BLA 125387/S-075
`Page 4
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use EYLEA
`safely and effectively. See full prescribing information for EYLEA.
`
`EYLEA® (aflibercept) Injection, for intravitreal use
`Initial U.S. Approval: 2011
`
`__________________
`__________________RECENT MAJOR CHANGES
`2/2023
`Indications and Usage (1.5)
`Dosage and Administration (2)
` 2/2023
`Dosage and Administration (2.2, 2.4)
`8/2022
`Warnings and Precautions (5.3)
`2/2023
`__________________INDICATIONS AND USAGE __________________
`EYLEA 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)
`Retinopathy of Prematurity (ROP) (1.5)
`_______________DOSAGE AND ADMINISTRATION _______________
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
`intravitreal injection every 4 weeks (approximately every 28 days,
`
`monthly) for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal
`injection once every 8 weeks (2 months). (2.5)
`Although EYLEA 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 EYLEA 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). (2.5)
`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. (2.5)
`Macular Edema Following Retinal Vein Occlusion (RVO)
`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
`intravitreal injection once every 4 weeks (approximately every 25 days,
`monthly). (2.6)
`Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
`intravitreal injection every 4 weeks (approximately every 28 days,
`monthly) for the first 5 injections followed by 2 mg (0.05 mL) via
`intravitreal injection once every 8 weeks (2 months). (2.7, 2.8)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`Although EYLEA 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 EYLEA 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). (2.7, 2.8)
`Retinopathy of Prematurity (ROP)
`The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters)
`administered by intravitreal injection. Treatment may be given bilaterally
`on the same day. Injections may be repeated in each eye. The treatment
`interval between doses injected into the same eye should be at least 10
`days.(2.9)
`______________DOSAGE FORMS AND STRENGTHS ______________
` Injection: 2 mg/0.05 mL solution in a single-dose pre-filled syringe (3)
` Injection: 2 mg/0.05 mL solution in a single-dose vial (3)
`____________________CONTRAINDICATIONS ____________________
`Ocular or periocular infection (4.1)
`Active intraocular inflammation (4.2)
`Hypersensitivity (4.3)
`_______________
`_______________WARNINGS AND PRECAUTIONS
`Endophthalmitis and retinal detachments may occur following intravitreal
`
`injections. Patients and/or caregivers should be instructed to report any signs
`and/or symptoms suggestive of endophthalmitis or retinal detachment 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)
`In infants with ROP, treatment with EYLEA will necessitate extended periods of
`ROP monitoring (5.3)
`
`There is a potential risk of arterial thromboembolic events following intravitreal
`use of VEGF inhibitors. (5.4)
`____________________ADVERSE REACTIONS ____________________
`The most common adverse reactions (≥5%) reported in patients receiving
`EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment,
`vitreous floaters, and intraocular pressure increased. (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.
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 2/2023
`
`1
`
`2
`
`INDICATIONS AND USAGE
`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)
`
`1.5 Retinopathy of Prematurity (ROP)
`DOSAGE AND ADMINISTRATION
`2.1
`Important Injection Instructions
`2.2
`Preparation for Administration – Pre-filled Syringe
`
`Preparation for Administration - Vial
`2.3
`2.4
`Injection Procedure in Adults
`2.5 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.6 Macular Edema Following Retinal Vein Occlusion (RVO)
`2.7 Diabetic Macular Edema (DME)
`2.8 Diabetic Retinopathy (DR)
`2.9 Retinopathy of Prematurity (ROP)
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1 Ocular or Periocular Infections
`4.2 Active Intraocular Inflammation
`4.3 Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`5.1 Endophthalmitis and Retinal Detachments
`5.2
`Increase in Intraocular Pressure
`5.3 Extended Monitoring and Additional Treatment in ROP
`
`3
`4
`
`6
`
`8
`
`5.4 Thromboembolic Events
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`11
`DESCRIPTION
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.6 Immunogenicity
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`14.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO)
`14.3 Macular Edema Following Branch Retinal Vein Occlusion (BRVO)
`14.4 Diabetic Macular Edema (DME)
`14.5 Diabetic Retinopathy (DR)
`
`13
`
`14
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 1
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`BLA 125387/S-075
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`
`14.6 Retinopathy of Prematurity (ROP)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`
`EYLEA is indicated for the treatment of:
`
`1.1
`1.2
`1.3
`1.4
`1.5
`
`2
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`Macular Edema Following Retinal Vein Occlusion (RVO)
`Diabetic Macular Edema (DME)
`Diabetic Retinopathy (DR)
`Retinopathy of Prematurity (ROP)
`
`DOSAGE AND ADMINISTRATION
`
`Important Injection Instructions
`2.1
`For ophthalmic intravitreal injection. EYLEA 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 (19-gauge × 1½-inch), a 1-mL Luer lock syringe and a
`30-gauge × ½-inch sterile injection needle are needed.
`
`EYLEA is available packaged as follows:
`
` Pre-filled Syringe
`
` Vial Kit with Injection Components (filter needle, syringe, injection needle)
`
`[see How Supplied/Storage and Handling (16)].
`
`Preparation for Administration - Pre-filled Syringe
`2.2
`
` The EYLEA pre-filled glass syringe is sterile and for single use only. Do not use the EYLEA
`pre-filled syringe for the treatment of ROP.
`
`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. The
`appearance of the syringe cap on the pre-filled syringe may vary (for example, color and design).
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 2
`
`

