These Highlights Do Not Include All The Information Needed To Use Eylea Safely And Effectively. See Full Prescribing Information For Eylea.

Recommended Dosage

The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters of 40 mg/mL solution) administered by intravitreal injection. Treatment is initiated with a single injection per eligible eye and may be given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval between doses injected into the same eye should be at least 10 days [see Clinical Pharmacology (12.3) and Clinical Studies (14.6)].

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

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 (aflibercept) Injection is a sterile, clear, and colorless to pale yellow solution. EYLEA does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose pre-filled glass syringe or a single-dose glass vial designed to deliver 0.05 mL (50 microliters) of solution containing 2 mg of aflibercept in polysorbate 20 (0.015 mg), sodium chloride (0.117 mg), sodium phosphate monobasic monohydrate (0.055 mg), sodium phosphate dibasic heptahydrate (0.027 mg), sucrose (2.5 mg) and water for injection with a pH of 6.2.

Each pre-filled syringe or vial is a clear, colorless to pale yellow solution and is for single eye use only. EYLEA is supplied in the following presentations [see Dosage and Administration (2.1), (2.2), (2.3), (2.4) and (2.9)]. Discard unused portion.

The safety and effectiveness of EYLEA have been demonstrated in two clinical studies of pre-term infants with ROP.

These two studies randomized pre-term infants between initial treatment with EYLEA or laser. Efficacy of each treatment is supported by the demonstration of a clinical course which was better than would have been expected without treatment [see Dosage and Administration (2.9), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.6)].

In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

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, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. Similarly, after unilateral or bilateral dosing in pediatric ROP studies, antibodies to EYLEA were detected in less than 1% of patients.

There were no differences in efficacy or safety between patients with or without immunoreactivity.

• Ocular or periocular infection (4.1)
• Active intraocular inflammation (4.2)
• Hypersensitivity (4.3)

The following potentially serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see Contraindications (4.3)]
• Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion [see Warnings and Precautions (5.1)]
• Increase in intraocular pressure [see Warnings and Precautions (5.2)]
• Thromboembolic events [see Warnings and Precautions (5.4)]

EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, 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).

EYLEA is indicated for the treatment of:

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.

Refrigerate EYLEA at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyond the date stamped on the carton and container label. Store in the original carton until time of use to protect from light. Do not open sealed blister tray until time of use.

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 of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the EYLEA group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 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; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies.

• Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately. (5.1)
• Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2)
• In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP monitoring (5.3)
• There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.4)

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
  • The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.5)
  • Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). (2.5)
  • Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly. (2.5)
• Macular Edema Following Retinal Vein Occlusion (RVO)
  • The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly). (2.6)
• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
  • The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.7, 2.8)
  • Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). (2.7, 2.8)
• Retinopathy of Prematurity (ROP)
  • The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters of 40 mg/mL solution) administered by intravitreal injection. Treatment may be given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval between doses injected into the same eye should be at least 10 days. (2.9)

EYLEA is a clear, colorless to pale yellow solution available as:

• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose pre-filled glass syringe
• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose glass vial

The following adverse reactions have been identified during postapproval use of aflibercept. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye disorders:

• Retinal vasculitis and occlusive retinal vasculitis related to intravitreal injection with aflibercept (reported at a rate of 0.6 and 0.2 per 1 million injections, respectively, based on postmarketing experience from November 2011 until November 2023).
• Scleritis.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

Efficacy and safety data of EYLEA in diabetic retinopathy (DR) are derived from the VIVID, VISTA, and PANORAMA studies.

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 2980 adult patients treated with EYLEA constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

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. Protocol-specified visits occurred every 28±7 days. 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. This statistically superior improvement in BCVA was maintained at week 100 in both studies.

Results from the analysis of the VIVID and VISTA studies are shown in Table 8 and Figure 17 below.

Figure 17: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 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.

