Aflibercept-Mrbb

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 plunger edge aligns with the line that marks 0.05 mL on the syringe (see Figure 12a and Figure 12b). 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 [see Patient Counseling Information (17)]. 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. (2.2) 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). (2.3) Diabetic Macular 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). (2.4, 2.5) 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 20 weeks (5 months). (2.4, 2.5) 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

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)] 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 2980 adult patients treated with aflibercept constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with aflibercept including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased. Neovascular (Wet) Age-Related Macular Degeneration (AMD) The data described below reflect exposure to aflibercept in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, controlled clinical studies (VIEW1 and VIEW2) for 24 months (with active control in year 1) [see Clinical Studies (14.1)]. Safety data observed in the aflibercept group in a 52-week, double-masked, Phase 2 study were consistent with these results. Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies Adverse Reactions Baseline to Week 52 Baseline to Week 96 Aflibercept (N=1824) Active Control (ranibizumab) (N=595) Aflibercept (N=1824) Control (ranibizumab) (N=595) Conjunctival hemorrhage 25% 28% 27% 30% Eye pain 9% 9% 10% 10% Cataract 7% 7% 13% 10% Vitreous detachment 6% 6% 8% 8% Vitreous floaters 6% 7% 8% 10% Intraocular pressure increased 5% 7% 7% 11% Ocular hyperemia 4% 8% 5% 10% Corneal epithelium defect 4% 5% 5% 6% Detachment of the retinal pigment epithelium 3% 3% 5% 5% Injection site pain 3% 3% 3% 4% Foreign body sensation in eyes 3% 4% 4% 4% Lacrimation increased 3% 1% 4% 2% Vision blurred 2% 2% 4% 3% Intraocular inflammation 2% 3% 3% 4% Retinal pigment epithelium tear 2% 1% 2% 2% Injection site hemorrhage 1% 2% 2% 2% Eyelid edema 1% 2% 2% 3% Corneal edema 1% 1% 1% 1% Retinal detachment <1% <1% 1% 1% Less common serious adverse reactions reported in <1% of the patients treated with aflibercept were hypersensitivity, retinal tear, and endophthalmitis. Macular Edema Following Retinal Vein Occlusion (RVO) The data described below reflect 6 months exposure to aflibercept with a monthly 2 mg dose in 218 patients following central retinal vein occlusion (CRVO) in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following branch retinal vein occlusion (BRVO) in one clinical study (VIBRANT) [see Clinical Studies (14.2), (14.3)]. Table 2: Most Common Adverse Reactions (≥1%) in RVO Studies Adverse Reactions CRVO BRVO Aflibercept (N=218) Control (N=142) Aflibercept (N=91) Control (N=92) Eye pain 13% 5% 4% 5% Conjunctival hemorrhage 12% 11% 20% 4% Intraocular pressure increased 8% 6% 2% 0% Corneal epithelium defect 5% 4% 2% 0% Vitreous floaters 5% 1% 1% 0% Ocular hyperemia 5% 3% 2% 2% Foreign body sensation in eyes 3% 5% 3% 0% Vitreous detachment 3% 4% 2% 0% Lacrimation increased 3% 4% 3% 0% Injection site pain 3% 1% 1% 0% Vision blurred 1% <1% 1% 1% Intraocular inflammation 1% 1% 0% 0% Cataract <1% 1% 5% 0% Eyelid edema <1% 1% 1% 0% Less common adverse reactions reported in <1% of the patients treated with aflibercept in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis. Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) The data described below reflect exposure to aflibercept in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100 [see Clinical Studies (14.4)]. Table 3: Most Common Adverse Reactions (≥1%) in DME Studies Adverse Reactions Baseline to Week 52 Baseline to Week 100 Aflibercept (N=578) Control (N=287) Aflibercept (N=578) Control (N=287) Conjunctival hemorrhage 28% 17% 31% 21% Eye pain 9% 6% 11% 9% Cataract 8% 9% 19% 17% Vitreous floaters 6% 3% 8% 6% Corneal epithelium defect 5% 3% 7% 5% Intraocular pressure increased 5% 3% 9% 5% Ocular hyperemia 5% 6% 5% 6% Vitreous detachment 3% 3% 8% 6% Foreign body sensation in eyes 3% 3% 3% 3% Lacrimation increased 3% 2% 4% 2% Vision blurred 2% 2% 3% 4% Intraocular inflammation 2% <1% 3% 1% Injection site pain 2% <1% 2% <1% Eyelid edema <1% 1% 2% 1% Less common adverse reactions reported in <1% of the patients treated with aflibercept were hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage. Safety data observed in 269 patients with nonproliferative diabetic retinopathy (NPDR) through week 52 in the PANORAMA trial were consistent with those seen in the phase 3 VIVID and VISTA trials (see Table 3 above). 6.1 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). The most common adverse reactions (≥5%) reported in patients receiving aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Formycon at 1-800-387-2746 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION.