Aflibercept is a recombinant fusion protein. It binds vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF) and thereby inhibits the binding and activation of these receptors. The drug is approved to treat neovascular (wet) age-related macular degeneration (AMD), macular edema following central retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy, and retinopathy of prematurity (ROP). Guidelines recommend aflibercept as a first-line therapy for the management of eyes with central-involved diabetic macular edema (CIDME). In some patients with proliferative diabetic retinopathy, aflibercept is a reasonable alternative to traditional panretinal laser photocoagulation and can reduce the risk of vision loss. Aflibercept is administered via intravitreal injection by a qualified physician. Avoid use of the drug in patients with ocular or periocular infections and patients with active intraocular inflammation.
For the treatment of neovascular AMD, the efficacy of aflibercept 2 mg every other month and monthly was clinically comparable to monthly injections of ranibizumab 0.5 mg. In 2 studies, 94% to 95% of patients in the aflibercept 2 mg every 8 weeks group and 95% of patients in the aflibercept 2 mg every 4 weeks group maintained visual acuity as compared with 94% to 95% of patients in the ranibizumab group. For macular edema following central RVO, 56% to 60% of aflibercept recipients gained at least 15 letters in the best corrected visual acuity from baseline as compared with 12% to 22% of sham recipients. Results from DME trials showed a mean change from baseline in best corrected visual acuity of 10.5 to 12.5 letters for patients receiving aflibercept compared to 0.2 to 1.2 letters for the control group (macular laser photocoagulation). In patients with diabetic retinopathy (both with and without central-involved DME), the proportion of patients with a 2 step or more improvement in early treatment diabetic retinopathy study (ETDRS) diabetic retinopathy severity scale (ETDRS-DRSS) was significantly greater in the aflibercept groups compared with control.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-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.
Other Injectable Administration
-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.
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.
Intravitreal use of vascular endothelial growth factor (VEGF) inhibitors, such as aflibercept, may be associated with arterial thromboembolic events (ATEs), such as thromboembolism, nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). During the first year of aflibercept in the VIEW1 and VIEW2 studies for neovascular age-related macular degeneration, 1.8% of patients (32 of 1,824) in the combined group of patients treated with aflibercept 2 mg had an ATE, compared with 1.5% of patients (9 of 595) treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 of 1,824) for aflibercept 2 mg and 3.2% (19 of 595) for ranibizumab. No ATEs were reported during the first 6 months of clinical trials for aflibercept 2 mg for macular edema after retinal vein occlusion. The incidence of ATE in the 52 week VIVID and VISTA studies for diabetic macular edema was 3.3% (19 of 578) in the combined group of patients treated with aflibercept 2 mg and 2.8% (8 of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 of 578) for aflibercept 2 mg and 4.2% (12 of 287) in the control group. In the PULSAR study for wet age-related macular degeneration, the incidence of thromboembolic events reported from baseline through Week 48 was 0.4% (3 of 673) in the combined group of patients treated with aflibercept 8 mg compared to 1.5% (5 of 336) in patients treated with aflibercept 2 mg. The incidence of reported thromboembolic events in the diabetic macular edema study (PHOTON) from baseline to Week 48 was 3.1% (15 of 491) in the combined group of patients treated with aflibercept 8 mg and 3.6% (6 of 167) in patients receiving aflibercept 2 mg.
In phase 3 clinical trials comparing aflibercept 2 mg (n = 1,824) to ranibizumab (n = 595) for neovascular, age-related macular degeneration (AMD), ocular adverse reactions included detachment of the retinal pigment epithelium (5% of aflibercept group vs. 5% of ranibizumab group) and retinal pigment epithelium tear (2% vs. 2%). Additional adverse reactions also noted in patients treated for macular edema after central or branched retinal vein occlusion were ocular hemorrhage (27% for AMD and 12% to 20% for macular edema), ocular pain (10% for AMD and 4% to 13% for macular edema), cataracts (13% for AMD and up to 5% for macular edema), vitreous detachment (8% for AMD and 2% to 3% for macular edema), vitreous floaters (8% for AMD and 1% to 5% for macular edema), corneal erosion (5% for AMD and 2% to 5% for macular edema), conjunctival hyperemia (5% for AMD and 2% to 5% for macular edema), lacrimation increased (4% for AMD and 3% for macular edema), foreign body sensation (4% for AMD and 3% for macular edema), blurred vision (4% for AMD and 1% for macular edema), blepharedema (2% for AMD and up to 1% for macular edema), corneal edema (1% for AMD and less than 1% for macular edema), and injection site reaction such as injection site hemorrhage (2% for AMD) and injection site pain (3% for both populations). In regard to the AMD population, the above adverse reactions occurred in a similar percentage of ranibizumab recipients. Ocular adverse reactions reported in 168 premature neonates with retinopathy of prematurity (ROP) randomized to receive aflibercept 0.4 mg intravitreally included ocular hemorrhage (5% to 9%), corneal edema (1%), eyelid edema (3%), lenticular opacities (1%), and corneal epithelium defect (1%). Of note, instruct patients to immediately report if ocular pain, conjunctival hyperemia, or blurred vision occurs, as these may be signs of a detached retina or of an eye infection. In the PULSAR and PHOTON clinical trials, the safety of aflibercept 8 mg intravitreal injections (n = 1,164) was compared with aflibercept 2 mg doses (n = 503). Adverse reactions reported for the 8 mg and 2 mg doses, respectively, included cataracts (3% to 6% vs. 3% to 4%), conjunctival hemorrhage (2% to 4% vs. 1% to 4%), ocular pain or ocular irritation (2% to 4% vs. 2% to 4%), blurred vision (3% to 6% vs. 4% to 7%), vitreous floaters (1% to 5% vs. 3%), corneal epithelium defect (2% to 6% vs. 1% to 3%), retinal hemorrhage (up to 4% vs. 1% to 4%), vitreous hemorrhage (up to 2% vs. 1%), and foreign body sensation (up to 1% vs. up to 2%).