In the days following EYLEA administration, patients are at risk of developing endophthalmitis, retinal detachment, or retinal vasculitis with or without occlusion. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients and/or caregivers 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. In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP monitoring.

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.

Pre-filled syringe: Inject by pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. A small residual volume may remain in the syringe after a full dose has been injected. This is normal. Do not administer any residual solution observed in the syringe.

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 and/or caregivers should be instructed to report any signs and/or 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 sterile, pre-filled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new sterile, pre-filled syringe or 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.

EYLEA is contraindicated in patients with ocular or periocular infections.

EYLEA is contraindicated in patients with active intraocular inflammation.

For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician.

Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided.

Vial: A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL Luer lock syringe and a 30-gauge × ½-inch sterile injection needle are needed.

EYLEA is available packaged as follows:

• Pre-filled Syringe
• Vial Kit with Injection Components (filter needle, syringe, injection needle)

[see How Supplied/Storage and Handling (16)].

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 vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.4)].

Efficacy and safety data of EYLEA in ROP are derived from two studies (BUTTERFLEYE and FIREFLEYE/FIREFLEYE NEXT). BUTTERFLEYE was a 52-week study. FIREFLEYE included 24 weeks of treatment and follow-up. FIREFLEYE NEXT was an observational follow-up of FIREFLEYE through week 52.

Both BUTTERFLEYE and FIREFLEYE studies assessed the efficacy, safety and tolerability of EYLEA in randomized, 2-arm, open-label, parallel-group studies. The studies were conducted in pre-term infants with ROP providing a comparison between EYLEA treatment and laser photocoagulation therapy (laser). Each eligible eye received the assigned study treatment at baseline. Re-treatment and/or rescue treatment was administered if needed based on pre-specified criteria. Rescue treatment could potentially include the alternative treatment (EYLEA or laser). Re-treatment with aflibercept, if required, was administered up to 2 times in a particular eye, with at least 28 days between consecutive injections.

Eligible patients had a maximum gestational age at birth of 32 weeks or a maximum birth weight of 1500 g, had to weigh > 800 g on the day of treatment and had treatment-naïve ROP classified according to the International Classification for Retinopathy of Prematurity (IC-ROP 2005) in at least one eye with one of the following retinal findings:

• ROP Zone 1 Stage 1+, 2+, 3 or 3+, or
• ROP Zone II Stage 2+ or 3+, or
• AP-ROP (aggressive posterior ROP)

The primary efficacy endpoint of each study was the proportion of patients with absence of active ROP and unfavorable structural outcomes (retinal detachment, macular dragging, macular fold, retrolental opacity) at week 52 of chronological age.

In BUTTERFLEYE, patients were randomized in a 3:1 ratio to receive 1 of 2 treatment regimens: 1) EYLEA 0.4 mg at baseline and if required, up to 2 additional injections and 2) laser photocoagulation in each eye at baseline and if required, retreatment. In FIREFLEYE, patients were randomized to the same two treatments, but in a 2:1 ratio. Rescue treatment was administered if required, per pre-specified criteria. In both studies, greater than 92% of all treated patients in the aflibercept group received bilateral injections during the study.

Results from week 52 of chronological age in the BUTTERFLEYE and FIREFLEYE/FIREFLEYE NEXT studies are shown in Table 12 below.

The proportion of patients without clinically significant reactivations of ROP who also did not develop unfavorable structural outcomes was higher in each arm of each study than would have been expected in infants who had not received treatment. Neither trial demonstrated superiority of one arm compared to the other arm. Neither trial demonstrated inferiority of one arm compared to the other arm.

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

The glass vial is for one-time use in one eye only.

Use aseptic technique to carry out the following preparation steps:

Prepare for intravitreal injection with the following medical devices for single use:

• a 5-micron sterile filter needle (18-gauge × 1½-inch)
• a 1-mL sterile Luer lock syringe with marking to measure 0.05 mL for adults or 0.01 mL for pre-term infants with ROP
• a sterile injection needle (30-gauge × ½-inch)

• Remove the protective plastic cap from the vial (see Figure 6).
  
