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Editor: Jack Stringham Updated: 7/4/2023 12:28:03 AM


Aflibercept is a humanized recombinant fusion protein that functions as a vascular endothelial growth factor (VEGF) inhibitor, thus preventing choroidal neovascularization. The VEGF signaling pathway is implicated in the induction of gene expression, regulation of vascular permeability, proliferation, and survival. 

Studies demonstrate increased levels of VEGF-A in the aqueous and vitreous fluid of eyes with diabetic macular edema and proliferative diabetic retinopathy. Aflibercept was first FDA-approved in 2011 for neovascular (wet) age-related macular degeneration (NVAMD).[1] 

Since then, additional FDA approval has been granted for macular edema associated with retinal vein occlusion (RVO), diabetic macular edema (DME), myopic choroidal neovascularization (mCNV), and diabetic retinopathy (DR).[2][3][4]

Mechanism of Action

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Mechanism of Action

Aflibercept is a dimeric glycoprotein (molecular weight= 115 kDa) that acts as a soluble protein decoy for VEGF receptors (VEGFR-1 and VEGFR-2) present on the surface of endothelial cells in the retina.[5] Aflibercept preferentially binds to VEGF-A and PIGF with a much greater affinity than its natural angiogenic competitors (VEGFR-1 and VEGFR-2).

Through this mechanism, aflibercept prevents ligand-induced dimerization of VEGFR-2, preventing downstream activation of the intracellular tyrosine kinase domains from inhibiting pathologic angiogenesis.

Aflibercept exerts its inhibitory effects on VEGF receptors preventing endothelial proliferation, vascular permeability, and neovascularization. This targeted intravitreal injection therapy aims to inhibit VEGF signaling, which underlies angiogenesis and vascular leak characteristic of NVAMD.[6]

Compared to other VEGF inhibitors, aflibercept is thought to have at least a 200-fold higher affinity for VEGF, which explains optimal therapeutic outcomes of patients receiving intravitreal aflibercept therapy. In addition, the relatively small molecular size of aflibercept allows for enhanced diffusion into the retina and choroid.[7]


Aflibercept is delivered as an intravitreal injection into the affected eye. Aflibercept is a colorless solution that comes packaged in prefilled syringes. It must be stored in a refrigerator for extended periods but can be kept at room temperature for less than 24 hours. Clinicians should practice proper sterile surgical procedures when delivering any intravitreal injection.

According to the initial FDA approval dosage and administration, the recommended dose for aflibercept is 2 mg (0.05 mL) administered by intravitreal injection every four weeks (monthly) for the first three months, followed by 2 mg (0.05 mL) once every eight weeks (two months).[8]

Landmark trials have established the benefit of the Treat-and-Extend regimen (TAE) compared to fixed dosing, which involves fewer injections and visits in total and superior outcomes. This regimen, which has become standard of care, involves aflibercept injections based on response to treatment. Treat-and-extend dosing regimens minimize the risk of recurrence of submacular edema and reduce capacity-planning in AMD services and treatment delays.[9] 

Understanding administration guidelines and following a strict, standardized protocol is essential to avoid severe complications of intravitreal aflibercept administration such as endophthalmitis, retinal tear, retinal detachment, and lens injury.[10] The standard antiseptic protocol includes hand disinfection, sterile gloves, a sterile speculum, and topical microbicide solution on the eye.[11]

Injection Protocol

  • First, the patient is placed in a comfortable, supine position.
  • Lids, lashes, and surrounding skin are sterilized with 10% povidone-iodine.
  • Several drops of Proparacaine Hydrochloride are instilled in the conjunctival cul-de-sac.
  • Following the instillation of povidone-iodine and proparacaine drops, a speculum is inserted in the eye.
  • Then, the physician determines the injection site by measuring 3.5 to 4 millimeters posterior to the limbus in the superotemporal quadrant. Accurate measurement from the limbus is critical to prevent lens damage in phakic patients. Additionally, superior temporal intravitreal injection is generally preferred to avoid iatrogenic inferior retinal detachment.
  • The patient is instructed to look in a particular direction depending on the injection site.
  • The medication is injected gently through pars plana.
  • After injection, the speculum is removed, and the eye is washed with a basic saline solution.[12]

Adverse Effects

Adverse effects associated with aflibercept use include eye irritation, vitreous detachment, temporary blurred vision, eyelid swelling, and conjunctival hemorrhage. Serious adverse reactions related to the administration of aflibercept and the injection procedure include retinal detachment, traumatic cataracts, thromboembolic events, and increased intraocular pressure (IOP). These complications are observed in less than 0.1% of intravitreal injections with aflibercept.[13]

A temporary rise in intraocular pressure within 60 minutes of administration can be expected and should return to baseline in minutes following injection. Intraocular pressure may take longer to normalize in patients with glaucoma and other ocular comorbidities. Patients should be educated about common and severe adverse effects and know when to notify their doctor.[14]


Contraindications to intravitreal aflibercept include ocular or periocular infections, active ocular inflammation, and known hypersensitivity to aflibercept or any excipients found in the formulation. Patients should be counseled on the common symptoms of hypersensitivity reactions, including rash, urticaria, pruritus, severe ocular intraocular inflammation, or severe anaphylactic reactions. Patients who have an ocular infection, have recently undergone ocular surgery, or have increased intraocular pressure should avoid intravitreal aflibercept use.[15]

There is no data on the effects of intravitreal aflibercept on human fertility. Data in primate studies showed reversibly impaired fertility and function in female reproductive systems at intravenous administration doses 1500 times higher than the human systemic level. As such, the FDA has recommended effective contraception in reproductive-aged females before, during treatment, and at least three months following the last intravitreal injection of aflibercept.[16]

