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 Injection
`Initial U.S. Approval:
` 2011
`__________________ INDICATIONS AND USAGE _________________
`EYLEA is indicated for the treatment of patients with Neovascular (Wet)
`Age-Related Macular Degeneration (AMD). (1)
`_______________ DOSAGE AND ADMINISTRATION ______________
`●
`For ophthalmic intravitreal injection only. (2.1)
`
`●
`
`●
`
`The recommended dose for EYLEA is 2 mg (0.05 mL) administered by
`intravitreal injection every 4 weeks (monthly) for the first 3 months,
`followed by 2 mg (0.05 mL) via intravitreal injection once every
`8 weeks (2 months). (2.2)
`Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
`(monthly), additional efficacy was not demonstrated when EYLEA was
`dosed every 4 weeks compared to every 8 weeks. (2.2)
` ______________ DOSAGE FORMS AND STRENGTHS _____________
`40 mg/mL solution for intravitreal injection in a single-use vial (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 
`2 
`
`3 
`4 
`
`INDICATIONS AND USAGE 
`DOSAGE AND ADMINISTRATION 
`2.1  General Dosing Information 
`2.2  Dosing 
`2.3 
`Preparation for Administration 
`2.4  Administration 
`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  Thromboembolic Events 
`ADVERSE REACTIONS 
`6.1 
`Injection Procedure 
`6.2  Clinical Studies Experience 
`
`6 
`
`___________________ 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 should be instructed to report any
`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)
`____________________ADVERSE REACTIONS____________________
`The most common adverse reactions (≥5%) reported in patients receiving
`EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous
`detachment, vitreous floaters, and increased intraocular pressure. (6.2)
`
`•
`
`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: 11/2011
`
`8 
`
`Immunogenicity 
`6.3 
`USE IN SPECIFIC POPULATIONS 
`8.1 
`Pregnancy 
`8.3  Nursing Mothers 
`8.4 
`Pediatric Use 
`8.5  Geriatric Use 
`11  DESCRIPTION 
`12  CLINICAL PHARMACOLOGY 
`12.1  Mechanism of Action 
`12.2  Pharmacodynamics 
`12.3  Pharmacokinetics 
`13  NONCLINICAL TOXICOLOGY 
`13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility 
`13.2  Animal Toxicology and/or Pharmacology 
`14  CLINICAL STUDIES 
`16  HOW SUPPLIED/STORAGE AND HANDLING 
`17 
`PATIENT COUNSELING INFORMATION 
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`_______________________________________________________________________________________________________________________________________
`
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`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`EYLEA is indicated for the treatment of patients with Neovascular (Wet) Age-Related Macular
`Degeneration (AMD).
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. EYLEA must only be
`administered by a qualified physician.
`
`Dosing
`2.2
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (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 (monthly), additional efficacy was not
`demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks [see Clinical
`Studies (14)].
`
`Preparation for Administration
`2.3
`EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or
`discoloration are visible, the vial must not be used.
`Using aseptic technique, the intravitreal injection should be performed with a 30-gauge x ½-inch
`injection needle.
`
`Vial
`The glass vial is for single use only.
`1. Remove the protective plastic cap from the vial (see Figure 1).
`
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`Figure 1:
`
`
`
`
`
`Figure 2:
`
`
`
`2. Clean the top of the vial with an alcohol wipe (see Figure 2).
`
`3. Remove the 19-gauge x 1½-inch, 5-micron, filter needle from its pouch and remove the
`1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by
`twisting it onto the Luer lock syringe tip (see Figure 3).
`
`Figure 3:
`
`
`
`
`
`
`
`
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`4. Push the filter needle into the center of the vial stopper until the needle touches the bottom
`edge of the vial.
`5. 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 (see Figure 4).
`Figure 4:
`
`
`
`
`
`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 the plastic pouch and attach the
`injection needle to the syringe by firmly twisting the injection needle onto the Luer lock
`syringe tip (see Figure 5).
`
`Figure 5:
`
`
`
`9. When ready to administer EYLEA, 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
`6).
`
`
`
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`Figure 6:
`
`
`
`
`
`
`
`11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so
`that the plunger tip aligns with the line that marks 0.05 mL on the syringe (see Figures 7 and
`8).
`
`Figure 7:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 8:
`
`
`
`Administration
`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.
`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 should be instructed to report any symptoms suggestive
`of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia,
`blurring of vision) without delay [see Patient Counseling Information (17)].