Intravitreal injections of aflibercept have been associated with retinal detachment (up to 1% of adults and 5% to 6% of neonates), vitreous detachment (1% to 4%), retinal pigment epithelial detachment (up to 2%), retinal tear (less than 1%), retinal pigment epithelial tear (up to 2%), endophthalmitis, and retinal vasculitis with or without occlusion (0.2 to 0.6 per 1 million injections). Monitoring for infection during the week after the injection is advised to permit early treatment of any ocular infection that may develop. Proper aseptic injection technique should always be used to help minimize the likelihood of an infection. Instruct patients to seek immediate care if symptoms of endophthalmitis or retinal detachment develop (e.g., ocular pain, hyperemia of the conjunctiva, photophobia, blurry vision).
Increased intraocular pressure (ocular hypertension) was reported in 1% to 8% of aflibercept-treated patients during controlled-clinical trials. Acute increases in intraocular pressure have been noted within 60 minutes of intravitreal aflibercept injection; less than 0.1% of patients have experienced serious acute increased intraocular pressure related to the injection procedure. In addition, sustained increases in intraocular pressure have been reported after repeated intravitreal dosing with VEGF inhibitors. After the injection, monitor the intraocular pressure and optic nerve head perfusion; medical management of any abnormality may be needed. Monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.
As with all therapeutic proteins, antibody formation to aflibercept may occur. In clinical trials, the pretreatment incidence of immunoreactivity was 1% to 3% across treatment groups. After dosing for up to 100 weeks, antibodies to aflibercept were detected in a similar percentage range of patients. There was no difference in safety or efficacy in patients with immunoreactivity compared to those without immunoreactivity.
Ocular inflammation has been noted in up to 3% of patients receiving aflibercept during clinical trials, and severe intraocular inflammation may be a manifestation of hypersensitivity reactions. Other hypersensitivity reactions associated with aflibercept include anaphylactic or anaphylactoid reactions, rash (unspecified), pruritus, and urticaria.
Aflibercept is contraindicated in patients with hypersensitivity to aflibercept or to any of the components of the product. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe inflammation of the eye, or severe anaphylactic or anaphylactoid reactions.
As with other intravitreal injections, aflibercept is contraindicated in patients with ocular infection or periocular infection. Intravitreal injections, including those with aflibercept, have been associated with endophthalmitis and retinal detachments, which may lead to blindness. The risk for serious complications from a single intraocular injection is low, but the cumulative risk exposure can be greater. A broad-spectrum ocular microbicide should be given prior to the injection. Use controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). In addition, patients should be monitored during the days after the injection to permit early treatment should an infection occur.
Aflibercept is contraindicated in patients with active intraocular inflammation.
Use with caution in patients with a history of glaucoma. Increased intraocular pressure (IOP) has occurred within 60 minutes of aflibercept injection in some patients. Sustained increased IOP has also been reported after repeated dosing of intravitreal VEGF inhibitors. Monitor for increased IOP and perfusion of the optic nerve head. In neonates, reactivation of abnormal angiogenesis and tortuosity may occur after treatment with aflibercept. Monitor neonates closely after aflibercept injection until retinal vascularization has completed or until the examiner is confident that reactivation of retinopathy of prematurity (ROP) will not occur. Extended periods of ROP monitoring is necessary in neonates.
Intravitreous injections have been associated with endophthalmitis. Any ocular surgery that disrupts the integrity of the globe can lead to exogenous endophthalmitis (e.g., cataract, retinal surgeries, radial keratotomy). Patients who have received or will receive aflibercept and have recently undergone or will undergo an ocular surgical procedure should be monitored for signs and symptoms of endophthalmitis (pain, redness, lid swelling, decreased visual acuity) and be counseled on when to seek medical attention. Monitor patients during the week after injection to permit early treatment should an infection occur.
Because patients may experience temporary visual disturbances after aflibercept administration, driving or operating machinery should be avoided until visual function has recovered.
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.
