EYLEA

Wet AMD Treatment Agents

Only for use by physicians trained in these specialized administration techniques.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if particulates, cloudiness, or discoloration are visible, or if the package is open or damaged. Do not use if any part of the prefilled syringe is damaged or if the syringe cap is detached from the Luer lock.[46841]

Do NOT use the prefilled syringe for the treatment of retinopathy of prematurity (ROP).
 
Product Preparation for Eylea
Check the label on the vial or prefilled syringe to ensure you have the correct aflibercept strength.
Single-use vial:
Using aseptic technique, withdraw all the vial contents through a 5-micron 19-gauge filter needle attached to the 1 mL syringe supplied by the manufacturer.
Keep the vial upright and slightly tilted, so that the bevel of the needle can remain submerged in the liquid.
After vial contents are withdrawn, discard the filter needle and replace with the sterile 30-gauge by half-inch needle for the intravitreal injection. Expel any air bubbles and the contents of the syringe until the plunger tip is aligned with the line that marks the appropriate volume (0.05 mL for adult patients or 0.01 mL for premature neonates).
Single-use prefilled syringe:
Using aseptic technique, remove the syringe from the sterilized blister pack.
Twist off (do not snap off) the syringe cap by holding the syringe in 1 hand and the syringe cap with the thumb and forefinger of the other hand.
Attach a 30-gauge by half-inch needle onto Luer lock syringe tip. Holding the syringe with needle tip pointing up, gently tap the syringe with finger to levitate any bubbles. Expel any air bubbles and excess drug by slowly depressing the plunger rod until the plunger dome edge is aligned with the black dosing line on the syringe (equivalent to 0.05 mL).
NOTE: The prefilled syringe contains more than the recommended dose of 2 mg (0.05 mL); the excess volume MUST be discarded prior to administration.[46841]
 
Product Preparation for Eylea HD
Check the label on the vial to ensure you have the correct aflibercept strength.
Use aseptic technique.
Attach the 5-micron 18-gauge filter needle to the 1-mL syringe. Withdraw all the contents of the vial into the syringe. Ensure 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.
Attach the 30-gauge 0.5-inch injection needle to the syringe.
Holding the syringe with the needle pointing up, check for bubbles. If there are bubbles, gently tap the syringe with a finger until bubbles rise to the top. Eliminate all the bubbles and expel excess drug. SLOWLY depress the plunger so the plunger tip aligns with the line that marks 0.07 mL on the syringe.
 
Intravitreous Administration
Use controlled aseptic conditions, which include the use of surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).
Administer adequate anesthesia and a topical broad-spectrum microbicide prior to the injection.
Use each prefilled syringe or vial for the treatment of a single eye ONLY. If the contralateral eye requires treatment, use a new prefilled syringe or vial and change the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles prior to administration to the other eye.
For the prefilled syringe, inject by pressing the plunger carefully and with constant pressure. Do no apply additional pressure once the plunger has reached the bottom of the syringe. A small residual volume may remain in the syringe after injection of the full dose. This is normal. Do not administer any residual solution. After injection, discard any unused product.
For the treatment of ROP, insert the injection needle into the eye 1 mm from the limbus with the needle angled to avoid the lens and to avoid the retina.
Immediately after the intravitreal injection, monitor the patient for elevation in intraocular pressure (IOP). Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. A sterile paracentesis needle should be available if required.
Instruct patients or caregivers to report any symptoms of endophthalmitis or retinal detachment immediately.[46841]

ocular hemorrhage / Delayed / 0-27.0
ocular hypertension / Rapid / 1.0-8.0
thromboembolism / Delayed / 0-6.4
retinal detachment / Delayed / 0-6.0
corneal erosion / Delayed / 2.0-5.0
retinal hemorrhage / Delayed / 0-4.0
endophthalmitis / Delayed / 0-1.0
myocardial infarction / Delayed / Incidence not known
stroke / Early / Incidence not known
vasculitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

cataracts / Delayed / 0-13.0
blurred vision / Early / 1.0-7.0
conjunctival hyperemia / Early / 2.0-5.0
ocular inflammation / Early / 0-3.0
corneal edema / Early / 0-1.0
ocular infection / Delayed / Incidence not known
photophobia / Early / Incidence not known
antibody formation / Delayed / Incidence not known

ocular pain / Early / 2.0-13.0
lacrimation / Early / 3.0-4.0
ocular irritation / Rapid / 2.0-4.0
foreign body sensation / Rapid / 0-4.0
injection site reaction / Rapid / 2.0-3.0
blepharedema / Early / 0-2.0
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known

