Aflibercept - Dosage, Indications, Contraindications, and Side Effects

Overview

Aflibercept is a recombinant protein found in the Chinese Hamster Ovary (CHO) cells that contain receptors for specific domains of human vascular endothelial growth factors, VEGF-R1 and VEGF-R2, linked to the Fc component of immunoglobulin gamma1 (IgG1 Fc). Aflibercept has a strong affinity for VEGF than its native receptors, and the stability of the Aflibercept-VEGF complex prevents VEGF from binding to sites of action inside the retina.

What are the Indications of Aflibercept?

Aflibercept is indicated in:

Managing patients with neovascular (wet) age-related macular degeneration (AMD). It is also used for the treatment of swelling in the part of the retina (macular edema) after obstruction of the retinal vein, diabetic macular edema (DME), and diabetic retinopathy (DR).

Dosage and Administration

• Dosage Formand Strength: A single-use glass vial containing 0.05 milliliter of a 40 milligram per milliliter solution injecting intravitreally.

• Dosing: The recommended intravitreal Aflibercept injection dosage is 2.0 milligrams in 0.05 milliliter. The recommended dose schedule and frequency changes based on the disease condition.

  • Neovascular (Wet) Age-Related Macular Degeneration (AMD): For the first 12 weeks (three months), the recommended dose of Aflibercept is two milligrams (0.05 milliliter or 50 microliters) intravitreal injection given every four weeks (monthly), followed by two milligrams (0.05 milliliter) intravitreal injection given once every eight weeks (two months).

  • Macular Edema After Retinal Vein Occlusion (RVO): The recommended dose of Aflibercept is two milligrams (0.05 milliliter or 50 microliters) given intravitreally once every four weeks (monthly).

  • Diabetic Macular Edema (DME) And Diabetic Retinopathy (DR) In DME Patients: Aflibercept is prescribed at a dosage of two milligrams (0.05 microliter or 50 microliters).

Contraindications

• Ocular or periocular infections, ongoing ocular inflammation, and known hypersensitivity to Aflibercept or any active ingredients in the formulation are all contraindications to intravitreal Aflibercept.

• Patients should be advised about the most usual signs of hypersensitivity responses, such as rash, urticaria, itching, severe intraocular inflammation, or severe anaphylactic reactions.

• Patients with an eye infection, recent ocular surgery, or high intraocular pressure should prevent using intravitreal Aflibercept.

Warnings and Precautions

• Endophthalmitis and Retinal Detachments: Endophthalmitis and retinal detachment have been linked to intravitreal administrations, particularly those using Aflibercept. When delivering Aflibercept, an aseptic injection technique must always be employed. Patients should be advised to report any symptoms of endophthalmitis or retinal detachment as soon as possible, and they should be addressed accordingly.

• Increase in Intraocular Pressure: Acute intraocular pressure rise has been observed within one hour of intravitreal injection, including with Aflibercept. A prolonged rise in intraocular pressure has also been observed with repeated intravitreal VEGF inhibitor therapy. Therefore, intraocular pressure and optic nerve head perfusion should be monitored and adjusted as needed.

• Thromboembolic Events: Following intravitreal administration of VEGF inhibitors, including Aflibercept, there is a higher chance of arterial thromboembolic events (ATEs). Nonfatal stroke, nonfatal myocardial infarction, or vascular deaths of unknown causes are all manifestations of ATEs.

For Patients

What Are Aflibercept and What Are Its Uses?

Aflibercept is an injectable solution used for the treatment of adult eye conditions such as neovascular (wet) age-related macular degeneration (wet AMD), poor eyesight caused by the swelling in the part of the retina (macular edema) secondary to occlusion of the retinal vein (branch RVO (BRVO), or central RVO (CRVO)), diabetic macular edema (DME), and vision impairment due to myopic choroidal neovascularization (myopic CNV).

• The main ingredient in Aflibercept inhibits the function of vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF).

• TVEGF-A and PIGF, present in abundance, are implicated in the aberrant growth of new blood vessels in the eyes of individuals with wet AMD and myopic CNV. These new blood vessels have the potential to leak the components of blood into the eye, causing harm to the tissues in the eye necessary for vision.

• A blockage forms in the primary blood vessel that carries blood away from the retina in people with central retinal vein occlusion (CRVO). In reaction, VEGF levels rise, allowing fluid to flow into the retina and, as a result, a swelling of the macula (the section of the retina essential for proper vision), known as macular edema. Central vision becomes blurry whenever the macula swells with fluid.

