for the treatment of wet amd*
`
`tIme between treatmentS®†
`More Information available at www.EYLEA.com
`
`*Neovascular (wet) Age-related Macular Degeneration
`
`Important preScrIbIng InformatIon for eyLea
` †EYLEA® (aflibercept) Injection is indicated for the treatment of patients with neovascular (Wet) Age-related Macular Degeneration (AMD).
`The recommended dose for EYLEA is 2 mg administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months),
`followed by 2 mg 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.
` EYLEA is indicated for the treatment of patients with Macular Edema following Central Retinal Vein Occlusion (CRVO). The recommended dose
`for EYLEA is 2 mg administered by intravitreal injection every 4 weeks (monthly).
`
`Important Safety InformatIon for eyLea
`increases in intraocular pressure have also been
`EYLEA is contraindicated in patients with
` The most common adverse reactions (≥5%)
`reported after repeated intravitreal dosing with
`ocular or periocular infections, active intraocular
`reported in patients receiving EYLEA were
`VEGF inhibitors. Intraocular pressure and the
`inflammation, or known hypersensitivity to
`conjunctival hemorrhage, eye pain, cataract,
`perfusion of the optic nerve head should be
`aflibercept or to any of the excipients in EYLEA.
`vitreous detachment, vitreous floaters, and
`monitored and managed appropriately.
`increased intraocular pressure.
`
`Intravitreal injections, including those
` There is a potential risk of arterial
`with EYLEA, have been associated with
` Serious adverse reactions related to the
`thromboembolic events (ATEs) following use of
`endophthalmitis and retinal detachments. Proper
`injection procedure have occurred in <0.1%
`intravitreal VEGF inhibitors, including EYLEA,
`aseptic injection technique must always be used
`of intravitreal injections with EYLEA including
`defined as nonfatal stroke, nonfatal myocardial
`when administering EYLEA. Patients should be
`endophthalmitis, traumatic cataract, increased
`infarction, or vascular death (including deaths
`instructed to report any symptoms suggestive of
`intraocular pressure, and vitreous detachment.
`of unknown cause). The incidence of ATEs in the
`endophthalmitis or retinal detachment without
`VIEW 1 and VIEW 2 wet AMD studies in patients
`delay and should be managed appropriately.
`treated with EYLEA was 1.8% during the first
`Intraocular inflammation has been reported
`year. The incidence of ATEs in the COPERNICUS
`during the post approval use of EYLEA.
`and GALILEO CRVO studies was 0% in patients
` Acute increases in intraocular pressure have
`treated with EYLEA compared with 1.4% in
`been seen within 60 minutes of intravitreal
`patients receiving sham control during the first
`injection, including with EYLEA. Sustained
`six months.
`Please see brief summary of full Prescribing Information on the following page.
`EYLEA and Time Between Treatments are registered trademarks of Regeneron Pharmaceuticals, Inc.
`
`©2013, Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591
`
`All rights reserved
`
` 2/2013
`
` LEA-0065F-5
`
`Exhibit 2136
`
`Page 01 of 02
`
`

`

`Less common adverse reactions reported in <1% of the patients treated with
`EYLEA were cataract, eyelid edema, corneal edema, retinal tear, hypersensitivity,
`and endophthalmitis.
`Immunogenicity. 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 wet AMD and CRVO studies, the pre-treatment incidence of
`immunoreactivity to EYLEA was 1% to 3% across treatment groups. After dosing
`with EYLEA for 52 weeks (wet AMD), or 24 weeks (CRVO), antibodies to EYLEA
`were detected in a similar percentage range of patients. Both in the wet AMD
`and in the CRVO studies, there were no differences in efficacy or safety between
`patients with or without immunoreactivity.
`Postmarketing Experience. The following adverse reaction has been identified
`during postapproval use of EYLEA: intraocular inflammation. Because these
`reactions are reported voluntarily from a population of uncertain size, it is
`not always possible to reliably estimate their frequency or establish a causal
`relationship to drug exposure.
`USE IN SPECIFIC POPULATIONS
`Pregnancy. 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. 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. The safety and effectiveness of EYLEA in pediatric patients have
`not been established.
`Geriatric Use. In the clinical studies, approximately 85% (1728/2034) of
`patients randomized to treatment with EYLEA were ≥65 years of age and
`approximately 58% (1177/2034) were ≥75 years of age. No significant
`differences in efficacy or safety were seen with increasing age in these studies.
`Patients with 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 for either wet AMD or CRVO patients.
`PATIENT COUNSELING INFORMATION
`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).
`Patients may experience temporary visual disturbances after an intravitreal
`injection with EYLEA and the associated eye examinations (see Adverse
`Reactions). Patients should be advised not to drive or use machinery until visual
`function has recovered sufficiently.
`
`Thromboembolic Events. 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). The incidence in the
`COPERNICUS and GALILEO CRVO studies during the first 6 months was 0%
`(0/218) in patients treated with EYLEA 2 mg every 4 weeks compared with 1.4%
`(2/142) in patients receiving sham treatment (see Clinical Studies).
