AFLI

Aflibercept is a recombinant protein composed of the binding domains of two human vascular endothelial growth factor (VEGF) receptors, VEGFR1 and VEGFR2, fused with the Fc region of human immunoglobulin gamma 1 (IgG1).

Structurally, Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kilo Daltons (kDa).

It contains approximately 15% glycosylation to give a total molecular weight of 115 kDa.

All five putative

N-glycosylation sites on each polypeptide chain predicted by the primary sequence can be occupied with carbohydrates and exhibit some degree of chain heterogeneity, including heterogeneity in terminal sialic acid residues, except at the single unsialylated site associated with the Fc domain. 5, 6 Due to the 2 fused VEGFR, aflibercept has a higher affinity to the cognate ligands than the endogenous individual receptor.

However, it lacks the intracellular structure to propagate subsequent signal transduction, thus essentially sequestering the ligands to prevent activation of VEGFR. 3, 9 Ziv-aflibercept, under the brand name Zaltrap, was developed as an intravenous injection for the treatment of metastatic colorectal cancer, and it was approved by the FDA and EMA in August and February 2013, respectively. 11, 12 The intravitreal formulation, under the brand name EYELEA, was approved by the FDA for the treatment of retinopathy of prematurity in preterm infants in February and for the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy in August 2023.

An aflibercept biosimilar, Yesafili, was approved for use in the EU in September 2023.

Three aflibercept biosimilars—Yesafili (aflibercept-jbvf) 16 and Opuviz (aflibercept-yszy) 15, approved in May 2024, and Ahzantive (aflibercept-mrbb) 17, approved in July 2024—were authorized by the FDA as treatments for retinal diseases; Enzeevi (aflibercept-abzv) 18, approved in August 2024, was also approved by the FDA for similar indications.

The opthalmic agent is used for the treatment of neovascular (Wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), and retinopathy of prematurity (ROP). 7, 9 The systemic injection, known as ziv-aflibercept, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is for the treatment of metastatic colorectal cancer that is resistant to or progressed following treatment with oxaliplatin.

The equilibrium dissociation constants (K D ) for aflibercept for various human receptors are as follow: 0.5 pM for VEGF-A 165, 0.36 pM for VEGF-A 121, 1.92 pM for VEGF-B, and 39 pM for PlGF-2.

The effect of 6 mg per kg intravenous aflibercept every three weeks on QTc interval was evaluated in 87 patients with solid tumors in a randomized, placebo-controlled study.

No large changes in the mean

QT interval from baseline (i.e., greater than 20 ms as corrected for placebo) based on the Fridericia correction method were detected in the study.

However, a small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded due to the limitations of the study design.

Vascular endothelial growth factor

A, long form Inhibitor Binder Placenta growth factor Inhibitor Binder Vascular endothelial growth factor B Inhibitor Binder.

Following unilateral intravitreal administration of 8 mg aflibercept, the mean (SD) C max of free aflibercept in plasma was 0.30 mg/L, and the median time to maximal concentration in plasma was 2.9 days.

The accumulation of free aflibercept in plasma following three initial monthly intravitreal doses was minimal (mean accumulation ratio 1.2); subsequently, no further accumulation was observed.

In patients with wet age-related macular degeneration (AMD), retinopathy of prematurity (RVO), and diabetic macular edema (DME), the mean C max of free aflibercept in the plasma was 0.02 mcg/mL (range: 0-0.054 mcg/mL), 0.05 mcg/mL (range: 0-0.081 mcg/mL), and 0.03 mcg/mL (range: 0-0.076 mcg/mL), respectively and was attained in 1-3 days following intravitreal administration of 2 mg per eye.

The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients.

The volume of distribution of free aflibercept following intravenous (Intravenous). administration of aflibercept is approximately 7 L.

Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted.

Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis.

For the intravitreal formulation, the half-life was estimated to be 7.13 days.

For the intravenous formulation, following a dose of 4 mg per kg every two weeks administered Intravenous, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4-7 days).