  Figure 6:

• Clean the top of the vial with an alcohol wipe (see Figure 7).
  
  Figure 7:

• Remove the 18-gauge × 1½-inch, 5-micron, filter needle and the 1-mL syringe from their packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 8).
  
  

  Figure 8:
  
  

• 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.
• 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 Figure 9a and Figure 9b).

  Figure 9a:	Figure 9b:

• Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
• 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.
• Remove the 30-gauge × ½-inch injection needle from its packaging and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 10).

  Figure 10:
  
  

• When ready to administer EYLEA, remove the plastic needle shield from the needle.
• 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 11).
  
  Figure 11:
  Administration in Adults:
• To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger rod so that the plunger edge aligns with the line that marks 0.05 mL on the syringe (see Figure 12a and Figure 12b).

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 adult patients after an intravitreal dose of 2 mg and 2-fold higher based on C_max when compared to corresponding values observed in pre-term infants from FIREFLEYE. Similar effects were not seen in other clinical studies [see Clinical Studies (14)].

NDC 61755-005-02

EYLEA^®

(aflibercept) Injection

For Intravitreal Injection

2 mg (0.05 mL of a 40 mg/mL solution)

Single-Dose Vial

Carton contents: Each EYLEA carton contains

• one single-dose, 3-mL, glass vial of EYLEA
• one 18-gauge x 1½-inch, 5-micron, filter needle
  
  for withdrawal of the vial contents (filter needle not
  
  to be used for intravitreal injection)
• one 30-gauge x ½-inch needle for intravitreal injection
• one 1-mL plastic syringe for administration
• one Prescribing Information

Rx ONLY

NDC 61755-005-01

Rx ONLY

EYLEA^®

(aflibercept) Injection

For Intravitreal Injection

2 mg (0.05 mL of a 40 mg/mL solution)

Single-dose Pre-filled Syringe

Carton contents:

• one blister pack containing
  
  one sterile, single-dose
  
  pre-filled glass syringe
• one Prescribing Information

REGENERON

Reactivation of abnormal angiogenesis and tortuosity may occur following treatment with EYLEA. Infants should be monitored closely after injection with EYLEA until retinal vascularization has completed or until the examiner is assured that reactivation of ROP will not occur. In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP monitoring and additional EYLEA injections and/or laser treatments may be necessary.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see Clinical Studies (14.2), (14.3)].

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) for free aflibercept that was approximately 1500 times higher than the systemic exposure observed in adult patients after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.

The EYLEA pre-filled glass syringe is sterile and for one-time use in one eye only. Do not use the EYLEA pre-filled syringe for the treatment of ROP.

The pre-filled syringe should be inspected visually prior to administration. Do not use if particulates, cloudiness, or discoloration are visible, or if the package is open or damaged. The appearance of the syringe cap on the pre-filled syringe may vary (for example, color and design). Do not use if any part of the pre-filled syringe is damaged or if the syringe cap is detached from the Luer lock.

The intravitreal injection should be performed with a 30-gauge × ½-inch injection needle (not provided).

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 50 microliters). The excess volume must be discarded prior to the administration.

PRE-FILLED SYRINGE DESCRIPTION – Figure 1:

Use aseptic technique to carry out the following steps:

1. PREPARE

When ready to administer EYLEA, open the carton and remove sterilized blister pack. Carefully peel open the sterilized blister pack ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready for assembly.

2. REMOVE SYRINGE

Using aseptic technique, remove the syringe from the sterilized blister pack.

3. TWIST OFF SYRINGE CAP

Twist off (do not snap off) the syringe cap by holding the syringe in one hand and the syringe cap with the thumb and forefinger of the other hand (see Figure 2).

Note: To avoid compromising the sterility of the product, do not pull back on the plunger.

