0.05 ML aflibercept 40 MG/ML Prefilled Syringe [Eylea]

These highlights do not include all the information needed to use AHZANTIVE safely and effectively. See full prescribing information for AHZANTIVE. Initial U.S. Approval: 2024 1 INDICATIONS AND USAGE AHZANTIVE is indicated for the treatment of: 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) 1.2 Macular Edema Following Retinal Vein Occlusion (RVO) 1.3 Diabetic Macular Edema (DME) 1.4 Diabetic Retinopathy (DR) AHZANTIVE is a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1) Macular Edema Following Retinal Vein Occlusion (RVO) (1.2) Diabetic Macular Edema (DME) (1.3) Diabetic Retinopathy (DR) (1.4)

2. DOSAGE AND ADMINISTRATION 2.1 Important Injection Instructions For ophthalmic intravitreal injection. AHZANTIVE must only be administered by a qualified physician. Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided. Vial: 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: Pre-filled Syringe. The AHZANTIVE pre-filled syringe cap and plunger are not made with natural rubber latex. Vial Only. The AHZANTIVE vial stopper is not made with natural rubber latex. [see How Supplied/Storage and Handling (16)]. 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). 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 [see Clinical Studies (14.1)] . 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) [see Clinical Studies (14.2), (14.3)]. 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). 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 [see Clinical Studies (14.4)] . 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). 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 [see Clinical Studies (14.5)] . 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. PRE-FILLED SYRINGE DESCRIPTION - 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. REMOVE SYRINGE Using aseptic technique, remove the syringe from the sterilized blister pack. 3. TWIST OFF SYRINGE CAP 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 (see Figure 2). Figure 2: 4. ATTACH NEEDLE Using aseptic technique, firmly twist a 30-gauge x ½-inch injection needle onto the Luer lock syringe tip (see Figure 3). Figure 3: Note: When ready to administer AHZANTIVE, remove the plastic needle shield from the needle. 5. DISLODGE AIR BUBBLES 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 (see Figure 4). Figure 4: 6. EXPEL AIR AND SET THE DOSE To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod to align the plunger dome edge (see Figure 5a) with the black dosing line on the syringe (equivalent to 50 microliters) (see Figure 5b). 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 (see Figure 6). Figure 6: 2. Clean the top of the vial with an alcohol wipe (see Figure 7). 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 (see Figure 8). 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 (see Figure 9a and Figure 9b). 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. Note: 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 (see Figure 10). Figure 10: 9. When ready to administer AHZANTIVE, remove the plastic needle shield from the needle. 10. 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 (see Figure 11). Figure 11: 11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger rod so that the plu

5. WARNINGS AND PRECAUTIONS 5.1 Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion Intravitreal injections, including those with aflibercept products, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)] and, more rarely, retinal vasculitis with or without occlusion [see Adverse Reactions (6.2)]. Proper aseptic injection technique must always be used when administering AHZANTIVE. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately [see Dosage and Administration (2.7) and Patient Counseling Information (17)]. 5.2 Increase in Intraocular Pressure Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with aflibercept products [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.7)]. 5.3 Thromboembolic Events There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including aflibercept products. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with aflibercept compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the aflibercept group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with aflibercept compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with aflibercept compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with aflibercept in the first six months of the RVO studies. Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment or retinal vasculitis without delay and should be managed appropriately. (5.1) Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2) There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.3)

4. CONTRAINDICATIONS 4.1 Ocular or Periocular 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 (4.1) Active intraocular inflammation (4.2) Hypersensitivity (4.3)

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability. Aflibercept products act as soluble decoy receptors that bind VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors. 12.2 Pharmacodynamics Neovascular (Wet) Age-Related Macular Degeneration (AMD) In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions during the first year. Macular Edema Following Retinal Vein Occlusion (RVO) Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions [see Clinical Studies (14.2), (14.3)]. Diabetic Macular Edema (DME) Reductions in mean retinal thickness were observed in VIVID and VISTA at weeks 52 and 100 compared to baseline. Anatomic data were not used to influence aflibercept treatment decisions [see Clinical Studies (14.4)]. 12.3 Pharmacokinetics Aflibercept is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of aflibercept, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex). Absorption/Distribution Following intravitreal administration of 2 mg per eye of aflibercept to patients with wet AMD, RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF. The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L. Metabolism/Elimination 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. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept. Specific Populations Renal Impairment Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a RVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, RVO, or DME patients. Other No dosage modification is required based on gender or in the elderly. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of aflibercept or of other aflibercept products. In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to aflibercept was approximately 1% to 3% across treatment groups. After dosing with aflibercept for 24-100 weeks, antibodies to aflibercept were detected in a similar percentage range of patients. There were no differences in efficacy or safety between patients with or without immunoreactivity.