` BLA 125387/S-051
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` Page 4
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use EYLEA
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` safely and effectively. See full prescribing information for EYLEA.
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`5/2016
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`5/2016
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`5/2016
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`__________________
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` EYLEA® (aflibercept) Injection
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`For Intravitreal Injection
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`Initial U.S. Approval: 2011
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`__________________RECENT MAJOR CHANGES
`__________________
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`Dosage and Administration, Neovascular (Wet) Age-Related
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`
`Macular Degeneration (AMD) (2.2)
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`Dosage and Administration, Diabetic Macular Edema
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`(DME) (2.4)
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`Dosage and Administration, Diabetic Retinopathy (DR) in
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`Patients with DME (2.5)
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`__________________INDICATIONS AND USAGE
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`EYLEA is indicated for the treatment of patients with:
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`Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
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`Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
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`Diabetic Macular Edema (DME) (1.3)
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`Diabetic Retinopathy (DR) in Patients with DME (1.4)
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`
`_______________DOSAGE AND ADMINISTRATION _______________
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`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
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`●
`intravitreal injection every 4 weeks (monthly) for the first 3 months,
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`followed by 2 mg (0.05 mL) via intravitreal injection once every
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`8 weeks (2 months). (2.2)
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`Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
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`(monthly), additional efficacy was not demonstrated in most patients
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`when EYLEA was dosed every 4 weeks compared to every 8 weeks.
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`Some patients may need every 4 week (monthly) dosing after the first
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`12 weeks (3 months). (2.2)
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`Macular Edema Following Retinal Vein Occlusion (RVO)
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`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
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`intravitreal injection once every 4 weeks (monthly). (2.3)
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`●
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`Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in
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`Patients with Diabetic Macular Edema
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`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
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`intravitreal injection every 4 weeks (monthly) for the first 5 injections
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`followed by 2 mg (0.05 mL) via intravitreal injection once every
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`8 weeks (2 months). (2.4, 2.5)
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`Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
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`(monthly), additional efficacy was not demonstrated in most patients
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`when EYLEA was dosed every 4 weeks compared to every 8 weeks.
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`Some patients may need every 4 week (monthly) dosing after the first
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`20 weeks (5 months). (2.4, 2.5)
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`______________DOSAGE FORMS AND STRENGTHS
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`40 mg/mL solution for intravitreal injection in a single-use vial (3)
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`____________________CONTRAINDICATIONS ____________________
`Ocular or periocular infection (4.1)
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`Active intraocular inflammation (4 2)
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`Hypersensitivity (4.3)
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`_______________WARNINGS AND PRECAUTIONS
`_______________
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`Endophthalmitis and retinal detachments may occur following
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`intravitreal injections. Patients should be instructed to report any
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`symptoms suggestive of endophthalmitis or retinal detachment without
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`delay and should be managed appropriately. (5.1)
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`Increases in intraocular pressure have been seen within 60 minutes of an
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`intravitreal injection. (5.2)
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`There is a potential risk of arterial thromboembolic events following
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`intravitreal use of VEGF inhibitors. (5.3)
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`____________________ADVERSE REACTIONS ____________________
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`The most common adverse reactions (≥5%) reported in patients receiving
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`EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters,
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`intraocular pressure increased, and vitreous detachment. (6.1)
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`
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`To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at
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`1-855-395-3248 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`See 17 for PATIENT COUNSELING INFORMATION.
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`Revised: 5/2016
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`8
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`11
`12
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`13
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`14
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`USE IN SPECIFIC POPULATIONS
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`Pregnancy
`8.1
`8.3 Nursing Mothers
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`Pediatric Use
`8.4
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`8.5 Geriatric Use
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`DESCRIPTION
`CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`13.2 Animal Toxicology and/or Pharmacology
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`CLINICAL STUDIES
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`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`14.2 Macular Edema Following Central Retinal Vein Occlusion
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`(CRVO)
`14.3 Macular Edema Following Branch Retinal Vein Occlusion
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`(BRVO)
`14.4 Diabetic Macular Edema (DME)
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`14.5 Diabetic Retinopathy (DR) in Patients with DME
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`PATIENT COUNSELING INFORMATION
`17
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`*Sections or subsections omitted from the full prescribing information
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`are not listed
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`1
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`2
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`3
`4
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`INDICATIONS AND USAGE
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`1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
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`1.3 Diabetic Macular Edema (DME)
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`1.4 Diabetic Retinopathy (DR) in Patients with DME
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`DOSAGE AND ADMINISTRATION
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`Important Injection Instructions
`2.1
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`2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
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`2.4 Diabetic Macular Edema (DME)
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`2.5 Diabetic Retinopathy (DR) in Patients with DME
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`Preparation for Administration
`2.6
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`Injection Procedure
`2.7
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`DOSAGE FORMS AND STRENGTHS
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`CONTRAINDICATIONS
`4.1 Ocular or Periocular Infections
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`4.2 Active Intraocular Inflammation
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`4.3 Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
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`5.1 Endophthalmitis and Retinal Detachments
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`Increase in Intraocular Pressure
`5.2
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`5.3 Thromboembolic Events
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`ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`Immunogenicity
`6.2
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`6
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`_______________________________________________________________________________________________________________________________________
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 1
`Biocon Exhibit 1050 - Page 1
`
`