Counsel patients about aflibercept associated reproductive risk and contraception requirements. Patients of reproductive potential are advised to use effective contraception prior to the initial dose, during treatment, and for at least 3 months after the last 2 mg dose or at least 4 months after the last 8 mg dose. In addition, based on animal data, aflibercept may cause impaired fertility or infertility. Specifically, aflibercept affected female and male reproductive systems in cynomolgus monkeys when administered via intravenous injection at a dose 1,500-times higher than the systemic concentration observed in humans receiving a 2 mg intravitreal dose or 91-times higher than the estimated systemic concentration in humans receiving an 8 mg intravitreal dose. These finding were found to be reversible within 20 weeks after cessation of treatment. Data regarding effects of the drug on human fertility are not available.
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.
For the treatment of neovascular (wet) age-related macular degeneration (AMD):
Intravitreal dosage (Eylea only):
Adults: 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.
Intravitreal dosage (Eylea HD only):
Adults: 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).
For the treatment of diabetic macular edema:
Intravitreal dosage (Eylea only):
Adults: 2 mg by intravitreal injection in the affected eye(s) every 4 weeks for 5 doses, followed by 2 mg by intravitreal injection in the affected eye(s) every 8 weeks. Some may require every 4 week dosing after the first 5 doses. However, additional efficacy was not demonstrated in most when administered every 4 weeks vs. every 8 weeks. Guidelines recommend intravitreous anti-vascular endothelial growth factor agents, such as aflibercept, as first-line therapies for the management of central-involved diabetic macular edema.
Intravitreal dosage (Eylea HD only):
Adults: 8 mg by intravitreal injection in the affected eye(s) every 4 weeks for 3 doses, followed by 8 mg by intravitreal injection in the affected eye(s) every 8 to 16 weeks. Guidelines recommend intravitreous anti-vascular endothelial growth factor agents, such as aflibercept, as first-line therapies for the management of central-involved diabetic macular edema.
For the treatment of diabetic retinopathy:
Intravitreal dosage (Eylea only):
Adults: 2 mg by intravitreal injection in the affected eye(s) every 4 weeks for 5 doses, followed by 2 mg by intravitreal injection in the affected eye(s) every 8 weeks. Some may require every 4 week dosing after the first 5 doses. However, additional efficacy was not demonstrated in most 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.
Intravitreal dosage (Eylea HD only):
Adults: 8 mg by intravitreal injection in the affected eye(s) every 4 weeks for 3 doses, followed by 8 mg by intravitreal injection in the affected eye(s) every 8 to 12 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.
For the treatment of macular edema following retinal vein occlusion (including central or branch retinal vein occlusion):
Intravitreal dosage (Eylea only):
Adults: 2 mg (0.05 mL) via intravitreal injection into the affected eye(s) every 4 weeks (approximately every 25 days, monthly).
For the treatment of choroidal neovascularization (CNV)* due to presumed ocular histoplasmosis syndrome (POHS):
Intravitreal dosage (Eylea only):
Adults: 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.
For the treatment of retinopathy of prematurity:
Intravitreal dosage (Eylea only):
Premature Neonates: 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.
Maximum Dosage Limits:
-Adults
2 mg per eye intravitreally for Eylea; 8 mg per eye intravitreally for Eylea HD.
-Geriatric
2 mg per eye intravitreally for Eylea; 8 mg per eye intravitreally for Eylea HD.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
0.4 mg per eye intravitreally for Eylea; Safety and efficacy have not been established for Eylea HD.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustment is needed.
*non-FDA-approved indication
There are no drug interactions associated with Aflibercept products.
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
-Route-Specific Pharmacokinetics
Other Route(s)
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.
-Special Populations
Hepatic Impairment
Mild hepatic impairment has no influence on systemic exposures to aflibercept compared to patients with normal hepatic function. No data are available for patients with moderate or severe hepatic impairment.
Renal Impairment
Pharmacokinetic analysis of a subgroup of patients in 1 clinical trial included adult patients with renal impairment (mild = 120, moderate = 74, and severe = 16). No differences were found in plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks in patients with any degree of renal dysfunction.
Pediatrics
Premature neonates
During a pharmacokinetic evaluation in premature neonates, after intravitreal administration of 0.4 mg per eye unilaterally or bilaterally, a mean maximum free aflibercept plasma serum concentration of 0.583 mcg/mL at Day 1 declined to 0.0406 mcg/mL at Day 28 in bilaterally treated patients. In bilateral and unilaterally treated patients combined, mean maximum free aflibercept plasma serum concentration of 0.481 mcg/mL at Day 1 declined to 0.13 mcg/mL at Day 28. Concentrations subsequently declined to values below or close to the lower limit of quantitation within approximately 8 weeks. When an intravitreal dose of aflibercept 0.4 mg per eye bilaterally was given at 10 or 14 day intervals, the population pharmacokinetic estimated mean maximal accumulation ratio of free aflibercept in plasma was approximately 2 and 1.4. No accumulation is expected at dosing intervals of 21 days or longer.