Aflibercept is not recommended while breastfeeding due to the potential for drug excretion in breast milk and the threat to infant growth and development. Studies have not yet established the safety and effectiveness of aflibercept in pediatric patients.[17]


Following aflibercept administration, patient self-monitoring is essential to detect signs of infection, pain, and/or decreased visual acuity. Patients should be instructed on Amsler grid use to monitor reactivation of Neovascular age-related macular degeneration (NVAMD). Severe complications such as endophthalmitis, retinal detachment, and increased intraocular pressure (IOP) have been associated with intravitreal injection. Intraocular pressure should be monitored before and after intravitreal injection of aflibercept.[18]

Overall systemic exposure is low due to rapid elimination after passing through the vitreous. No drug metabolism studies have been conducted. As a low-molecular-weight glycoprotein, aflibercept is believed to undergo proteolysis and elimination via target-mediated elimination by binding free endogenous VEGF. For a dose of 2 to 4 mg/kg, aflibercept has a half-life (t1/2) of approximately 5 to 6 days after 2 to 4 mg/kg intravitreal injection (IVI).[19] 

Few rare toxicities have been reported involving minimal systemic absorption. Single case reports describe intravitreal aflibercept crossing the blood-retina barrier leading to vascular-related thromboembolism, heart attack, stroke, and even death.[20]

Other case studies describe worsening of preexisting chronic kidney disease (CKD), acute interstitial nephritis (AIN) in the background of diabetic glomerulosclerosis, and focal and segmental glomerulosclerosis (FSGS). These are very rare but highlight the potential of deleterious systemic and renal pathological disorders in the setting of intravitreal VEGF blockade. Additionally, patients with macular ischemia should be carefully monitored when considering prolonged anti-VEGF therapy due to an already compromised blood supply.[21]

Despite rarely observed adverse effects, aflibercept has a highly desirable therapeutic profile compared to other anti-VEGF analogs. Aflibercept use is associated with rapid visual improvement, less frequent need for subsequent injection therapy, and prolonged maintenance. Randomized clinical trials of intravitreal aflibercept administration demonstrate superior outcomes of eight-week dosing regimens compared to monthly dosing, resulting in an overall decreased frequency of injections.[22]


Aflibercept is intended for intravitreal administration to exert local effects in the eye. IVI allows the medication to penetrate all retinal layers, minimizing systemic effects. No cytotoxic effects have been observed in studies that exposed cultured corneal endothelial cells to varying concentrations of aflibercept.[23]

However, there has been an interest in the potential for drug overdose with intravitreal aflibercept therapy due to a slight misalignment of the plunger in prefilled syringes. These small mismeasurements can lead to delivering double the intended volume of medication. In part, aflibercept overdose accounts for a number of intraocular pressure elevations since its launch. Unfortunately, there is no known antidote for aflibercept overdose. Proper adherence to instructions for use can minimize dosing errors and prevent toxicity of intravitreal aflibercept.[24]

Enhancing Healthcare Team Outcomes

Aflibercept is a humanized recombinant fusion protein designed for intraocular use. Intravitreal injection is indicated for the treatment of neovascular (wet) age-related macular degeneration (NVAMD), macular edema associated with retinal vein occlusion (RVO), diabetic macular edema (DME), myopic choroidal neovascularization (mCNV), and diabetic retinopathy.

Proper diagnosis and management of ocular diseases can significantly impact a patient's quality of life. Managing the treatment of ocular disease with abnormal angiogenesis such as NVAMD and DR requires an interprofessional team of providers (physicians, including specialists, mid-level practitioners, nurses, and pharmacists) to ensure effective treatment.[2][3]

To ensure patient safety, specific roles of healthcare team members should be well-defined, and medical personnel should be well trained in their specific roles. The team members include healthcare practitioners, specialists, technicians, surgical assistants, and optometrists. Clinical ophthalmic technicians update patient history and test visual acuity and pressure before the patient sees the retinal specialist.

Clinical technicians also obtain imaging studies, including optical coherence tomography (OCT) and fundus photography. OCT produces cross-sectional images of the retina to see different layers and evaluate disease progression and the effect of prior treatments. When therapy is indicated, ophthalmic technicians counsel patients on risks and benefits before obtaining consent for the procedure.

At the time of the procedure, nurses review the timeout sheet, which should include the correct eye, procedure, and drug to be administered. Surgical assistants prepare the procedure tray, gown and drape the patient, clean and disinfect the injection site, and assist the clinician during administration. Specialists follow standardized protocol guidelines to ensure safe intravitreal aflibercept administration.

Technicians may administer post-injection antibiotics, remove the patient's drape and wash the eye with a basic saline solution. Technicians provide post-injection care instructions and schedule return visits. Optometrists are crucial in closely monitoring response to aflibercept therapy at follow-up visits.[25]

The patient should be educated and monitored for signs of elevated intraocular pressure. Patients should also be advised to call or return to the clinic if they begin to experience severe eye pain after receiving an injection. All team members must continue to monitor the patient as they have interactions with them, documenting their observations in the patient's medical record. If they note any concerns, including therapeutic failure or adverse events, they must immediately communicate these to the appropriate team members so additional evaluation can occur, potentially leading to corrective action.[18]

Patient self-monitoring is crucial to detect signs of infection and decreased visual acuity. An interprofessional team-based approach involving clinicians, specialists, optometrists, ophthalmic technicians, and patients leads to desired therapeutic outcomes, minimizes the risk of disease progression, and improves the quality of life.[18] [Level 5] 



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