• One or more branches of the primary blood vessel that takes blood away from the retina are obstructed in individuals with branch retinal vein obstruction (BRVO). In reaction, VEGF levels rise, allowing fluid to flow into the retina and cause macular edema.

• Diabetic macular edema is a retina swelling caused by fluid leakage from blood vessels inside the macula in diabetic individuals. The macula is the retina’s area crucial for good vision. Central vision gets fuzzy as the macula expands with fluid.

• Aflibercept has been found to inhibit the formation of new aberrant blood vessels in the eye, which frequently causes fluid leaks or bleeding. Aflibercept can aid in stabilizing and enhancing vision loss caused by wet AMD, CRVO, BRVO, DME, and myopic CNV.

What the Patient Needs to Know Before Having Aflibercept:

1. Do Not Take Aflibercept:

• If the patient is allergic to Aflibercept or other components used in the drug.

• If the patient has an infection in or around the eye that is current or suspected.

• If the patient has significant eye irritation (indicated by pain or redness).

• If the patient is planning for pregnancy.

2. Warnings and Precautions:

If the doctor, before the administration of:

• If the patient is suffering from glaucoma.

• If the patient has a history of seeing flashes of light or floaters, and if the size and number of floaters suddenly increase.

• If the patient has undergone or planned eye surgery within the next four weeks.

• If the patient has a severe type of CRVO or BRVO (ischaemic CRVO or BRVO), Eylea medication is not advised.

Children and Adolescents

• Aflibercept has not been evaluated in children or adolescents under eighteen since wet AMD, CRVO, BRVO, DME, and myopic CNV are commonly seen in adults. As a result, its application in this age range is irrelevant.

Pregnancy and Breastfeeding

• Women of reproductive age must take contraceptive methods during therapy and at least three months after the final Aflibercept injection.

• There has been no evidence of Aflibercept in pregnant women. Therefore, unless the possible benefit surpasses the potential harm to the unborn child, Aflibercept should not be taken during pregnancy.

• If the patient is pregnant or plans to become pregnant, discuss this with the doctor before using Aflibercept. Aflibercept is not indicated during breastfeeding because it is uncertain whether it transfers to human milk.

How to Use Aflibercept?

Aflibercept is indicated for intraocular injection. The patient is advised not to take the injection on their own. A well-trained medical professional will administer it in aseptic (clean and sterile) settings. To avoid infection, the doctor will use an antibacterial eyewash to clean your eye before the injection gently. To alleviate pain associated with a local anesthetic injection administered by a doctor.

What if the Patient Misses a Dose?

Fix an appointment with the doctor to examine and take another injection.

What Are the Possible Side Effects?

Hypersensitivity reactions are possible. These could be dangerous and need an emergency visit to the doctor.

Due to the injection with Aflibercept, some adverse effects may be

• Blindness in the eyes.

• Severe infection or inflammation inside the eye (endophthalmitis).

• Detachment or a tear in the retina.

• Bleeding in the back of the eye.

• Clouding of the lens (cataract).

• Bleeding in the eye (vitreous hemorrhage).

• Gel-like substance getting detached within the eye from the retina (vitreous detachment).

• An increase in pressure inside the eye is a possibility.

In clinical trials, these significant adverse effects involving the eyes appeared in less than 1 in 1,900 doses.

Very Common Adverse Effects (Out of Every Ten People, More than One Gets Affected):

• Degradation of the vision.

• Bloodshot eyes produced by bleeding from tiny blood vessels in the eye's outer layers - eye ache.

Common Side Effects (One in Ten People Gets Affected):

• Detachment or tear of any of the layers at the back of the eye, causing flashes of light and floaters and occasionally leading to vision loss (retinal pigment epithelial tear or detachment).

• Retinal deterioration (causing disturbed vision).

• Ocular bleeding (vitreous hemorrhage).

• Some kind of clouding in the lens(cataract).

• Injury to the eyeball's front layer (the cornea).

• A rise in intraocular pressure.

• Shifting vision spots (floaters).

• Vitreous detachment (detachment of the gel-like material inside the eye from the retina, resulting in flashes of light with floaters).

• A constant irritation in the eye.

• Increased production of tears.

• Enlargement of the eyelid.

• Bleeding at the site of injection.

• Increased redness in the eye.

• Conditions related to wet AMD are seen only in wet AMD patients.

Uncommon Side Effects (One in Hundred People Gets Affected):

• Hypersensitivity reactions.

• Severe infection or inflammation of the eye (endophthalmitis).

• A severe infection or inflammation of the eye (endophthalmitis) is an inflammation of the other eye parts (iritis, uveitis, iridocyclitis, flare in the anterior chamber).