`Each vial should only be used for the treatment of a single eye. If the contralateral eye requires
`treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid
`
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`speculum, filter, and injection needles should be changed before EYLEA is administered to the
`other eye.
`After injection, any unused product must be discarded.
`No special dosage modification is required for any of the populations that have been studied
`(e.g., gender, elderly).
`
`DOSAGE FORMS AND STRENGTHS
`3
`Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution for intravitreal
`injection.
`
`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.
`
`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 should be instructed to report any
`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 VEGF inhibitors. Intraocular
`pressure and the perfusion of the optic nerve head should be monitored and managed
`appropriately [see Dosage and Administration (2.4)].
`
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`Thromboembolic Events
`5.3
`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 in the VIEW1
`and VIEW2 wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined
`group of patients treated with EYLEA [see Clinical Studies (14)].
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in detail in other sections of the labeling:
`• Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)]
`•
`Increased intraocular pressure [see Warnings and Precautions (5.2)]
`● Thromboembolic events [see Warnings and Precautions (5.3)]
`The most common adverse reactions (≥5%) reported in patients receiving EYLEA were
`conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased
`intraocular pressure.
`
`Injection Procedure
`6.1
`Serious adverse reactions related to the injection procedure have occurred in <0.1% of
`intravitreal injections with EYLEA including endophthalmitis, traumatic cataract, and increased
`intraocular pressure.
`
`Clinical Studies Experience
`6.2
`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 the clinical trials
`of another drug and may not reflect the rates observed in practice.
`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, active-controlled clinical studies
`(VIEW1 and VIEW2) for 12 months [see Clinical Studies (14)].
`Table 1:
`Most Common Adverse Reactions (≥1%) in Phase 3 wet AMD studies
`Adverse Reactions
`EYLEA
`Active Control
`(ranibizumab)
`(N=1824)
` (N=595)
`28%
`9%
`7%
`6%
`7%
`
`Conjunctival hemorrhage
`Eye pain
`Cataract
`Vitreous detachment
`Vitreous floaters
`
`25%
`9%
`7%
`6%
`6%
`
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`

`Adverse Reactions
`
`EYLEA
`(N=1824)
`
`Active Control
`(ranibizumab)
` (N=595)
`7%
`8%
`5%
`3%
`
`5%
`4%
`4%
`3%
`
`Intraocular pressure increased
`Conjunctival hyperemia
`Corneal erosion
`Detachment of the retinal pigment
`epithelium
`3%
`3%
`Injection site pain
`4%
`3%
`Foreign body sensation in eyes
`1%
`3%
`Lacrimation increased
`2%
`2%
`Vision blurred
`1%
`2%
`Retinal pigment epithelium tear
`2%
` 1%
`Injection site hemorrhage
`2%
`1%
`Eyelid edema
`1%
`1%
`Corneal edema
`Less common serious adverse reactions reported in <1% of the patients treated with EYLEA
`were retinal detachment, retinal tear, and endophthalmitis. Hypersensitivity has also been
`reported in less than 1% of the patients treated with EYLEA.
`
`Immunogenicity
`6.3
`As with all therapeutic proteins, there is a potential for an immune response in patients treated
`with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The
`immunogenicity data reflect the percentage of patients whose test results were considered
`positive for antibodies to EYLEA in immunoassays. The detection of an immune response is
`highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of
`sample collection, concomitant medications, and underlying disease. For these reasons,
`comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other
`products may be misleading.
`In the phase 3 studies, the pre-treatment incidence of immunoreactivity to EYLEA was 1% to
`3% across treatment groups. After dosing with EYLEA for 52 weeks, antibodies to EYLEA were
`detected in a similar percentage range of patients. There were no differences in efficacy or safety
`between patients with or without immunoreactivity.
`
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`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered during
`organogenesis in pregnant rabbits at intravenous doses of 3 to 60 mg/kg. A series of external,
`visceral, and skeletal malformations were observed in the fetuses. The maternal No Observed
`Adverse Effect Level (NOAEL) was 3 mg/kg, whereas the fetal NOAEL was below 3 mg/kg. At
`this dose, the systemic exposures based on Cmax and AUC for free aflibercept were
`approximately 2900 times and 600 times higher, respectively, when compared to corresponding
`values observed in humans after an intravitreal dose of 2 mg.