Following an hour of intravenous infusion of 2-9 mg/kg every 2 or 3 week in cancer patients, the clearances of free and bound aflibercept were estimated to be 0.88 L/day and 0.14 L/day respectively.

Healthy subjects have a similar clearance of free aflibercept but slightly faster clearance of bound aflibercept (0.19 L/day).

Patients with a low albumin or high alkaline phosphatase levels also typically exhibit faster clearance of free aflibercept.

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For all intravitreal

VEGF inhibitors, there is increased risk of stroke and myocardial infarction.

An increase in intraocular pressure may also occur.

When used

Intravenous, most common adverse reactions were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

Adequate and well-controlled studies with aflibercept have not been conducted in pregnant women.

Aflibercept produced adverse embryofetal effects in rabbits, including external, visceral, and skeletal malformations.

A fetal No Observed Adverse Effect

Level (NOAEL) was not identified.

At the lowest dose shown to produce adverse embryofetal effects, systemic exposure (based on AUC for free aflibercept) was approximately 0.9 -fold of the population pharmacokinetic estimated exposure in humans after an intravitreal dose of 8 mg.

Animal reproduction studies are not always predictive of human response, and it is not known whether EYLEA HD can cause fetal harm when administered to a pregnant woman.

Based on the anti-VEGF mechanism of action for aflibercept, treatment with aflibercept may pose a risk to human embryofetal development.

Aflibercept should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Overdosing with increased injection volume may increase intraocular pressure.

Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.

Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3-30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels.

In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles.

These changes correlated with uterine and vaginal atrophy.

All changes were reversible within 20 weeks after cessation of treatment.

Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) for free aflibercept that was 91 times higher than the population pharmacokinetic estimated systemic exposure in humans after an intravitreal dose of 8 mg.

Infections AHZANTIVE is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation AHZANTIVE is contraindicated in patients with active intraocular inflammation. 4.3 Hypersensitivity AHZANTIVE is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in AHZANTIVE.

Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

Ocular or periocular infections Active intraocular inflammation Hypersensitivity.

ADMINISTRATION 2.1 Important Injection Instructions For ophthalmic intravitreal injection.

AHZANTIVE must only be administered by a qualified physician.

A 30-gauge × ½-inch sterile injection needle is needed but not provided.

A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL sterile Luer lock syringe and a 30‑gauge × ½-inch sterile injection needle are needed, but not provided.

AHZANTIVE is available packaged as follows

AHZANTIVE pre-filled syringe cap and plunger are not made with natural rubber latex.

AHZANTIVE vial stopper is not made with natural rubber latex. . 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months).

AHZANTIVE may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks.

Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months).

Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy.

Patients should be assessed regularly. 2.3 Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly) . 2.4 Diabetic Macular Edema (DME) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months).

Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). 2.5 Diabetic Retinopathy (DR) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months).

Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). 2.6 Preparation for Administration.

• Pre-filled Syringe The AHZANTIVE pre-filled syringe is sterile and for one-time use in one eye only.

The pre-filled syringe should be inspected visually prior to administration.

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 pre-filled syringe is damaged or if the syringe cap is detached from the Luer lock.

The intravitreal injection should be performed with a 30-gauge x ½-inch injection needle (not provided).

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept-mrbb (equivalent to 50 microliters).

The excess volume must be discarded prior to the administration.

• Figure 1: Use aseptic technique to carry out the following steps: 1.

PREPARE When ready to administer

AHZANTIVE, open the carton and remove sterilized blister pack.

Carefully peel open the sterilized blister pack ensuring the sterility of its contents.

Keep the syringe in the sterile tray until you are ready for assembly. 2.

Using aseptic technique, remove the syringe from the sterilized blister pack. 3.

Twist off (do not snap off) the syringe cap by holding the syringe in one hand and the syringe cap with the thumb and forefinger of the other hand.

Figure 2: 4.

Using aseptic technique, firmly twist a 30-gauge x ½-inch injection needle onto the Luer lock syringe tip.

Figure 3: Note: When ready to administer AHZANTIVE, remove the plastic needle shield from the needle. 5.

