DailyMed Label: EYLEA

DailyMed Label: EYLEA

2023

DailyMed Prescription

EYLEA

aflibercept

Regeneron Pharmaceuticals, Inc.

NDC: 61755-005

NDC: 61755-005

NDC: 61755-005

NDC: 61755-005

NDC: 61755-005

NDC: 61755-005

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.

EYLEA is indicated for the treatment of:

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

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

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 )

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

Risk Summary Adequate and well-controlled studies with EYLEA have not been conducted in pregnant women. Aflibercept produced adverse embryofetal effects in rabbits, including external, visceral, and skeletal malformations. A fetal No Observed Adverse Effect Level (NOAEL) was not identified. At the lowest dose shown to produce adverse embryofetal effects, systemic exposures (based on AUC for free aflibercept) were approximately 6 times higher than AUC values observed in humans after a single intravitreal treatment at the recommended clinical dose [see Animal Data ]. Animal reproduction studies are not always predictive of human response, and it is not known whether EYLEA can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for aflibercept [see Clinical Pharmacology (12.1) ], treatment with EYLEA may pose a risk to human embryofetal development. EYLEA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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. NDC NUMBER CARTON TYPE CARTON CONTENTS 61755-005-01 Pre-filled Syringe one blister pack containing one EYLEA 2 mg (0.05 mL of a 40 mg/mL solution) sterile, single-dose pre-filled glass syringe one Prescribing Information 61755-005-02 Vial Kit with Injection Components one EYLEA 2 mg (0.05 mL of a 40 mg/mL solution) single-dose glass vial one 18-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 Prescribing Information

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.

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 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. Table 5: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and VIEW2 Studies VIEW1 VIEW2 EYLEA 2 mg Q8 weeks After treatment initiation with 3 monthly doses EYLEA 2 mg Q4 weeks ranibizu-mab 0.5 mg Q4 weeks EYLEA 2 mg Q8 weeks EYLEA 2 mg Q4 weeks ranibizu-mab 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 Efficacy Outcomes Proportion of patients who maintained visual acuity (%) (<15 letters of BCVA loss) 94% 95% 94% 95% 95% 95% Difference EYLEA group minus the ranibizumab group (%) (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) 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.

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