`There are no adequate and well-controlled studies in pregnant women. EYLEA should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Nursing Mothers
`8.3
`It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted
`in human milk, a risk to the breastfed child cannot be excluded. EYLEA is not recommended
`during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue
`treatment with EYLEA, taking into account the importance of the drug to the mother.
`
`Pediatric Use
`8.4
`The safety and effectiveness of EYLEA in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`In the clinical studies, approximately 89% (1616/1817) of patients randomized to treatment with
`EYLEA were ≥65 years of age and approximately 63% (1139/1817) were ≥75 years of age. No
`significant differences in efficacy or safety were seen with increasing age in these studies.
`
`DESCRIPTION
`11
`EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF
`receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an
`iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a
`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.
`Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.
`EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a
`preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL
`(50 microliters) of EYLEA (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride,
`0.03% polysorbate 20, and 5% sucrose, pH 6.2).
`
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`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are
`members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and
`vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases,
`VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to
`VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by
`VEGF-A can result in neovascularization and vascular permeability.
`Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can
`inhibit the binding and activation of these cognate VEGF receptors.
`
`Pharmacodynamics
`12.2
`In the phase 3 studies anatomic measures of disease activity improved similarly in all treatment
`groups from baseline to week 52. Anatomic data were not used to influence treatment decisions.
`
`Pharmacokinetics
`12.3
`EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD,
`following intravitreal administration of EYLEA, a fraction of the administered dose is expected
`to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once
`absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept
`(unbound to VEGF) and a more predominant stable inactive form with circulating endogenous
`VEGF (i.e., aflibercept: VEGF complex).
`
`Absorption/Distribution
`Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD, the
`mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL) and
`was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two
`weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as
`repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of
`2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than
`100 fold lower than the concentration of aflibercept required to half-maximally bind systemic
`VEGF.
`The volume of distribution of free aflibercept following intravenous (I.V.) administration of
`aflibercept has been determined to be approximately 6L.
`
`Metabolism/Elimination
`Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted.
`Aflibercept is expected to undergo elimination through both target-mediated disposition via
`binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination
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`half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V.
`administration of doses of 2 to 4 mg/kg aflibercept.
`Specific Populations
`Renal Impairment
`Pharmacokinetic analysis of a subgroup of patients (n=492) in one Phase 3 study, of which 43%
`had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences
`with respect to plasma concentrations of free aflibercept after intravitreal administration every 4
`or 8 weeks. No dose adjustment based on renal impairment status is needed.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.
`Effects on male and female fertility were assessed as part of a 6-month study in monkeys with
`intravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or
`irregular menses associated with alterations in female reproductive hormone levels and changes
`in sperm morphology and motility were observed at all dose levels. In addition, females showed
`decreased ovarian and uterine weight accompanied by compromised luteal development and
`reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No
`Observed Adverse Effect Level (NOAEL) was not identified. Based on Cmax and AUC for free
`aflibercept observed at the lowest dose used of 3 mg/kg, the systemic exposures were
`approximately 4900 times and 1500 times higher, respectively, than the exposure observed in
`humans after an intravitreal dose of 2 mg. All changes were reversible.
`
`Animal Toxicology and/or Pharmacology
`13.2
`Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with
`aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg/eye. At the NOAEL of
`0.5 mg/eye in monkeys, the systemic exposure was 42 times and 56 times higher based on Cmax
`and AUC, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg.
`Similar effects were not seen in clinical studies [see Clinical Studies (14)].
`
`CLINICAL STUDIES
`14
`The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-
`masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were
`treated and evaluable for efficacy (1817 with EYLEA) in the two studies (VIEW1 and VIEW2).
`In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens:
`1) EYLEA administered 2 mg every 8 weeks following 3 initial monthly doses (EYLEA 2Q8);
`2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered
`every 4 weeks (EYLEA 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks
`(ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years.
`
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`In both studies, the primary efficacy endpoint was the proportion of patients who maintained
`vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline.
`Data are available through week 52. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to
`have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group.
`Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 2 and
`Figure 9 below.
