EYLEA HD

1 INDICATIONS AND USAGE EYLEA HD is indicated for the treatment of: EYLEA HD is a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (nAMD) ( 1.1 ) Diabetic Macular Edema (DME) ( 1.2 ) Diabetic Retinopathy (DR) ( 1.3 ) Macular Edema Following Retinal Vein Occlusion (RVO) ( 1.4 ) 1.1 Neovascular (Wet) Age-Related Macular Degeneration (nAMD) 1.2 Diabetic Macular Edema (DME) 1.3 Diabetic Retinopathy (DR) 1.4 Macular Edema Following Retinal Vein Occlusion (RVO)

2 DOSAGE AND ADMINISTRATION Neovascular (Wet) Age-Related Macular Degeneration (nAMD) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week. ( 2.2 ) Some patients did not maintain a response with 8 mg once every 8 to 16 weeks, +/- 1 week, after successful response to the three initial monthly doses. These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). ( 2.2 ) Extended dosing intervals (8 mg once every 20 weeks, +/- 1 week) may be considered after one year of successful response based on visual and anatomic outcomes. ( 2.2 ). Diabetic Macular Edema (DME) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week. ( 2.3 ) Some patients did not maintain a response with 8 mg once every 8 to 16 weeks, +/- 1 week, after successful response to the three initial monthly doses. These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). ( 2.3 ) Extended dosing intervals (8 mg once every 20 weeks, +/- 1 week) may be considered after one year of successful response based on visual and anatomic outcomes. ( 2.3 ) Diabetic Retinopathy (DR) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 12 weeks, +/- 1 week. ( 2.4 ) Some patients did not maintain a response with 8 mg once every 8 to 12 weeks, +/- 1 week, after successful response to the three initial monthly doses. These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). ( 2.4 ) Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three to five doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 weeks, +/- 1 week. ( 2.5 ) Some patients did not maintain a response with extended dosing intervals after successful response to the first three to five initial monthly doses. These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). ( 2.5 ) 2.1 Important Injection Instructions For ophthalmic intravitreal injection. EYLEA HD must only be administered by a qualified physician. A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL Luer lock syringe and a 30-gauge × ½-inch sterile injection needle are needed. EYLEA HD is available packaged as follows: Vial Only Vial Kit with Injection Components (filter needle, syringe, injection needle) [see How Supplied/Storage and Handling (16) ] . 2.2 Neovascular (Wet) Age-Related Macular Degeneration (nAMD) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week. Some patients did not maintain a response with 8 mg once every 8 to 16 weeks,+/- 1 week, after successful response to the three initial monthly doses [see Clinical Studies (14.1) ] . These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). Extended dosing intervals (8 mg once every 20 weeks, +/- 1 week) may be considered after one year of successful response based on visual and anatomic outcomes [see Clinical Studies (14.1) ]. 2.3 Diabetic Macular Edema (DME) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 16 weeks, +/- 1 week. Some patients did not maintain a response with 8 mg once every 8 to 16 weeks, +/- 1 week, after successful response to the three initial monthly doses [see Clinical Studies (14.2) ] . These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). Extended dosing intervals (8 mg once every 20 weeks, +/- 1 week) may be considered after one year of successful response based on visual and anatomic outcomes [see Clinical Studies (14.2) ]. 2.4 Diabetic Retinopathy (DR) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 12 weeks, +/- 1 week. Some patients did not maintain a response with 8 mg once every 8 to 12 weeks, +/- 1 week, after successful response to the three initial monthly doses [see Clinical Studies (14.3) ] . These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). 2.5 Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first three to five doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 weeks, +/- 1 week. Some patients did not maintain a response with extended dosing intervals after successful response to the first three to five initial monthly doses [see Clinical Studies (14.4) ] . These patients may benefit from resuming every 4-week dosing (approximately every 28 days +/- 7 days). 2.6 Preparation for Administration The EYLEA HD glass vial is for one-time use in one eye only. Discard unused portion. EYLEA HD does not contain an anti-microbial preservative. Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection. Do not use if the package or its components are expired, damaged, or have been tampered with. Check the label on the vial to make sure you have the correct aflibercept strength. Prepare for intravitreal injection with the following medical devices for single use. a 5-micron sterile filter needle (18-gauge × 1½-inch) a 1-mL sterile Luer lock syringe (with marking to measure 0.07 mL) a sterile injection needle (30-gauge × ½-inch) 1. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the vial if particulates, cloudiness, or discoloration are visible. 2. Remove the protective plastic cap from the vial (see Figure 1 ). Figure 1: 3. Clean the top of the vial with an alcohol wipe (see Figure 2 ). Figure 2: 4. Use aseptic technique to carry out steps 4 – 11. Remove the 18-gauge × 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 3 ). Figure 3: 5. 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. 6. Withdraw all of the EYLEA HD 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 4a and Figure 4b ). Figure 4a: Figure 4b: 7. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. 8. 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. 9. Remove the 30-gauge × 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 5 ). Figure 5: 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 6 ). Figure 6: 11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.07 mL on the syringe (see Figure 7a and Figure 7b ). Figure 7a: Figure 7b: Figure 1 Figure 2 Figure 3 Figure 4a Figure 4b Figure 5 Figure 6 Figure 7a Figure 7b 2.7 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. 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 [see Patient Counseling Information (17) ]. Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field (including a new syringe, gloves, drapes, eyelid speculum, filter and injection needles) should be changed before EYLEA HD is administered to the other eye. After injection, discard any unused product or waste material in accordance with local regulations.