`

`BLA 125387/S-075
`Page 6
`
`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 (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 EYLEA, 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.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 3
`
`

`

`BLA 125387/S-075
`Page 7
`
`TWIST OFF SYRINGE CAP
`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 (see Figure 2).
`
`Note: To avoid compromising the sterility of the product, do not pull back on the plunger.
`
`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 EYLEA, remove the plastic needle shield from the needle.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 4
`
`

`

`BLA 125387/S-075
`Page 8
`
`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:
`
`EXPEL AIR AND SET THE DOSE
`6.
`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:
`
`The pre-filled syringe is for single use only. After injection any unused product must be
`7.
`discarded.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 5
`
`

`

`BLA 125387/S-075
`Page 9
`
`Preparation for Administration - Vial
`2.3
`EYLEA 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 single use only.
`
`Use aseptic technique to carry out the following preparation steps:
`Prepare for intravitreal injection with the following medical devices for single use:
` a 5-micron sterile filter needle (19-gauge × 1½-inch)
` a 1-mL sterile Luer lock syringe with marking to measure 0.05 mL for adults or 0.01 mL
`for pre-term infants with ROP
` a sterile injection needle (30-gauge × ½-inch)
`Remove the protective plastic cap from the vial (see Figure 6).
`
`Figure 6:
`
`Clean the top of the vial with an alcohol wipe (see Figure 7).
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 6
`
`

`

`BLA 125387/S-075
`Page 10
`
`Figure 7:
`
`Remove the 19-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:
`
`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.
`
`Using aseptic technique withdraw all of the EYLEA 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
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 7
`
`

`

`BLA 125387/S-075
`Page 11
`
`
`
` 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:
`
`Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to
`completely empty the filter needle.
`
`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.
`
`
`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:
`
`When ready to administer EYLEA, remove the plastic needle shield from the needle.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 8
`
`

`

`BLA 125387/S-075
`Page 12
`
`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:
`
`Administration in Adults:
`
`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).
`
`Injection Procedure for Adults
`2.4
`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.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 9
`
`

`

`BLA 125387/S-075
`Page 13
`
`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, pre-filled syringe or vial should only be used for the treatment of a single eye. If the
`contralateral eye requires treatment, a new sterile, pre-filled syringe or vial should be used and
`the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be
`changed before EYLEA is administered to the other eye.
`
`After injection, any unused product must be discarded.
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.5
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) 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) via intravitreal injection once every 8 weeks
`(2 months). Although EYLEA 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 EYLEA 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.
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`2.6
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see
`Clinical Studies (14.2), (14.3)].
`
`Diabetic Macular Edema (DME)
`2.7
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first
`5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks
`(2 months). Although EYLEA 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 EYLEA 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).
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 10
`
`