`

`
` BLA 125387/S-051
`
` Page 5
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` FULL PRESCRIBING INFORMATION
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`1
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` INDICATIONS AND USAGE
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` EYLEA is indicated for the treatment of:
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` Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`1.1
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`1.2
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` 1.3
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` 1.4
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`2
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` Macular Edema Following Retinal Vein Occlusion (RVO)
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` Diabetic Macular Edema (DME)
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` Diabetic Retinopathy (DR) in Patients with DME
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` DOSAGE AND ADMINISTRATION
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` Important Injection Instructions
`2.1
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` For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified
`physician.
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` Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.2
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` The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
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` intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by
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` 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may
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` be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not
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` demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every
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` 8 weeks [see Clinical Studies (14.1)]. Some patients may need every 4 week (monthly) dosing
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` after the first 12 weeks (3 months).
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` Macular Edema Following Retinal Vein Occlusion (RVO)
`2.3
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` The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
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` intravitreal injection once every 4 weeks (monthly) [see Clinical Studies (14.2), (14.3)].
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` Diabetic Macular Edema (DME)
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` 2.4
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` The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
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` intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg
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` (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be
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` dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated
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` in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see
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` Clinical Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first
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` 20 weeks (5 months).
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 2
`Biocon Exhibit 1050 - Page 2
`
`

`

`
` BLA 125387/S-051
`
` Page 6
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` Diabetic Retinopathy (DR) in Patients with DME
`2.5
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` The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
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` intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg
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` (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be
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` dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated
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` in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks [see
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` Clinical Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first
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` 20 weeks (5 months).
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`2.6
` Preparation for Administration
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` EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or
` discoloration are visible, the vial must not be used.
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` Using aseptic technique, the intravitreal injection should be performed with a 30-gauge x ½-inch
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` injection needle.
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`Vial
` The glass vial is for single use only.
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` 1. Remove the protective plastic cap from the vial (see Figure 1).
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` Figure 1:
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`2. Clean the top of the vial with an alcohol wipe (see Figure 2).
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 3
`Biocon Exhibit 1050 - Page 3
`
`

`

`
` BLA 125387/S-051
`
` Page 7
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` Figure 2:
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`3. Remove the 19-gauge x 1½-inch, 5-micron, filter needle from its pouch and remove the
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`1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by
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`twisting it onto the Luer lock syringe tip (see Figure 3).
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`Figure 3:
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`4. Push the filter needle into the center of the vial stopper until the needle is completely inserted
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`into the vial and the tip touches the bottom or bottom edge of the vial.
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`5. Using aseptic technique withdraw all of the EYLEA vial contents into the syringe, keeping
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`the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the
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`introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue
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`to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the
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`liquid (see Figures 4a and 4b).
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 4
`Biocon Exhibit 1050 - Page 4
`
`

