter needle from its pouch and remove the 1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 3).

  4. Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.
  5. Using aseptic technique withdraw all of the Eylea vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid (see Figures 4a and 4b).

  6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
  7. Remove the filter needle from the syringe and properly dispose of the filter needle. Note: Filter needle is not to be used for intravitreal injection.
  8. Remove the 30-gauge × ½-inch injection needle from the plastic pouch and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 5).

  9. When ready to administer Eylea, remove the plastic needle shield from the needle.
  10. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 6).

  11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe (see Figures 7a and 7b).

Administration

The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.

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, a sterile paracentesis needle should be available.

Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient Counseling Information (17)].

Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before Eylea is administered to the other eye.

After injection, any unused product must be discarded.

No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly).

Dosage Forms and Strengths

Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution for intravitreal injection.

Contraindications

Ocular or Periocular Infections

Eylea is contraindicated in patients with ocular or periocular infections.

Active Intraocular Inflammation

Eylea is contraindicated in patients with active intraocular inflammation.

Hypersensitivity

Eylea is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in Eylea. Hypersensitivity reactions may manifest as severe intraocular inflammation.

Warnings and Precautions

Endophthalmitis and Retinal Detachments

Intravitreal injections, including those with Eylea, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must always be used when administering Eylea. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately [see Dosage and Administration (2.6) and Patient Counseling Information (17)].

Increase in Intraocular Pressure

Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with Eylea [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.6)].

Thromboembolic Events

There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including Eylea. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence in the VIEW1 and VIEW2 wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with Eylea [see Clinical Studies (14.1)]. The incidence in the COPERNICUS and GALILEO CRVO studies during the first 6 months was 0% (0/218) in patients treated with Eylea 2 mg every 4 weeks compared with 1.4% (2/142) in patients receiving sham treatment [see Clinical Studies (14.2)]. The incidence in the VIVID and VISTA DME studies during the 52 weeks was 3.3% (19 out of 578) in the combined group of patients treated with Eylea compared with 2.8% (8 out of 287) in the control group [see Clinical Studies (14.3)].

Adverse Reactions

The following adverse reactions are discussed in greater detail in the Warnings and Precautions (5) section of the labeling:

  • Endophthalmitis and retinal detachments
  • Increased intraocular pressure
  • Thromboembolic events

The most common adverse reactions (≥5%) reported in patients receiving Eylea were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.

Injection Procedure

Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with Eylea including endophthalmitis, retinal detachment, cataract, intraocular pressure increased, and vitreous detachment.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.

A total of 2620 patients treated with Eylea constituted the safety population in six phase 3 studies. Among those, 2019 patients were treated with the recommended dose of 2 mg.

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The data described below reflect exposure to Eylea in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months [see Clinical Studies (14.1)].

Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies
Adverse Reactions Eylea
(N=1824)
Active Control (ranibizumab)
(N=595)
Conjunctival hemorrhage 25% 28%
Eye pain 9% 9%
Cataract 7% 7%
Vitreous detachment 6% 6%
Vitreous floaters 6% 7%
Intraocular pressure increased 5% 7%
Conjunctival hyperemia 4% 8%
Corneal erosion 4% 5%
Detachment of the retinal pigment epithelium 3% 3%
Injection site pain 3% 3%
Foreign body sensation in eyes 3% 4%
Lacrimation increased 3% 1%
Vision blurred 2% 2%
Intraocular inflammation 2% 3%
Retinal pigment epithelium tear 2% 1%
Injection site hemorrhage 1% 2%
Eyelid edema 1% 2%
Corneal edema 1% 1%

Less common serious adverse reactions reported in <1% of the patients treated with Eylea were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis.

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The data described below reflect exposure to Eylea in 218 patients with macular edema following CRVO treated with 2 mg dose in 2 double-masked, controlled clinical studies (COPERNICUS and GALILEO) for 6 months [see Clinical Studies (14.2)].