`

`BLA 125387/S-075
`Page 14
`
`Diabetic Retinopathy (DR)
`2.8
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first
`5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks
`(2 months). Although EYLEA 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 EYLEA 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).
`
`Retinopathy of Prematurity (ROP)
`2.9
`Recommended Dosage
`
`The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters) administered by
`intravitreal injection. Treatment is initiated with a single injection per eligible eye and may be
`
`given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval
`between doses injected into the same eye should be at least 10 days [see Clinical Pharmacology
`
`(12.3) and Clinical Studies (14.6)].
`
`Administration Instructions in Pre-Term Infants with ROP
`
`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 sterile vial should only be used for the treatment of a single eye. Do not use the EYLEA
`
`pre-filled syringe for the treatment of ROP. 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 EYLEA is administered to the other eye.
`
`Follow steps 1-10 listed in 2.3 Preparation for Administration – Vial.
`
`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 0.01 mL on the syringe (see Figure 13a and
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 11
`
`

`

`BLA 125387/S-075
`Page 15
`
`Figure 13b).
`
`For the treatment of ROP, the injection needle should be inserted into the eye 1 mm from the
`limbus with the needle angled to avoid the lens and to avoid the retina.
`
`After injection, any unused product must be discarded.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`EYLEA is a clear, colorless to pale yellow solution available as:
`
`
`
`
`
`Injection: 2 mg/0.05 mL in a single-dose pre-filled glass syringe
`
`Injection: 2 mg/0.05 mL in a single-dose glass vial
`
`4
`
`CONTRAINDICATIONS
`
`Ocular or Periocular Infections
`4.1
`EYLEA is contraindicated in patients with ocular or periocular infections.
`
`Active Intraocular Inflammation
`4.2
`EYLEA is contraindicated in patients with active intraocular inflammation.
`
`Hypersensitivity
`4.3
`EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the
`excipients in EYLEA. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe
`anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 12
`
`

`

`BLA 125387/S-075
`Page 16
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Endophthalmitis and Retinal Detachments
`5.1
`Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis
`and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must
`always be used when administering EYLEA. Patients and/or caregivers should be instructed to
`
`
`report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment without
`delay and should be managed appropriately [see Dosage and Administration (2.4) and
`Patient Counseling Information (17)].
`
`Increase in Intraocular Pressure
`5.2
`Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection,
`
`including with EYLEA [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 (2.4)].
`
`Extended Monitoring and Additional Treatment in ROP
`5.3
`Reactivation of abnormal angiogenesis and tortuosity may occur following treatment with
`EYLEA. Infants should be monitored closely after injection with EYLEA until retinal
`vascularization has completed or until the examiner is assured that reactivation of ROP will not
`occur. In infants with ROP, treatment with EYLEA will necessitate extended periods of ROP
`monitoring and additional EYLEA injections and/or laser treatments may be necessary.
`
`Thromboembolic Events
`5.4
`There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of
`VEGF inhibitors, including EYLEA. 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 EYLEA 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 EYLEA 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 EYLEA 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 EYLEA compared with 4.2% (12 out of 287) in the control group. There were no
`reported thromboembolic events in the patients treated with EYLEA in the first six months of the
`RVO studies.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 13
`
`

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`BLA 125387/S-075
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`6
`
`ADVERSE REACTIONS
`
`The following potentially serious adverse reactions are described elsewhere in the labeling:
`
`Hypersensitivity [see Contraindications (4.3)]
`
`
`
`Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)]
`
`
`Increase in intraocular pressure [see Warnings and Precautions (5.2)]
`
`
`Thromboembolic events [see Warnings and Precautions (5.4)]
`
`
`Clinical Trials Experience
`6.1
`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 EYLEA 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 EYLEA including endophthalmitis and retinal detachment. The most
`
`
`common adverse reactions (≥5%) reported in patients receiving EYLEA 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 EYLEA 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 EYLEA group in a 52-week, double-masked, Phase 2 study were
`consistent with these results.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 14
`
`

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`BLA 125387/S-075
`Page 18
`
`25%
`9%
`7%
`6%
`6%
`5%
`4%
`4%
`3%
`
`27%
`10%
`13%
`8%
`8%
`7%
`5%
`5%
`5%
`
`Most Common Adverse Reactions (≥1%) in Wet AMD Studies
`Table 1:
`Adverse Reactions
`Baseline to Week 52
`Baseline to Week 96
`EYLEA
`Active Control
`EYLEA
`Control
`(ranibizumab)
`(ranibizumab)
`(N=1824)
`(N=1824)
`(N=595)
`(N=595)
`28%
`30%
`9%
`10%
`7%
`10%
`6%
`8%
`7%
`10%
`7%
`11%
`8%
`10%
`5%
`6%
`3%
`5%
`
`Conjunctival hemorrhage
`Eye pain
`Cataract
`Vitreous detachment
`Vitreous floaters
`Intraocular pressure increased
`Ocular hyperemia
`Corneal epithelium defect
`Detachment of the retinal pigment
`epithelium
`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 EYLEA
`were hypersensitivity, retinal tear, and endophthalmitis.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 15
`
`