4 CONTRAINDICATIONS Ocular or periocular infection ( 4.1 ) Active intraocular inflammation ( 4.2 ) Hypersensitivity ( 4.3 ) 4.1 Ocular or Periocular Infections EYLEA HD is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation EYLEA HD is contraindicated in patients with active intraocular inflammation. 4.3 Hypersensitivity EYLEA HD is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA HD. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

5 WARNINGS AND PRECAUTIONS Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections. Patients should be instructed to report any 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 ) 5.1 Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion Intravitreal injections including those with aflibercept 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 EYLEA HD. 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 EYLEA HD [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 EYLEA HD. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in the wet AMD study (PULSAR) from baseline through week 96 was 1.8% (12 out of 673) in the combined group of patients treated with EYLEA HD compared with 3.3% (11 out of 336) in patients treated with EYLEA 2 mg. The incidence of reported thromboembolic events in the DME study (PHOTON) from baseline to week 96 was 6.7% (33 out of 491) in the combined group of patients treated with EYLEA HD compared with 7.2% (12 out of 167) in patients treated with EYLEA 2 mg. The incidence of reported thromboembolic events in the RVO study (QUASAR) from baseline to week 36 was 0.5% (3 out of 591) in the combined group of patients treated with EYLEA HD compared with 1.7% (5 out of 301) in patients treated with EYLEA 2 mg.