Figure 2:

4. ATTACH NEEDLE

Using aseptic technique, firmly twist a 30-gauge × ½-inch injection needle onto the Luer lock syringe tip (see Figure 3).

Figure 3:

Note: When ready to administer EYLEA, remove the plastic needle shield from the needle.

5. DISLODGE AIR BUBBLES

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 4).

Figure 4:

6. EXPEL AIR AND SET THE DOSE

To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod to align the plunger dome edge (see Figure 5a) with the black dosing line on the syringe (equivalent to 50 microliters) (see Figure 5b).

7. The pre-filled syringe is for one-time use in one eye only. After injection any unused product must be discarded.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.1)]. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly.

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, up to week 52, 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). Protocol-specified visits occurred every 28±3 days. 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. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group in year 1.

Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 5 and Figure 14 below.

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

Figure 14: Mean Change in Visual Acuity from Baseline to Week 96* in VIEW1 and VIEW2 Studies

*Patient dosing schedules were individualized from weeks 52 to 96 using a modified 12-week dosing regimen.

VIEW1 and VIEW2 studies were both 96 weeks in duration. However, after 52 weeks patients no longer followed a fixed dosing schedule. Between week 52 and week 96, patients continued to receive the drug and dosage strength to which they were initially randomized on a modified 12 week dosing schedule (doses at least every 12 weeks and additional doses as needed). Therefore, during the second year of these studies there was no active control comparison arm.

The safety and efficacy of EYLEA were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with EYLEA) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 42 to 94 years with a mean of 65 years.

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. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.

Detailed results from the analysis of the VIBRANT study are shown in Table 7 and Figure 16 below.

Figure 16: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study

Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations.

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. Protocol-specified visits occurred every 28±7 days. 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 6 and Figure 15 below.

Figure 15: 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.

Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)] and, more rarely, retinal vasculitis with or without occlusion [see Adverse Reactions (6.2)]. Proper aseptic injection technique must always be used when administering EYLEA. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately [see Dosage and Administration (2.4) and Patient Counseling Information (17)].

Recommended Dosage

The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters of 40 mg/mL solution) administered by intravitreal injection. Treatment is initiated with a single injection per eligible eye and may be given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval between doses injected into the same eye should be at least 10 days [see Clinical Pharmacology (12.3) and Clinical Studies (14.6)].

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

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 (aflibercept) Injection is a sterile, clear, and colorless to pale yellow solution. EYLEA does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose pre-filled glass syringe or a single-dose glass vial designed to deliver 0.05 mL (50 microliters) of solution containing 2 mg of aflibercept in polysorbate 20 (0.015 mg), sodium chloride (0.117 mg), sodium phosphate monobasic monohydrate (0.055 mg), sodium phosphate dibasic heptahydrate (0.027 mg), sucrose (2.5 mg) and water for injection with a pH of 6.2.

Each pre-filled syringe or vial is a clear, colorless to pale yellow solution and is for single eye use only. EYLEA is supplied in the following presentations [see Dosage and Administration (2.1), (2.2), (2.3), (2.4) and (2.9)]. Discard unused portion.

The safety and effectiveness of EYLEA have been demonstrated in two clinical studies of pre-term infants with ROP.

These two studies randomized pre-term infants between initial treatment with EYLEA or laser. Efficacy of each treatment is supported by the demonstration of a clinical course which was better than would have been expected without treatment [see Dosage and Administration (2.9), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.6)].

In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

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, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. Similarly, after unilateral or bilateral dosing in pediatric ROP studies, antibodies to EYLEA were detected in less than 1% of patients.

There were no differences in efficacy or safety between patients with or without immunoreactivity.

• Ocular or periocular infection (4.1)
• Active intraocular inflammation (4.2)
• Hypersensitivity (4.3)

The following potentially serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see Contraindications (4.3)]
• Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion [see Warnings and Precautions (5.1)]
• Increase in intraocular pressure [see Warnings and Precautions (5.2)]
• Thromboembolic events [see Warnings and Precautions (5.4)]

EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, 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).