`Table 2:
`Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and
`VIEW2 Studies
`
`EYLEA
`2 mg Q8
`weeks a
`
`N=301
`
`94%
`
`VIEW1
`EYLEA
`2 mg Q4
`weeks
`
`N=304
`
`95%
`
`ranibizu-
`mab
`0.5 mg Q4
`weeks
`N=304
`
`EYLEA
`2 mg Q8
`weeks a
`
`VIEW2
`EYLEA
`2 mg Q4
`weeks
`
`N=306
`
`N=309
`
`ranibizu-
`mab
`0.5 mg Q4
`weeks
`N=291
`
`94%
`
`95%
`
`95%
`
`95%
`
`
`
`
`Full Analysis Set
`Efficacy Outcomes
`Proportion of patients
`who maintained
`visual acuity (%)
`(<15 letters of BCVA
`loss)
`
`0.6
` (-3.2, 4.4)
`7.9
`
`1.3
` (-2.4, 5.0)
`10.9
`
`0.3
`
`(-2.0, 2.5)
`92
`(31%)
`
`3.2
`
`(0.9, 5.4)
`114
`(38%)
`
`
`
`8.1
`
`
`
`94
`(31%)
`
`
`
`Differenceb (%)
`
`(95.1% CI)
`Mean change in
`BCVA as measured
`by ETDRS letter
`score from Baseline
`Differenceb in LS
`mean
`(95.1% CI)
`
`Number of patients
`who gained at least
`15 letters of vision
`from Baseline (%)
`Differenceb (%)
`-4.6
`-2.6
`6.6
`-0.4
` (-12.1, 2.9)
`(-10.2, 4.9)
`(-1.0, 14.1)
`(-7.7, 7.0)
`
`(95.1% CI)
`BCVA = Best Corrected Visual Acuity; CI = Confidence Interval; ETDRS = Early Treatment Diabetic Retinopathy
`Study; LOCF = Last Observation Carried Forward (baseline values are not carried forward); 95.1% confidence
`intervals were presented to adjust for safety assessment conducted during the study.
`a After treatment initiation with 3 monthly doses
`b EYLEA group minus the ranibizumab group
`
`
`0.6
` (-2.9, 4.0)
`8.9
`
`-0.3
` (-4.0, 3.3)
`7.6
`
`-0.9
`
` (-3.1, 1.3)
`96
`(31%)
`
`-2.0
`
` (-4.1, 0.2)
`91
`(29%)
`
`
`
`9.4
`
`
`
`99
`(34%)
`
`
`
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`

`Figure 9: Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and
`VIEW2 Studies
`
`
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`Each Vial is for single eye use only. EYLEA is supplied in the following presentation [see
`Dosage and Administration (2.3) and (2.4)].
`
`Samsung Bioepis Exhibit 1047 - Page 13
`Biocon Exhibit 1047 - Page 13
`
`

`

`NDC NUMBER
`61755-005-02
`
`CARTON TYPE
`Vial
`
`CARTON CONTENTS
`one single-use, sterile, 3-mL, glass vial containing
`a 0.278 mL fill of 40 mg/mL EYLEA
`one 19-gauge x 1½-inch, 5-micron, filter needle for
`withdrawal of the vial contents
`one 30-gauge x ½-inch injection needle for intravitreal
`injection
`one 1-mL syringe for administration
`one package insert
`
`Storage
`EYLEA should be refrigerated at 2°C to 8ºC (36°F to 46ºF). Do Not Freeze. Do not use beyond
`the date stamped on the carton and container label. Protect from light. Store in the original carton
`until time of use.
`
`PATIENT COUNSELING INFORMATION
`17
`Patients may experience temporary visual disturbances after an intravitreal injection with
`EYLEA and the associated eye examinations [see Adverse Reactions (6)]. Patients should be
`advised not to drive or use machinery until visual function has recovered sufficiently.
`In the days following EYLEA administration, patients are at risk of developing endophthalmitis
`or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in
`vision, the patient should seek immediate care from an ophthalmologist [see Warnings and
`Precautions (5.1)].
`
`Samsung Bioepis Exhibit 1047 - Page 14
`Biocon Exhibit 1047 - Page 14
`
`

`

`
`
`Manufactured by:
`Regeneron Pharmaceuticals, Inc.
`777 Old Saw Mill River Road
`Tarrytown, NY 10591-6707
`U.S. License Number 1760
`EYLEA™ is a trademark of Regeneron Pharmaceuticals, Inc.
`© 2011, Regeneron Pharmaceuticals, Inc.
`All rights reserved.
`V1.0
`Issue Date: November /2011
`Initial U.S. Approval: 2011
`Regeneron U.S. Patents 7,306,799; 7,531,173; 7,608,261; 7,070,959; 7,374,757; 7,374,758, and
`other pending patents
`
`Page 15 of 15
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`Samsung Bioepis Exhibit 1047 - Page 15
`Biocon Exhibit 1047 - Page 15
`
`