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`BLA 125387/S-075
`Page 19
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`The data described below reflect 6 months exposure to EYLEA 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)].
`
`Most Common Adverse Reactions (≥1%) in RVO Studies
`Table 2:
`CRVO
`Adverse Reactions
`
`BRVO
`
`EYLEA
`Control
`EYLEA
`Control
`(N=218)
`(N=142)
`(N=91)
`(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 EYLEA 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 EYLEA 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)].
`
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 16
`
`

`

`BLA 125387/S-075
`Page 20
`
`Most Common Adverse Reactions (≥1%) in DME Studies
`Table 3:
`Adverse Reactions
`Baseline to Week 52
`Baseline to Week 100
`EYLEA
`Control
`EYLEA
`Control
`(N=578)
`(N=287)
`(N=578)
`(N=287)
`28%
`17%
`31%
`21%
`
`Conjunctival
`hemorrhage
`Eye pain
`Cataract
`Vitreous floaters
` Corneal epithelium
`defect
`Intraocular pressure
`increased
`Ocular hyperemia
`Vitreous detachment
`Foreign body
`sensation in eyes
`Lacrimation increased
`Vision blurred
`Intraocular
`inflammation
`<1%
`2%
`<1%
`2%
`Injection site pain
`1%
`2%
`1%
`<1%
`Eyelid edema
`Less common adverse reactions reported in <1% of the patients treated with EYLEA were
`hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage.
`
`
`
`9%
`8%
`6%
`5%
`
`5%
`
`5%
`3%
`3%
`
`3%
`2%
`2%
`
`6%
`9%
`3%
`3%
`
`3%
`
`6%
`3%
`3%
`
`2%
`2%
`<1%
`
`11%
`19%
`8%
`7%
`
`9%
`
`5%
`8%
`3%
`
`4%
`3%
`3%
`
`9%
`17%
`6%
`5%
`
`5%
`
`6%
`6%
`3%
`
`2%
`4%
`1%
`
`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).
`
`Retinopathy of Prematurity (ROP)
`The data described below reflect exposure to EYLEA in 168 pre-term infants with ROP
`
`randomized to EYLEA and treated with the 0.4 mg dose in 2 clinical studies (BUTTERFLEYE
`and FIREFLEYE/FIREFLEYE NEXT) from time of first administration up to 52 weeks of
`
`chronological age [see Clinical Studies (14.6)]. Adverse reactions established for adult
`indications are considered applicable to pre-term infants with ROP, though not all were observed
`in the clinical studies.
`
`Reference ID: 5121900
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2140 Page 17
`
`

`

`BLA 125387/S-075
`Page 21
`
`Adverse Reactions in ROP Studies a
`Table 4:
`Baseline to 52 weeks of
`Adverse Reactions
`chronological age
`
`Baseline to 52 weeks of
`chronological age
`
`BUTTERFLEYE
`
`FIREFLEYE/FIREFLEYE
`NEXT
`
`EYLEA
`(N=75)
`5%
`9%
`4%
`0%
`3%
`1%
`1%
`
`Laser
`(N=28)
`5%
`0%
`0%
`0%
`8%
`3%
`0%
`
`EYLEA
`(N=93)
`6%
`Retinal detachment
`5%
`Conjunctival hemorrhageb
`0%
`Intraocular pressure increased
`1%
`Corneal epithelium defect
`0%
`Eyelid edema
`0%
`Corneal edema
`0%
`Lenticular Opacities
`a
` Five year follow-up studies are ongoing through 2026
`b
` Includes injection site hemorrhage
`
`Laser
`(N=27)
`7%
`0%
`0%
`0%
`4%
`0%
`0%
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Risk Summary
`
`
`Adequate and well-controlled studies with EYLEA 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