EYLEA is indicated for the treatment of:

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.

Refrigerate EYLEA at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyond the date stamped on the carton and container label. Store in the original carton until time of use to protect from light. Do not open sealed blister tray until time of use.

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 of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the EYLEA group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 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; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies.

• Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately. (5.1)
• Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2)
• In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP monitoring (5.3)
• There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.4)

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
  • The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.5)
  • Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). (2.5)
  • Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly. (2.5)
• Macular Edema Following Retinal Vein Occlusion (RVO)
  • The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly). (2.6)
• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
  • The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.7, 2.8)
  • Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). (2.7, 2.8)
• Retinopathy of Prematurity (ROP)
  • The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters of 40 mg/mL solution) administered by intravitreal injection. Treatment may be given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval between doses injected into the same eye should be at least 10 days. (2.9)

EYLEA is a clear, colorless to pale yellow solution available as:

• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose pre-filled glass syringe
• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose glass vial

The following adverse reactions have been identified during postapproval use of aflibercept. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye disorders:

• Retinal vasculitis and occlusive retinal vasculitis related to intravitreal injection with aflibercept (reported at a rate of 0.6 and 0.2 per 1 million injections, respectively, based on postmarketing experience from November 2011 until November 2023).
• Scleritis.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

Efficacy and safety data of EYLEA in diabetic retinopathy (DR) are derived from the VIVID, VISTA, and PANORAMA studies.

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 2980 adult patients treated with EYLEA constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

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. Protocol-specified visits occurred every 28±7 days. 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. This statistically superior improvement in BCVA was maintained at week 100 in both studies.

Results from the analysis of the VIVID and VISTA studies are shown in Table 8 and Figure 17 below.

Figure 17: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 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.

In the days following EYLEA administration, patients are at risk of developing endophthalmitis, retinal detachment, or retinal vasculitis with or without occlusion. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients and/or caregivers 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. In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP monitoring.

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.

Pre-filled syringe: Inject by pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. A small residual volume may remain in the syringe after a full dose has been injected. This is normal. Do not administer any residual solution observed in the syringe.

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 and/or caregivers should be instructed to report any signs and/or 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 sterile, pre-filled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new sterile, pre-filled syringe or 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.

EYLEA is contraindicated in patients with ocular or periocular infections.

EYLEA is contraindicated in patients with active intraocular inflammation.

For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician.

Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided.

Vial: A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL Luer lock syringe and a 30-gauge × ½-inch sterile injection needle are needed.

EYLEA is available packaged as follows:

• Pre-filled Syringe
• Vial Kit with Injection Components (filter needle, syringe, injection needle)

[see How Supplied/Storage and Handling (16)].

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 vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.4)].

Efficacy and safety data of EYLEA in ROP are derived from two studies (BUTTERFLEYE and FIREFLEYE/FIREFLEYE NEXT). BUTTERFLEYE was a 52-week study. FIREFLEYE included 24 weeks of treatment and follow-up. FIREFLEYE NEXT was an observational follow-up of FIREFLEYE through week 52.

Both BUTTERFLEYE and FIREFLEYE studies assessed the efficacy, safety and tolerability of EYLEA in randomized, 2-arm, open-label, parallel-group studies. The studies were conducted in pre-term infants with ROP providing a comparison between EYLEA treatment and laser photocoagulation therapy (laser). Each eligible eye received the assigned study treatment at baseline. Re-treatment and/or rescue treatment was administered if needed based on pre-specified criteria. Rescue treatment could potentially include the alternative treatment (EYLEA or laser). Re-treatment with aflibercept, if required, was administered up to 2 times in a particular eye, with at least 28 days between consecutive injections.

Eligible patients had a maximum gestational age at birth of 32 weeks or a maximum birth weight of 1500 g, had to weigh > 800 g on the day of treatment and had treatment-naïve ROP classified according to the International Classification for Retinopathy of Prematurity (IC-ROP 2005) in at least one eye with one of the following retinal findings:

• ROP Zone 1 Stage 1+, 2+, 3 or 3+, or
• ROP Zone II Stage 2+ or 3+, or
• AP-ROP (aggressive posterior ROP)

The primary efficacy endpoint of each study was the proportion of patients with absence of active ROP and unfavorable structural outcomes (retinal detachment, macular dragging, macular fold, retrolental opacity) at week 52 of chronological age.

In BUTTERFLEYE, patients were randomized in a 3:1 ratio to receive 1 of 2 treatment regimens: 1) EYLEA 0.4 mg at baseline and if required, up to 2 additional injections and 2) laser photocoagulation in each eye at baseline and if required, retreatment. In FIREFLEYE, patients were randomized to the same two treatments, but in a 2:1 ratio. Rescue treatment was administered if required, per pre-specified criteria. In both studies, greater than 92% of all treated patients in the aflibercept group received bilateral injections during the study.

Results from week 52 of chronological age in the BUTTERFLEYE and FIREFLEYE/FIREFLEYE NEXT studies are shown in Table 12 below.

The proportion of patients without clinically significant reactivations of ROP who also did not develop unfavorable structural outcomes was higher in each arm of each study than would have been expected in infants who had not received treatment. Neither trial demonstrated superiority of one arm compared to the other arm. Neither trial demonstrated inferiority of one arm compared to the other arm.

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

The glass vial is for one-time use in one eye only.

Use aseptic technique to carry out the following preparation steps:

Prepare for intravitreal injection with the following medical devices for single use:

• a 5-micron sterile filter needle (18-gauge × 1½-inch)
• a 1-mL sterile Luer lock syringe with marking to measure 0.05 mL for adults or 0.01 mL for pre-term infants with ROP
• a sterile injection needle (30-gauge × ½-inch)

• Remove the protective plastic cap from the vial (see Figure 6).
  
  Figure 6:

• Clean the top of the vial with an alcohol wipe (see Figure 7).
  
  Figure 7:

• Remove the 18-gauge × 1½-inch, 5-micron, filter needle and the 1-mL syringe from their packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 8).
  
  

  Figure 8:
  
  

• 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.
• 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 Figure 9a and Figure 9b).

  Figure 9a:	Figure 9b:

• Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
• 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.
• Remove the 30-gauge × ½-inch injection needle from its packaging and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 10).

  Figure 10:
  
  

• When ready to administer EYLEA, remove the plastic needle shield from the needle.
• 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 11).
  
  Figure 11:
  Administration in Adults:
• To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger rod so that the plunger edge aligns with the line that marks 0.05 mL on the syringe (see Figure 12a and Figure 12b).

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 adult patients after an intravitreal dose of 2 mg and 2-fold higher based on C_max when compared to corresponding values observed in pre-term infants from FIREFLEYE. Similar effects were not seen in other clinical studies [see Clinical Studies (14)].

NDC 61755-005-02

EYLEA^®

(aflibercept) Injection

For Intravitreal Injection

2 mg (0.05 mL of a 40 mg/mL solution)

Single-Dose Vial

Carton contents: Each EYLEA carton contains

• one single-dose, 3-mL, glass vial of EYLEA
• one 18-gauge x 1½-inch, 5-micron, filter needle
  
  for withdrawal of the vial contents (filter needle not
  
  to be used for intravitreal injection)
• one 30-gauge x ½-inch needle for intravitreal injection
• one 1-mL plastic syringe for administration
• one Prescribing Information

Rx ONLY

NDC 61755-005-01

Rx ONLY

EYLEA^®

(aflibercept) Injection

For Intravitreal Injection

2 mg (0.05 mL of a 40 mg/mL solution)

Single-dose Pre-filled Syringe

Carton contents:

• one blister pack containing
  
  one sterile, single-dose
  
  pre-filled glass syringe
• one Prescribing Information

REGENERON

Reactivation of abnormal angiogenesis and tortuosity may occur following treatment with EYLEA. Infants should be monitored closely after injection with EYLEA until retinal vascularization has completed or until the examiner is assured that reactivation of ROP will not occur. In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP monitoring and additional EYLEA injections and/or laser treatments may be necessary.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see Clinical Studies (14.2), (14.3)].