EYLEA, EYLEA HD

Rx

Recombinant fusion protein that binds VEGF-A and PlGF and inhibits activation
Used for neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and retinopathy of prematurity (ROP)
May cause increased IOP acutely or sustained

2 mg (0.05 mL) via intravitreal injection into the affected eye(s) every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) once every 8 weeks (2 months). Although monthly dosing may continue, additional efficacy was not demonstrated in most patients dosed every 4 weeks vs. every 8 weeks in chronic use. However, some patients may continue to require every 4 week (monthly) dosing after the first 3 months. Patients who have completed 1 year of effective therapy may be treated with 1 dose every 12 weeks; however, this regimen is not as effective as the recommended every 8 weeks dosing regimen, and therefore, these patients should be assessed regularly.

8 mg (0.07 mL) via intravitreal injection into the affected eye(s) every 4 weeks (approximately every 28 days, +/- 7 days) for the first 3 doses, followed by 8 mg (0.07 mL) once every 8 to 16 weeks (+/- 1 week).

2 mg (0.05 mL) by intravitreal injection in the affected eye(s) every 4 weeks (approximately every 28 days, monthly) for 5 months, then 2 mg (0.05 mL) by intravitreal injection in the affected eye(s) every 8 weeks (2 months). Some patients may require every 4 week dosing after the first 5 months. However, additional efficacy was not demonstrated in most patients when administered every 4 weeks vs. every 8 weeks. Guidelines recommend intravitreous anti-vascular endothelial growth factor (anti-VEGF) agents, such as aflibercept, as first-line therapies for the management of central-involved diabetic macular edema (CIDME).

8 mg (0.07 mL) by intravitreal injection in the affected eye(s) every 4 weeks (approximately every 28 days, +/- 7 days) for first 3 doses, followed by 8 mg (0.07 mL) by intravitreal injection in the affected eye(s) once every 8 to 16 weeks (+/- 1 week). Guidelines recommend intravitreous anti-vascular endothelial growth factor (anti-VEGF) agents, such as aflibercept, as first-line therapies for the management of central-involved diabetic macular edema (CIDME).

2 mg (0.05 mL) by intravitreal injection in the affected eye(s) every 4 weeks (approximately every 28 days, monthly) for 5 months, then 2 mg (0.05 mL) by intravitreal injection in the affected eye(s) every 8 weeks (2 months). Some patients may require every 4 week dosing after the first 5 months. However, additional efficacy was not demonstrated in most patients when administered every 4 weeks vs. every 8 weeks. Anti-vascular endothelial growth factor (anti-VEGF) agents, such as aflibercept, may be considered for management of proliferative diabetic retinopathy (PDR), especially if high-risk characteristics are present. Intravitreous anti-VEGF agents can reduce the risk of vision loss in patients with PDR.

8 mg (0.07 mL) by intravitreal injection in the affected eye(s) every 4 weeks (approximately every 28 days, +/- 7 days) for first 3 doses, followed by 8 mg (0.07 mL) by intravitreal injection in the affected eye(s) once every 8 to 12 weeks (+/- 1 week). Anti-vascular endothelial growth factor (anti-VEGF) agents, such as aflibercept, may be considered for management of proliferative diabetic retinopathy (PDR), especially if high-risk characteristics are present. Intravitreous anti-VEGF agents can reduce the risk of vision loss in patients with PDR.

2 mg (0.05 mL) via intravitreal injection into the affected eye(s) every 4 weeks (approximately every 25 days, monthly).

0.4 mg (0.01 mL) via intravitreal injection into the affected eye(s). Treatment may be given bilaterally on the same day. Injections may be repeated in each eye; allow a 10-day treatment interval before injecting into the same eye.