Holding the syringe with the needle pointing up, check the syringe for bubbles.

If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.

Figure 4: 6.

To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod to align the plunger dome edge with the black dosing line on the syringe (equivalent to 50 microliters) .

Figure 5a: Figure 5b: 7.

The pre-filled syringe is for one-time use in one eye only.

After injection any unused product must be discarded. 2.7 Preparation for Administration.

• Vial AHZANTIVE should be inspected visually prior to administration.

If particulates, cloudiness, or discoloration are visible, the vial must not be used.

The glass vial is for one-time use in one eye only.

Discard unused portion.

Use aseptic technique to carry out the following preparation steps: Prepare for intravitreal injection with the following medical devices for single use (not provided): a 5-micron sterile filter needle (18-gauge × 1½-inch) a 1-mL sterile Luer lock syringe (with marking to measure 0.05 mL) a sterile injection needle (30-gauge × ½-inch) 1.

Remove the protective plastic cap from the vial.

Figure 6: 2.

Clean the top of the vial with an alcohol wipe.

Figure 7: 3.

Remove the 18-gauge x 1½-inch, 5-micron, filter needle and the 1-mL syringe from their packaging.

Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip.

Figure 8: 4.

Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial. 5.

Using aseptic technique withdraw all of the AHZANTIVE vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal.

To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid.

Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid.

Figure 9a: Figure 9b: 6.

Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 7.

Remove the filter needle from the syringe and properly dispose of the filter needle.

Filter needle is not to be used for intravitreal injection. 8.

Remove the 30-gauge x ½-inch injection needle from its packaging and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip.

Figure 10: 9.

When ready to administer

AHZANTIVE, remove the plastic needle shield from the needle. 10.

Figure 11: 11.

To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger rod so that the plunger edge aligns with the line that marks 0.05 mL on the syringe.

Figure 12a: Figure 12b: 2.8 Injection Procedure The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and 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.

Pre-filled syringe

Inject by pressing the plunger carefully and with constant pressure.

Do not apply additional pressure once the plunger has reached the bottom of the syringe.

A small residual volume may remain in the syringe after a full dose has been injected.

This is normal.

Do not administer any residual solution observed in the syringe.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure.

Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry.

If required, a sterile paracentesis needle should be available.

Following intravitreal injection, patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Each sterile vial should only be used for the treatment of a single eye.

If the contralateral eye requires treatment, a new sterile vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before AHZANTIVE is administered to the other eye.

After injection, any unused product must be discarded.

Neovascular (Wet) Age-Related Macular Degeneration (AMD) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2. 2) Although AHZANTIVE may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks.

Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). (2. 2) Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy.

Patients should be assessed regularly.

Occlusion (RVO) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly).

Edema (DME) and Diabetic Retinopathy (DR) The recommended dose for AHZANTIVE is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months).

Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

Figure 1 figure 2 figure 3 figure 4 figure 5a figure 5b figure 6 figure 7 figure 8 figure 9a figure 9b figure 10 figure 11 figure 12a figure 12b.

Each pre-filled syringe or vial is for single eye use only.

Discard unused portion.

AHZANTIVE (aflibercept-mrbb) injection is a clear, colorless to pale yellow solution and is supplied in the following presentation.

Contents 85006-8092-1 Pre-filled Syringe one blister pack containing one AHZANTIVE 2 mg (0.05 mL of a 40 mg/mL solution) sterile, single‑dose pre-filled syringe one Prescribing Information 85006-2908-1 Vial Only one AHZANTIVE 2 mg (0.05 mL of a 40 mg/mL solution) single-dose glass vial one Prescribing Information The AHZANTIVE pre-filled syringe cap and plunger are not made with natural rubber latex.

AHZANTIVE vial stopper is not made with natural rubber latex. 16.2 Storage and Handling Refrigerate AHZANTIVE at 2°C to 8ºC (36°F to 46ºF).

Do not freeze.

Do not use beyond the date stamped on the carton and container label.

Store in the original carton until time of use to protect from light.