Table 2: Most Common Adverse Reactions (≥1%) in CRVO Studies
Adverse Reactions Eylea
(N=218)
Control
(N=142)
Eye pain 13% 5%
Conjunctival hemorrhage 12% 11%
Intraocular pressure increased 8% 6%
Corneal erosion 5% 4%
Vitreous floaters 5% 1%
Conjunctival hyperemia 5% 3%
Foreign body sensation in eyes 3% 5%
Vitreous detachment 3% 4%
Lacrimation increased 3% 4%
Injection site pain 3% 1%
Vision blurred 1% <1%
Intraocular inflammation 1% 1%

Less common adverse reactions reported in <1% of the patients treated with Eylea were cataract, eyelid edema, corneal edema, retinal tear, hypersensitivity, and endophthalmitis.

Diabetic Macular Edema (DME)

The data described below reflect exposure to Eylea in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) for 52 weeks [see Clinical Studies (14.3)].

Table 3: Most Common Adverse Reactions (≥1%) in DME Studies
Adverse Reactions Eylea
(N=578)
Control
(N=287)
Conjunctival hemorrhage 28% 17%
Eye pain 9% 6%
Cataract 8% 9%
Vitreous floaters 6% 3%
Corneal erosion 5% 3%
Intraocular pressure increased 5% 3%
Conjunctival hyperemia 5% 6%
Vitreous detachment 3% 3%
Foreign body sensation in eyes 3% 3%
Lacrimation increased 3% 2%
Vision blurred 2% 2%
Intraocular inflammation 2% <1%
Injection site pain 2% <1%

Less common adverse reactions reported in <1% of the patients treated with Eylea were hypersensitivity, eyelid edema, corneal edema, retinal detachment, injection site hemorrhage, and retinal tear.

Immunogenicity

As with all therapeutic proteins, there is a potential for an immune response in patients treated with Eylea. The immunogenicity of Eylea was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Eylea in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Eylea with the incidence of antibodies to other products may be misleading.

In the wet AMD, CRVO, and DME studies, the pre-treatment incidence of immunoreactivity to Eylea was approximately 1% to 3% across treatment groups. After dosing with Eylea for 52 weeks (wet AMD), 24 weeks (CRVO), or 52 weeks (DME), antibodies to Eylea were detected in a similar percentage range of patients. In the wet AMD, CRVO, and DME studies, there were no differences in efficacy or safety between patients with or without immunoreactivity.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg.

There are no adequate and well-controlled studies in pregnant women. Eylea should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted in human milk, a risk to the breastfed child cannot be excluded. Eylea is not recommended during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue treatment with Eylea, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Eylea in pediatric patients have not been established.

Geriatric Use

In the clinical studies, approximately 76% (1996/2610) of patients randomized to treatment with Eylea were ≥65 years of age and approximately 47% (1229/2610) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

Eylea Description

Eylea (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.

Eylea is a sterile, clear, and colorless to pale yellow solution. Eylea is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of Eylea (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).

Eylea - Clinical Pharmacology

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 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. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Pharmacodynamics

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions. [see Clinical Studies (14.1)].

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

Reductions in mean retinal thickness were observed in COPERNICUS and GALILEO at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions. [see Clinical Studies (14.2)].

Diabetic Macular Edema (DME)

Reductions in mean retinal thickness were observed in VIVID and VISTA at week 52 compared to baseline. Anatomic data were not used to influence Eylea treatment decisions. [see Clinical Studies (14.3)].

Pharmacokinetics

Eylea is administered intravitreally to exert local effects in the eye. In patients with wet AMD, CRVO, or DME, following intravitreal administration of Eylea, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).

Absorption/Distribution

Following intravitreal administration of 2 mg per eye of Eylea to patients with wet AMD, CRVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. 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.

The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L.

Metabolism/Elimination

Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept.

Specific Populations

Renal Impairment

Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a CRVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, CRVO, or DME patients.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per 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. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.

Animal Toxicology and/or Pharmacology

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in humans after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies [see Clinical Studies (14)].

Clinical Studies

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The safety and efficacy of Eylea were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with Eylea) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) Eylea administered 2 mg every 8 weeks following 3 initial monthly doses (Eylea 2Q8); 2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); 3) Eylea 0.5 mg administered every 4 weeks (Eylea 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Data are available through week 52. Both Eylea 2Q8 and Eylea 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group.

Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 4 and Figure 8 below.

Table 4: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and VIEW2 Studies
VIEW1 VIEW2
Eylea
2 mg Q8 weeks *
Eylea
2 mg Q4 weeks
ranibizumab
0.5 mg Q4 weeks
Eylea
2 mg Q8 weeks *
Eylea
2 mg Q4 weeks
ranibizumab
0.5 mg Q4 weeks
Full Analysis Set N=301 N=304 N=304 N=306 N=309 N=291
BCVA = Best Corrected Visual Acuity; CI = Confidence Interval; ETDRS = Early Treatment Diabetic Retinopathy Study; LOCF = Last Observation Carried Forward (baseline values are not carried forward); 95.1% confidence intervals were presented to adjust for safety assessment conducted during the study.
*
After treatment initiation with 3 monthly doses
Eylea group minus the ranibizumab group
Efficacy Outcomes
Proportion of patients who maintained visual acuity (%)
(<15 letters of BCVA loss)
94% 95% 94% 95% 95% 95%
Difference (%)
(95.1% CI)
0.6
(-3.2, 4.4)
1.3
(-2.4, 5.0)
0.6
(-2.9, 4.0)
-0.3
(-4.0, 3.3)
Mean change in BCVA as measured by ETDRS letter score from Baseline 7.9 10.9 8.1 8.9 7.6 9.4
Difference in LS mean
(95.1% CI)
0.3
(-2.0, 2.5)
3.2
(0.9, 5.4)
-0.9
(-3.1, 1.3)
-2.0
(-4.1, 0.2)
Number of patients who gained at least 15 letters of vision from Baseline (%) 92
(31%)
114
(38%)
94
(31%)
96
(31%)
91
(29%)
99
(34%)
Difference (%)
(95.1% CI)
-0.4
(-7.7, 7.0)
6.6
(-1.0, 14.1)
-2.6
(-10.2, 4.9)
-4.6
(-12.1, 2.9)

Figure 8: Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and VIEW2 Studies

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The safety and efficacy of Eylea were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with Eylea) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89 years with a mean of 64 years.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the Eylea 2 mg Q4 group was superior to the control group for the primary endpoint.

Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 5 and Figure 9 below.

Table 5: Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in COPERNICUS and GALILEO Studies
COPERNICUS GALILEO
Control Eylea
2 mg Q4 weeks
Control Eylea
2 mg Q4 weeks
N=73 N=114 N=68 N=103
*
Difference is Eylea 2 mg Q4 weeks minus Control
Difference and CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for baseline factors; 95.1% confidence intervals were presented to adjust for the multiple assessments conducted during the study.
p<0.01 compared with control
§
LS mean and CI based on an ANCOVA model
Efficacy Outcomes
Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 12% 56% 22% 60%
Weighted Difference *, (%)
(95.1% CI)
44.8%
(32.9, 56.6)
38.3%
(24.4, 52.1)
Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) -4.0
(18.0)
17.3
(12.8)
3.3
(14.1)
18.0
(12.2)
Difference in LS mean *,§
(95.1% CI)
21.7
(17.3, 26.1)
14.7
(10.7, 18.7)

Figure 9: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in COPERNICUS and GALILEO Studies

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.

Diabetic Macular Edema (DME)

The safety and efficacy of Eylea were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Patient ages ranged from 23 to 87 years with a mean of 63 years.

Of those, 576 were randomized to Eylea groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) Eylea administered 2 mg every 8 weeks following 5 initial monthly injections (Eylea 2Q8); 2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the Eylea groups could receive laser and patients in the laser group could receive Eylea.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both Eylea 2Q8 and Eylea 2Q4 groups was statistically superior to the control group.

Results from the analysis of the VIVID and VISTA studies are shown in Table 6 and Figure 10 below.