6 ADVERSE REACTIONS The following potentially serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications (4.3) ] Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion [see Warnings and Precautions (5.1) ] Increase in intraocular pressure [see Warnings and Precautions (5.2) ] Thromboembolic events [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥3%) reported in patients treated with EYLEA HD were cataract, conjunctival hemorrhage, corneal epithelium defect, intraocular pressure increased, ocular discomfort/eye pain/eye irritation, retinal hemorrhage, vision blurred, vitreous detachment, and vitreous floaters. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-855-395-3248 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice. A total of 1755 patients were treated with EYLEA HD and 804 patients were treated with EYLEA 2 mg in three clinical studies. The most common adverse reactions reported in ≥3% of patients treated with EYLEA HD were cataract, conjunctival hemorrhage, corneal epithelium defect, intraocular pressure increased, ocular discomfort/eye pain/eye irritation, retinal hemorrhage, vision blurred, vitreous detachment and vitreous floaters. Neovascular (Wet) Age-Related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) The data described below reflect exposure to EYLEA HD administered every 12 weeks (HDq12), EYLEA HD administered every 16 weeks (HDq16), or EYLEA 2 mg administered every 8 weeks (2q8) in controlled clinical studies (PULSAR and PHOTON), each for 96 weeks [see Clinical Studies (14.1 , 14.2) ]. Table 1: Adverse Reactions (≥1%) in at least one group in the PULSAR or PHOTON studies Adverse Reactions PULSAR PHOTON EYLEA HDq12 EYLEA HDq16 EYLEA 2q8 EYLEA HDq12 EYLEA HDq16 EYLEA 2q8 n=335 n=338 n=336 n=328 n=163 n=167 Cataract Represents grouping of related terms 10% 10% 10% 10% 13% 7% Vision blurred 9% 9% 8% 5% 4% 6% Intraocular pressure increased 5% 4% 3% 4% 1% 5% Conjunctival hemorrhage 3% 3% 3% 5% 5% 4% Ocular discomfort/eye pain/eye irritation 3% 4% 4% 5% 4% 4% Vitreous floaters 2% 6% 5% 6% 4% 4% Vitreous detachment 2% 4% 2% 5% 3% 4% Corneal epithelium defect 3% 3% 4% 4% 9% 2% Retinal hemorrhage 5% 6% 6% 0 4% 1% Dry eye 3% 3% 5% 2% 4% 2% Intraocular inflammation 2% 1% 2% 2% 1% 1% Retinal pigment epithelial tear/epitheliopathy 2% 2% 2% 1% 0 0 Vitreous hemorrhage <1% 1% 1% 2% 3% 2% Retinal Detachment 1% 1% <1% <1% 1% 0 Foreign body sensation in eyes 1% 2% 2% <1% 1% 0 Ocular hyperemia 1% <1% 1% <1% 0 0 Retinal pigment epithelial detachment 1% 1% 3% 0 0 0 Adverse drug reactions (ADRs) reported in <1% of participants treated with EYLEA HD were lacrimation increased, eyelid edema, hypersensitivity (includes adverse events of rash, urticaria, pruritus), and injection site hemorrhage. Macular Edema Following Retinal Vein Occlusion (RVO) The data described below reflects 36 weeks exposure to EYLEA HD administered every 8 weeks (HDq8) after 3 or 5 initial monthly doses (HDq4), or EYLEA 2 mg administered every 4 weeks (2q4) in a controlled clinical study (QUASAR). [see Clinical Studies (14.4) ] . Table 2: Most Common Adverse Reactions (≥1%) in at least one group in the QUASAR study Adverse Reactions EYLEA HDq8 following 3 initial doses (HDq4) (N=293) EYLEA HDq8 following 5 initial doses (HDq4) (N=298) EYLEA 2q4 (N=301) Intraocular pressure increased Represents grouping of related terms 7% 6% 3% Vision blurred 5% 3% 2% Conjunctival hemorrhage 3% 2% 2% Ocular discomfort/eye pain/eye irritation 3% 3% 1% Vitreous detachment 3% 3% 1% Cataract 2% 4% 3% Corneal epithelium defect 2% 2% 2% Dry eye 2% 2% 2% Vitreous floaters 1% 1% 1% Intraocular inflammation 1% <1% 1% Vitreous hemorrhage 1% 1% 0 Hypersensitivity Represents reported non-ocular adverse events of hypersensitivity, rash, urticaria and pruritus 1% 1% 1% Adverse reactions reported in <1% of the patients treated with EYLEA HD in the RVO study were foreign body sensation in eyes (includes foreign body sensation in eyes and sensation of foreign body), ocular hyperaemia (includes conjunctival hyperemia, conjunctival irritation, ocular hyperemia), retinal hemorrhage, retinal pigment epithelial detachment (includes detachment of retinal pigment epithelium), retinal pigment epithelial tear/epitheliopathy (includes retinal pigment epitheliopathy), and retinal tear. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of aflibercept. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye disorders : Retinal vasculitis and occlusive retinal vasculitis related to intravitreal injection with aflibercept (reported at a rate of 0.6 and 0.2 per 1 million injections, respectively, based on postmarketing experience from November 2011 until November 2023). Scleritis.

8.1 Pregnancy Risk Summary Adequate and well-controlled studies with EYLEA HD 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 (see Data ) . 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 [see Clinical Pharmacology (12.1) ] , treatment with EYLEA HD may pose a risk to human embryofetal development. EYLEA HD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In two embryofetal development studies, aflibercept produced adverse embryofetal effects when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days during organogenesis at subcutaneous doses ≥0.1 mg per kg. Adverse embryofetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was not identified. At the lowest dose shown to produce adverse embryofetal effects in rabbits (0.1 mg per kg), systemic exposure (AUC) of free aflibercept was approximately 0.9-fold of the population pharmacokinetic estimated systemic exposure (AUC) in humans after an intravitreal dose of 8 mg.