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) for free aflibercept that was approximately 1500 times higher than the systemic exposure observed in adult patients after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.

The EYLEA pre-filled glass syringe is sterile and for one-time use in one eye only. Do not use the EYLEA pre-filled syringe for the treatment of ROP.

The pre-filled syringe should be inspected visually prior to administration. Do not use if particulates, cloudiness, or discoloration are visible, or if the package is open or damaged. The appearance of the syringe cap on the pre-filled syringe may vary (for example, color and design). Do not use if any part of the pre-filled syringe is damaged or if the syringe cap is detached from the Luer lock.

The intravitreal injection should be performed with a 30-gauge × ½-inch injection needle (not provided).

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 50 microliters). The excess volume must be discarded prior to the administration.

PRE-FILLED SYRINGE DESCRIPTION – Figure 1:

Use aseptic technique to carry out the following steps:

1. PREPARE

When ready to administer EYLEA, open the carton and remove sterilized blister pack. Carefully peel open the sterilized blister pack ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready for assembly.

2. REMOVE SYRINGE

Using aseptic technique, remove the syringe from the sterilized blister pack.

3. TWIST OFF SYRINGE CAP

Twist off (do not snap off) the syringe cap by holding the syringe in one hand and the syringe cap with the thumb and forefinger of the other hand (see Figure 2).

Note: To avoid compromising the sterility of the product, do not pull back on the plunger.

Figure 2:

4. ATTACH NEEDLE

Using aseptic technique, firmly twist a 30-gauge × ½-inch injection needle onto the Luer lock syringe tip (see Figure 3).

Figure 3:

Note: When ready to administer EYLEA, remove the plastic needle shield from the needle.

5. DISLODGE AIR BUBBLES

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 4).

Figure 4:

6. EXPEL AIR AND SET THE DOSE

To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod to align the plunger dome edge (see Figure 5a) with the black dosing line on the syringe (equivalent to 50 microliters) (see Figure 5b).

7. The pre-filled syringe is for one-time use in one eye only. After injection any unused product must be discarded.

The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.1)]. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly.

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, up to week 52, 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). Protocol-specified visits occurred every 28±3 days. 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. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group in year 1.

Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 5 and Figure 14 below.

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

Figure 14: Mean Change in Visual Acuity from Baseline to Week 96* in VIEW1 and VIEW2 Studies

*Patient dosing schedules were individualized from weeks 52 to 96 using a modified 12-week dosing regimen.

VIEW1 and VIEW2 studies were both 96 weeks in duration. However, after 52 weeks patients no longer followed a fixed dosing schedule. Between week 52 and week 96, patients continued to receive the drug and dosage strength to which they were initially randomized on a modified 12 week dosing schedule (doses at least every 12 weeks and additional doses as needed). Therefore, during the second year of these studies there was no active control comparison arm.

The safety and efficacy of EYLEA were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with EYLEA) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 42 to 94 years with a mean of 65 years.

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. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.

Detailed results from the analysis of the VIBRANT study are shown in Table 7 and Figure 16 below.

Figure 16: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study

Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations.

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. Protocol-specified visits occurred every 28±7 days. 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 6 and Figure 15 below.

Figure 15: 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.

Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)] and, more rarely, retinal vasculitis with or without occlusion [see Adverse Reactions (6.2)]. Proper aseptic injection technique must always be used when administering EYLEA. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately [see Dosage and Administration (2.4) and Patient Counseling Information (17)].