Table 6: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIVID and VISTA Studies
VIVID VISTA
Eylea
2 mg Q8 weeks *
Eylea
2 mg Q4 weeks
Control Eylea
2 mg Q8 weeks *
Eylea
2 mg Q4 weeks
Control
Full Analysis Set N=135 N=136 N=132 N=151 N=154 N=154
*
After treatment initiation with 5 monthly injections
LS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, protocol specified stratification factors were included in the model.
Difference is Eylea group minus control group
§
p-value <0.01 compared with control
Difference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors.
Efficacy Outcomes
Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 10.7
(9.3)
10.5
(9.6)
1.2
(10.6)
10.7
(8.2)
12.5
(9.5)
0.2
(12.5)
Difference, in LS mean
(97.5% CI)
9.1§
(6.3, 11.8)
9.3§
(6.5, 12.0)
10.5§
(7.7, 13.2)
12.2§
(9.4, 15.0)
Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 33.3% 32.4% 9.1% 31.1% 41.6% 7.8%
Adjusted Difference, (%)
(97.5% CI)
24.2%§
(13.5, 34.9)
23.3%§
(12.6, 33.9)
23.3%§
(13.5, 33.1)
34.2%§
(24.1, 44.4)

Figure 10: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in VIVID and VISTA Studies

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.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations.

How Supplied/Storage and Handling

Each Vial is for single eye use only. Eylea is supplied in the following presentation [see Dosage and Administration (2.5) and (2.6)].

NDC NUMBER CARTON TYPE CARTON CONTENTS
61755-005-02 Vial one single-use, sterile, 3-mL, glass vial designed to deliver 0.05 mL of 40 mg/mL Eylea
one 19-gauge × 1½-inch, 5-micron, filter needle for withdrawal of the vial contents
one 30-gauge × ½-inch injection needle for intravitreal injection
one 1-mL syringe for administration
one package insert

Storage

Eylea should be refrigerated at 2°C to 8ºC (36°F to 46ºF). Do Not Freeze. Do not use beyond the date stamped on the carton and container label. Protect from light. Store in the original carton until time of use.

Patient Counseling Information

In the days following Eylea administration, patients are at risk of developing endophthalmitis or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an ophthalmologist [see Warnings and Precautions (5.1)].

Patients may experience temporary visual disturbances after an intravitreal injection with Eylea and the associated eye examinations [see Adverse Reactions (6)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

 
REGENERON

Manufactured by:

Regeneron Pharmaceuticals, Inc.

777 Old Saw Mill River Road

Tarrytown, NY 10591-6707

U.S. License Number 1760

Eylea is a registered trademark of Regeneron Pharmaceuticals, Inc.

© 2014, Regeneron Pharmaceuticals, Inc.

All rights reserved.

Issue Date: July 2014

Initial U.S. Approval: 2011

Regeneron U.S. Patents 7,306,799; 7,531,173; 7,608,261; 7,070,959; 7,374,757; 7,374,758, and other pending patents

PRINCIPAL DISPLAY PANEL - 2 mg/0.05 mL Vial Carton

NDC 61755-005-02

Eylea®
(aflibercept) Injection

For Intravitreal Injection

2 mg/0.05 mL
Single-use Vial

Rx ONLY

Eylea 
aflibercept injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:61755-005
Route of Administration INTRAVITREAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
aflibercept (aflibercept) aflibercept 40 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
sodium phosphate  
sodium chloride  
polysorbate 20  
sucrose  
Packaging
# Item Code Package Description
1 NDC:61755-005-02 1 VIAL, SINGLE-USE in 1 CARTON
1 0.05 mL in 1 VIAL, SINGLE-USE
2 NDC:61755-005-55 1 VIAL, SINGLE-USE in 1 CARTON
2 0.05 mL in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125387 11/21/2011
Labeler - Regeneron Pharmaceuticals, Inc. (194873139)
Establishment
Name Address ID/FEI Operations
Regeneron Pharmaceuticals, Inc. 945589711 API MANUFACTURE(61755-005), ANALYSIS(61755-005), LABEL(61755-005), MANUFACTURE(61755-005)
Revised: 07/2014
 
Regeneron Pharmaceuticals, Inc.
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