2 mg (0.05 mL) intravitreally every 4 weeks for 3 doses followed by every 8 weeks for 4 doses, or alternately, 2 mg (0.05 mL) intravitreally at baseline and monthly as needed. Assess monthly over 12 months when a dose is not scheduled for as needed intravitreal aflibercept use, which is recommended for loss of 2 or more lines of best-corrected visual acuity, any increase, persistence, or presence of subretinal fluid on spectral domain optical coherence tomography, persistent and/or new leakage on fluorescein angiography, new or persistent subretinal hemorrhage thought to be due to active CNV, or gain of more than 2 lines of best-corrected visual acuity from previous visit. May consider rescue therapy from months 3 to 12 with photodynamic therapy and/or intravitreal triamcinolone, tissue plasminogen activator and intravitreal gas, or submacular surgery.

†Indicates off-label use

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

No dosage adjustment is needed.

There are no drug interactions associated with Aflibercept products.

Aflibercept/EYLEA Intravitreal Inj Sol: 0.07mL, 1mL, 8mg, 40mg

2 mg per eye intravitreally for Eylea; 8 mg per eye intravitreally for Eylea HD.

2 mg per eye intravitreally for Eylea; 8 mg per eye intravitreally for Eylea HD.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

0.4 mg per eye intravitreally for Eylea; Safety and efficacy have not been established for Eylea HD.

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. It acts as a soluble decoy receptor that binds vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). VEGF-A and PIGF are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF-A interacts with VEGFR-1 and VEGFR-2 on the surface of endothelial cells. PIGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of VEGFR-1 and VEGFR-2 can result in neovascularization and vascular permeability. The binding of aflibercept to VEGF-A and PIGF prevents activation of these receptors.

Aflibercept is administered via intravitreal injection. Once absorbed into the systemic circulation, aflibercept is present in its unbound (free) form and a more predominant stable inactive form bound with endogenous VEGF (aflibercept: VEGF complex). The volume of distribution of free aflibercept after intravenous administration is 6 to 7 L. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. After intravitreal administration of aflibercept 2 mg, plasma concentrations of free aflibercept were undetectable 2 weeks post-dosing, and the drug did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. For the 8 mg intravitreal dose, the median time to reach non-quantifiable concentrations of free aflibercept was 3.5 weeks. Accumulation of free aflibercept in the plasma following the 3 initial monthly 8 mg doses was minimal (mean accumulation ratio 1.2), and no subsequent accumulation was observed. The terminal half-life of free aflibercept in plasma is 5 to 6 days after intravenous administration of 2 to 4 mg/kg.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Intravitreal Route
After intravitreal administration, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Aflibercept is absorbed into the systemic circulation and presents in the plasma as unbound aflibercept and a more predominant stable inactive aflibercept: VEGF complex. During pharmacokinetic evaluations, after intravitreal administration of 2 mg per eye to adult patients with wet age-related macular degeneration, macular edema following retinal vein occlusion, and diabetic macular edema, mean maximum serum concentrations of 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively, of free aflibercept in the plasma were attained within 1 to 3 days. The mean Cmax after intravitreal administration is estimated to be more than 100-fold lower than the concentration required to half-maximally bind systemic VEGF. Following unilateral intravitreal administration of aflibercept 8 mg, the mean Cmax of free aflibercept in the plasma was 0.3 mcg/mL, and the median time to maximal plasma concentration was 2.9 days.

There are no adequate and well-controlled studies regarding use of aflibercept in pregnant women. Animal embryo-fetal toxicity including postimplantation loss and fetal malformations such as anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart defects, major vessel defects, and skeletal malformations were reported when aflibercept was administered during organogenesis to rabbits at intravenous doses of at least 3 mg/kg every 3 days or subcutaneous doses of at least 0.1 mg/kg every 6 days. Administration of the lowest dose (0.1 mg/kg) assessed in rabbits resulted in systemic exposure approximately 6-times the systemic exposure observed in humans after an intravitreal dose of 2 mg or 0.9-fold the estimated systemic exposure in humans after an intravitreal dose of 8 mg. According to the manufacturer, aflibercept should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

According to the manufacturer, aflibercept is not recommended during breast-feeding. It is unknown whether aflibercept is excreted in human milk, affects the breast-fed infant, or affects milk production or excretion. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.