`

`
` BLA 125387/S-051
`
` Page 8
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` Figure 4a:
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` Figure 4b:
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` 6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to
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` completely empty the filter needle.
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` 7. Remove the filter needle from the syringe and properly dispose of the filter needle.
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` Note: Filter needle is not to be used for intravitreal injection.
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` 8. Remove the 30-gauge x ½-inch injection needle from the plastic pouch and attach the
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` injection needle to the syringe by firmly twisting the injection needle onto the Luer lock
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` syringe tip (see Figure 5).
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` Figure 5:
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`9. When ready to administer EYLEA, remove the plastic needle shield from the needle.
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`10. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are
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`bubbles, gently tap the syringe with your finger until the bubbles rise to the top
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`(see Figure 6).
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 5
`Biocon Exhibit 1050 - Page 5
`
`

`

`
` BLA 125387/S-051
`
` Page 9
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` Figure 6:
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`11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so
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`that the plunger tip aligns with the line that marks 0.05 mL on the syringe
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`(see Figures 7a and 7b).
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`Figure 7a:
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`Figure 7b:
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` Injection Procedure
`2.7
` The intravitreal injection procedure should be carried out under controlled aseptic conditions,
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` which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a
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` Immediately following the intravitreal injection, patients should be monitored for elevation in
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` Following intravitreal injection, patients should be instructed to report any symptoms suggestive
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` of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia,
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` blurring of vision) without delay [see Patient Counseling Information (17)].
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` Each vial should only be used for the treatment of a single eye. If the contralateral eye requires
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` treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 6
`Biocon Exhibit 1050 - Page 6
`
`

`

`
` BLA 125387/S-051
`
` Page 10
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` speculum, filter, and injection needles should be changed before EYLEA is administered to the
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` After injection, any unused product must be discarded.
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`3
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` DOSAGE FORMS AND STRENGTHS
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` Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution (2 mg) for intravitreal
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`injection.
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`4
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`CONTRAINDICATIONS
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`4.1
`Ocular or Periocular Infections
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` EYLEA is contraindicated in patients with ocular or periocular infections.
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` Active Intraocular Inflammation
`4.2
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` EYLEA is contraindicated in patients with active intraocular inflammation.
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`4.3
`Hypersensitivity
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`EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the
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`excipients in EYLEA. Hypersensitivity reactions may manifest as severe intraocular
`inflammation.
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`5
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` WARNINGS AND PRECAUTIONS
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`5.1
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` Endophthalmitis and Retinal Detachments
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` Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis
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` and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must
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` always be used when administering EYLEA. Patients should be instructed to report any
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` symptoms suggestive of endophthalmitis or retinal detachment without delay and should be
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` managed appropriately [see Dosage and Administration (2.7) and Patient Counseling
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` Information (17)].
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`5.2
` Increase in Intraocular Pressure
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` Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection,
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` including with EYLEA [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure
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` have also been reported after repeated intravitreal dosing with vascular endothelial growth factor
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` (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be
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` monitored and managed appropriately [see Dosage and Administration (2.7)].
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 7
`Biocon Exhibit 1050 - Page 7
`
`

`

`
` BLA 125387/S-051
`
` Page 11
`
`5.3
` Thromboembolic Events
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` There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of
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` VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial
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` infarction, or vascular death (including deaths of unknown cause). The incidence of reported
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` thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in
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` the combined group of patients treated with EYLEA. The incidence in the DME studies from
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` baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with
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` EYLEA compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the
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` incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA
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` compared with 4.2% (12 out of 287) in the control group. There were no reported
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` thromboembolic events in the patients treated with EYLEA in the first six months of the RVO
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`studies.
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`6
` ADVERSE REACTIONS
`
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` The following adverse reactions are discussed in greater detail in the Warnings and Precautions
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` (5) section of the labeling:
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`  Endophthalmitis and retinal detachments
` Increased intraocular pressure
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`
`  Thromboembolic events
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`6.1
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` Clinical Trials Experience
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` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
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` observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials
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` of the same or another drug and may not reflect the rates observed in practice.
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` A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3
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` studies. Among those, 2110 patients were treated with the recommended dose of 2 mg. Serious
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` adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal
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` injections with EYLEA including endophthalmitis and retinal detachment. The most common
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` adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage,
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` eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.
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` Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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` The data described below reflect exposure to EYLEA in 1824 patients with wet AMD, including
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` 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies
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` (VIEW1 and VIEW2) for 12 months [see Clinical Studies (14.1)].
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`
`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 8
`Biocon Exhibit 1050 - Page 8
`
`

