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  • CLASSES

    Wet AMD Treatment Agents

    DEA CLASS

    Rx

    DESCRIPTION

    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, and diabetic retinopathy
    May cause increased IOP acutely or sustained

    COMMON BRAND NAMES

    EYLEA

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of neovascular (wet) age-related macular degeneration (AMD).
    Intravitreous injection dosage
    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.

    For the treatment of macular edema following retinal vein occlusion (including central or branch retinal vein occlusion).
    Intravitreous injection dosage
    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 diabetic macular edema (DME) and diabetic retinopathy.
    Intravitreous dosage
    Adults

    2 mg (0.05 mL) by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 20 weeks (5 months), followed by 2 mg via intravitreal injection every 8 weeks. Although monthly dosing may continue, additional efficacy was not demonstrated in most patients dosed every 4 weeks vs. every 8 weeks (2 months) in chronic use. However, some patients may continue to require every 4 week (monthly) dosing after the first 5 months. The American Diabetes Association (ADA) recommends intravitreous anti-vascular endothelial growth factor (anti-VEGF) agents, such as aflibercept, as first-line therapies for the management of eyes with central-involved diabetic macular edema (CIDME).

    For the treatment of choroidal neovascularization (CNV)† due to presumed ocular histoplasmosis syndrome (POHS).
    Intravitreal dosage
    Adults

    2 mg intravitreally every 4 weeks for 3 doses followed by every 8 weeks for 4 doses, or alternately, 2 mg 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

    MAXIMUM DOSAGE

    Adults

    2 mg/eye intravitreally.

    Geriatric

    2 mg/eye intravitreally.

    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

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

    No dosage adjustment is needed.

    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.[46841]

    Other Injectable Administration

    Product Preparation
    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 0.05 mL.
    Single-use prefilled syringe: Using aseptic technique, removed the syringe from the sterilized blister pack. 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 pre-filled syringe contains more than the recommended dose of 2 mg (0.05 mL); the excess volume MUST be discarded prior to administration. [46841]
     
    Intravitreous Administration
    Use controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).
    Adequate anesthesia and a topical broad-spectrum microbicide should be given 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 pre-filled syringe, a small residual volume may remain in the syringe after injection of the full dose. This is normal.
    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 to report any symptoms of endophthalmitis or retinal detachment immediately.[46841]

    STORAGE

    EYLEA:
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Aflibercept is contraindicated in patients with hypersensitivity to aflibercept or to any of the components of the product.

    Ocular infection

    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.

    Inflammation

    Aflibercept is contraindicated in patients with active intraocular inflammation.

    Glaucoma, increased intraocular pressure

    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.

    Ocular surgery

    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.

    Driving or operating machinery

    Because patients may experience temporary visual disturbances after aflibercept administration, driving or operating machinery should be avoided until visual function has recovered.

    Children, infants, neonates

    The safety and efficacy of aflibercept have not been established in neonates, infants, children, or adolescents.

    Pregnancy

    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. According to the manufacturer, aflibercept should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about aflibercept associated reproductive risk and contraception requirements. Females of reproductive age are advised to use effective contraception prior to the initial dose, during treatment, and for at least 3 months after the last intravitreal 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 1500-times higher than the systemic concentration observed in humans receiving a 2 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.

    Breast-feeding

    According to the manufacturer, aflibercept is not recommended during breast-feeding. It is unknown whether aflibercept is excreted in human milk. 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    ocular hemorrhage / Delayed / 12.0-27.0
    ocular hypertension / Rapid / 2.0-8.0
    thromboembolism / Delayed / 0-6.4
    corneal erosion / Delayed / 2.0-5.0
    endophthalmitis / Delayed / 0-1.0
    retinal detachment / Delayed / 1.0-1.0
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    cataracts / Delayed / 0-13.0
    conjunctival hyperemia / Early / 2.0-5.0
    blurred vision / Early / 1.0-4.0
    ocular inflammation / Early / 0-3.0
    corneal edema / Early / 0-1.0
    photophobia / Early / Incidence not known
    ocular infection / Delayed / Incidence not known
    antibody formation / Delayed / Incidence not known

    Mild

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

    DRUG INTERACTIONS

    There are no drug interactions associated with Aflibercept products.

    PREGNANCY AND LACTATION

    Pregnancy

    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. 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. 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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 L. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. After the 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. The terminal half-life of free aflibercept in plasma is 5—6 days after intravenous administration of 2—4 mg/kg.

    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 evaluation, after intravitreal administration of 2 mg per eye, a mean maximum serum concentration of 0.02 mcg/ml (range: 0 to 0.054 mcg/ml) of free aflibercept in the plasma was attained within 1—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.