• Iris and inflammation of the other eye parts (iritis, uveitis, iridocyclitis, flare in the anterior chamber).

• Strange feeling in the eye.

• Inflammation of the eyelids.

• Enlargement of the eyeball's front layer (cornea).

• Allergic responses such as rash, itching (pruritus), hives (urticaria), and a few severe allergic reactions (anaphylactic or anaphylactoid) were recorded.

Rare Side Effects (One in Thousand People Gets Affected):

• Blindness.

• Lens clouding as a result of damage (traumatic cataract).

• Inflammation of the eye's gel-like material.

• Pus in the eye.

How to Store Aflibercept?

• Keep this drug out of children.

• Keep refrigerated (2 degrees Celsius to eight degrees Celsius). Do not freeze the vial.

• The unopened vial can be kept outside the refrigerator at temperatures below 25 degrees Celsius for up to 24 hours.

• Protect the vial from direct light by storing it in the original container.

• Do not dispose of any contents in wastewater or household trash.

• Inquire with your pharmacist about how to dispose of any medications left after use. These steps will aid in environmental protection.

For Doctors

What Is Aflibercept?

Aflibercept is a recombinant protein made up of the binding domains of two human VEGF receptors combined with the Fc portion of human immunoglobulin gamma 1 (IgG1) formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein having a molecular weight of 96.9 kilo Daltons (kDa). It has a total molecular weight of 115 kDa due to roughly 15 percent glycosylation. Except for the single unsialylated site associated with the Fc domain, all five putative N-glycosylation sites on each polypeptide chain are anticipated by the primary sequence to be filled with carbohydrates and show heterogeneity in the chain to some extent, such as heterogeneity in terminal sialic acid residues.

Clinical Pharmacology

Mechanism of Action:

Angiogenic factors that promote vasculogenesis and angiogenesisare the VEGF members, including vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF), which operate as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF operates on the surface of endothelial cells employing two receptor tyrosine kinases, VEGFR-1 and VEGFR-2. PlGF exclusively binds to VEGFR-1, which is found on the surface of leucocytes. VEGF-A activating these receptors can result in endothelial proliferation, neovascularization, and increased vascular permeability.

Aflibercept functions as a soluble decoy receptor that targets VEGF-A and PlGF, inhibiting the binding and activation of their respective VEGF receptors.

Pharmacodynamics:

Anatomic assessments of disease activity progressed comparably between the group from baseline to week 52 in the phase three investigations. Therefore, did not use anatomical information to affect treatment decisions.

Pharmacokinetics:

Aflibercept is given intravitreally to have local effects on the eye. After intravitreal injection of Aflibercept, a percentage of the given dosage is estimated to bind with endogenous vascular endothelial growth factor (VEGF) in the eye to produce an inactive Aflibercept: VEGF complex in individuals suffering from wet age-related macular degeneration (AMD). After entering into the systemic circulation, Aflibercept appears in plasma as free Aflibercept (unbound to VEGF) and with circulating endogenous VEGF as a more prevalent stable inactive form (Aflibercept: VEGF complex).

• Absorption and Distribution: The mean Cmax of free Aflibercept in the plasma after intravitreal injection of 2 mg for each eye to patients with wet age-related macular degeneration (AMD) was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL) and was achieved in one to three days. All individuals had negligible free Aflibercept plasma concentrations two weeks after treatment. Aflibercept did not accumulate in the plasma when injected intravitreally at four-week intervals repeatedly. The maximum average plasma concentration of free Aflibercept following an intravitreal dose of 2 mg to patients is expected to be more than 100 times less than the amount of Aflibercept necessary to bind systemic VEGF half-maximally. Following intravenous injection of Aflibercept, estimated the volume of distribution of free Aflibercept was to be about 6L.

• Metabolism and Elimination: Aflibercept is a therapeutic protein that has not been studied for drug metabolism. Aflibercept is predicted to be eliminated by target-mediated disposals through binding to free endogenous VEGF and proteolysis metabolism. After administering two to four mg/kg doses of Aflibercept, the final elimination half-life (t-half) of free Aflibercept in plasma was around five to six days.

Specific Populations

• Renal Impairment: A pharmacokinetic evaluation of a subset of patients (n=492) in one Phase 3 clinical trial, 43 percent of patients had renal impairment (mild n=120, moderate n=74, and severe n=16), indicated that no changes in plasma concentrations of free Aflibercept following intravitreal treatment for every four or eight weeks. Therefore, no dosage change is required depending on the patient's renal status.