`

`
` BLA 125387/S-051
`
` Page 12
`
`
`
`
`
` Most Common Adverse Reactions (≥1%) in Wet AMD Studies
` Table 1:
`
`
`Adverse Reactions
`EYLEA
`Active Control
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`(ranibizumab)
`(N=1824)
`(N=595)
`
`28%
`9%
`7%
`6%
`7%
`7%
`8%
`5%
`3%
`3%
`4%
`1%
`2%
`3%
`1%
`2%
`2%
`1%
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`Conjunctival hemorrhage
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`Eye pain
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`Cataract
`Vitreous detachment
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`Vitreous floaters
`Intraocular pressure increased
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`Ocular hyperemia
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`Corneal epithelium defect
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`Detachment of the retinal pigment epithelium
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`Injection site pain
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`Foreign body sensation in eyes
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`Lacrimation increased
`Vision blurred
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`Intraocular inflammation
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`Retinal pigment epithelium tear
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`Injection site hemorrhage
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`Eyelid edema
`Corneal edema
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`25%
`9%
`7%
`6%
`6%
`5%
`4%
`4%
`3%
`3%
`3%
`3%
`2%
`2%
`2%
`1%
`1%
`1%
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` Less common serious adverse reactions reported in <1% of the patients treated with EYLEA
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` were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis.
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`
`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 9
`Biocon Exhibit 1050 - Page 9
`
`

`

`
` BLA 125387/S-051
`
` Page 13
`
`
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`
` Macular Edema Following Retinal Vein Occlusion (RVO)
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` The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in
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` 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and
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` 91 patients following BRVO in one clinical study (VIBRANT) [see Clinical Studies (14.2),
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`(14.3)].
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`Most Common Adverse Reactions (≥1%) in RVO Studies
`Table 2:
`CRVO
`Adverse Reactions
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`BRVO
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`Eye pain
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`Conjunctival hemorrhage
`Intraocular pressure increased
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`Corneal epithelium defect
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`Vitreous floaters
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`Ocular hyperemia
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`Foreign body sensation in eyes
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`Vitreous detachment
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`Lacrimation increased
`Injection site pain
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`Vision blurred
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`Intraocular inflammation
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`Cataract
`Eyelid edema
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`
`EYLEA
`(N=218)
`13%
`12%
`8%
`5%
`5%
`5%
`3%
`3%
`3%
`3%
`1%
`1%
`<1%
`<1%
`
`Control
`(N=142)
`5%
`11%
`6%
`4%
`1%
`3%
`5%
`4%
`4%
`1%
`<1%
`1%
`1%
`1%
`
`EYLEA
`(N=91)
`4%
`20%
`2%
`2%
`1%
`2%
`3%
`2%
`3%
`1%
`1%
`0%
`5%
`1%
`
`Control
`(N=92)
`5%
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`0%
`1%
`0%
`0%
`0%
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` Less common adverse reactions reported in <1% of the patients treated with EYLEA in the
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` CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
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` Diabetic Macular Edema (DME)
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` The data described below reflect exposure to EYLEA in 578 patients with DME treated with the
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` 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to
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` week 52 and from baseline to week 100 [see Clinical Studies (14.4)].
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`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 10
`Biocon Exhibit 1050 - Page 10
`
`

`

`
` BLA 125387/S-051
`
` Page 14
`
`
`
` Most Common Adverse Reactions (≥1%) in DME Studies
` Table 3:
`
`
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`Adverse Reactions
`Baseline to Week 52
`Baseline to Week 100
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`Control
`Control
`EYLEA
`EYLEA
`(N=578)
`(N=287)
`(N=578)
`(N=287)
`28%
`17%
`31%
`21%
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`Conjunctival
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`hemorrhage
`Eye pain
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`Cataract
`Vitreous floaters
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`Corneal epithelium
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`defect
`Intraocular pressure
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`increased
`Ocular hyperemia
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`Vitreous detachment
`Foreign body
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`sensation in eyes
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`Lacrimation increased
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`Vision blurred
`Intraocular
`
`inflammation
`Injection site pain
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`Eyelid edema
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`9%
`8%
`6%
`5%
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`5%
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`5%
`3%
`3%
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`3%
`2%
`2%
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`2%
`<1%
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`6%
`9%
`3%
`3%
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`3%
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`6%
`3%
`3%
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`2%
`2%
`<1%
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`<1%
`1%
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`11%
`19%
`8%
`7%
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`9%
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`5%
`8%
`3%
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`4%
`3%
`3%
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`2%
`2%
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`9%
`17%
`6%
`5%
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`5%
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`6%
`6%
`3%
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`2%
`4%
`1%
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`<1%
`1%
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` Less common adverse reactions reported in <1% of the patients treated with EYLEA were
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` hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage.
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`Immunogenicity
`6.2
`As with all therapeutic proteins, there is a potential for an immune response in patients treated
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`with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The
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`immunogenicity data reflect the percentage of patients whose test results were considered
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`positive for antibodies to EYLEA in immunoassays. The detection of an immune response is
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`highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of
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`sample collection, concomitant medications, and underlying disease. For these reasons,
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`comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other
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`products may be misleading.
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`In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to
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`EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for
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`
`
`Reference ID: 3935884
`
`Samsung Bioepis Exhibit 1050 - Page 11
`Biocon Exhibit 1050 - Page 11
`
`

`

`
` BLA 125387/S-051
`
` Page 15
`
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` 24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients.
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` There were no differences in efficacy or safety between patients with or without
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`immunoreactivity.
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`8
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`
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` USE IN SPECIFIC POPULATIONS
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`
`8.1
`Pregnancy
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` Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered every
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` three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every
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` six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased
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` incidences of postimplantation loss and fetal malformations, including anasarca, umbilical
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` hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina
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` bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused
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` vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete
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` ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was
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` 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the
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` fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits
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` (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the
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` systemic exposure observed in humans after an intravitreal dose of 2 mg.
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` There are no adequate and well-controlled studies in pregnant women. EYLEA should be used
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` during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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` Females of reproductive potential should use effective contraception prior to the initial dose,
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` Nursing Mothers
`8.3
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` It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted
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` during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue
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` treatment with EYLEA, taking into account the importance of the drug to the mother.
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` Pediatric Use
`8.4
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` The safety and effectiveness of EYLEA in pediatric patients have not been established.
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` Geriatric Use
`8.5
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` In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with
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` EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age.
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` No significant differences in efficacy or safety were seen with increasing age in these studies.
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`11
`DESCRIPTION
`EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF
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`receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an
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`Reference ID: 3935884
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`Samsung Bioepis Exhibit 1050 - Page 12
`Biocon Exhibit 1050 - Page 12
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`

`

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` BLA 125387/S-051
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` Page 16
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` iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a
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` protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an
` additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.
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` Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.
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` EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a
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` preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL
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` (50 microliters) of EYLEA (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride,
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` 0.03% polysorbate 20, and 5% sucrose, pH 6.2).
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`12
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` CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are
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` members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and
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` vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases,
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` VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to
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` VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by
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` VEGF-A can result in neovascularization and vascular permeability.
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` Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can
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` inhibit the binding and activation of these cognate VEGF receptors.
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`12.2
`Pharmacodynamics
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`In the clinical studies anatomic measures of disease activity improved similarly in all treatment
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`groups from baseline to week 52. Anatomic data were not used to influence treatment decisions
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`[see Clinical Studies (14.1)].
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`Macular Edema Following Retinal Vein Occlusion (RVO)
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`Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and
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`VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence tre