`ADVERSE REACTIONS
`The following adverse reactions are discussed in detail in other sections of the
`labeling:
`• Endophthalmitis and retinal detachments (see Warnings and Precautions)
`•
`Increased intraocular pressure (see Warnings and Precautions)
`• Thromboembolic events (see Warnings and Precautions)
`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. Serious adverse reactions related to the injection
`procedure have occurred in <0.1% of intravitreal injections with EYLEA including
`endophthalmitis, traumatic cataract, increased intraocular pressure and vitreous
`detachment.
`Clinical Studies Experience. Because clinical trials are conducted under
`widely varying conditions, adverse reaction rates observed in the clinical trials of
`a drug cannot be directly compared to rates in other clinical trials of the same or
`another drug and may not reflect the rates observed in practice.
`A total of 2042 patients treated with EYLEA constituted the safety population
`in four phase 3 studies. Among those, 1441 patients were treated with the
`recommended dose of 2 mg.
`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,
`active-controlled clinical studies (VIEW1 and VIEW2) for 12 months (see Clinical
`Studies).
`
`Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies
`Active Control
`(ranibizumab)
`(N=595)
`28%
`
`EYLEA
`(N=1824)
`
`25%
`
`Adverse Reactions
`
`Conjunctival hemorrhage
`
`Eye pain
`
`Cataract
`
`Vitreous detachment
`
`Vitreous floaters
`
`Intraocular pressure increased
`
`Conjunctival hyperemia
`
`Corneal erosion
`
`Detachment of the retinal pigment epithelium
`
`Injection site pain
`
`Foreign body sensation in eyes
`
`Lacrimation increased
`
`Vision blurred
`
`Retinal pigment epithelium tear
`
`Injection site hemorrhage
`
`Eyelid edema
`
`Corneal edema
`
`9%
`
`7%
`
`6%
`
`6%
`
`5%
`
`4%
`
`4%
`
`3%
`
`3%
`
`3%
`
`3%
`
`2%
`
`2%
`
` 1%
`
`1%
`
`1%
`
`9%
`
`7%
`
`6%
`
`7%
`
`7%
`
`8%
`
`5%
`
`3%
`
`3%
`
`4%
`
`1%
`
`2%
`
`1%
`
`2%
`
`2%
`
`1%
`
`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.
`Macular Edema Following Central Retinal Vein Occlusion (CRVO). The data
`described below reflect exposure to EYLEA in 218 patients with macular edema
`following CRVO treated with 2 mg dose in 2 double-masked, controlled clinical
`studies (COPERNICUS and GALILEO) for 6 months (see Clinical Studies).
`
`Table 2: Most Common Adverse Reactions (≥1%) in CRVO Studies
`
`Adverse Reactions
`
`Control
`(N=142)
`
`
`BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`EYLEA® (aflibercept) Injection is indicated for the treatment of patients with
`Neovascular (Wet) Age-Related Macular Degeneration (AMD) and Macular
`Edema following Central Retinal Vein Occlusion (CRVO).
`DOSAGE AND ADMINISTRATION
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. EYLEA must only be
`administered by a qualified physician.
`Neovascular (Wet) Age-Related Macular Degeneration (AMD). 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).
`Macular Edema Following Central Retinal Vein Occlusion (CRVO). The
`recommended dose for EYLEA is 2 mg (0.05 mL) administered by intravitreal
`injection once every 4 weeks (monthly).
`Preparation for Administration
`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.
`The glass vial is for single use only. Remove the protective plastic cap from
`the vial. Clean the top of the vial with an alcohol wipe. 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. Push the filter needle into the center of
`the vial stopper until the needle touches the 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. 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 the
`plastic pouch and attach the injection needle to the syringe by firmly twisting the
`injection needle onto the Luer lock syringe tip.
`When ready to administer EYLEA, remove the plastic needle shield from the
`needle. 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. 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.
`Administration
`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).
`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 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
`Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution for
`intravitreal injection.
`CONTRAINDICATIONS
`EYLEA is contraindicated in patients with
`• Ocular or periocular infection
`• Active intraocular inflammation
`• Known hypersensitivity to aflibercept or any of the excipients in EYLEA.
` Hypersensitivity reactions may manifest as severe intraocular inflammation
`WARNINGS AND PRECAUTIONS
`Endophthalmitis and Retinal Detachments. Intravitreal injections, including
`those with EYLEA, have been associated with endophthalmitis and retinal
`detachments (see Adverse Reactions). 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 and Patient Counseling Information).
`Increase in Intraocular Pressure. Acute increases in intraocular pressure
`have been seen within 60 minutes of intravitreal injection, including with EYLEA
`(see Adverse Reactions). 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).
`
`Eye pain
`
`Conjunctival hemorrhage
`
`Intraocular pressure increased
`
`Corneal erosion
`
`Vitreous floaters
`
`Conjunctival hyperemia
`
`Foreign body sensation in eyes
`
`Vitreous detachment
`
`Lacrimation increased
`
`Injection site pain
`
`Vision blurred
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EYLEA
`(N=218)
`
`13%
`
`12%
`
`8%
`
`5%
`
`5%
`
`5%
`
`3%
`
`3%
`
`3%
`
`3%
`
`1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5%
`
`11%
`
`6%
`
`4%
`
`1%
`
`3%
`
`5%
`
`4%
`
`4%
`
`1%
`
`<1%
`
`
`Manufactured by: Regeneron Pharmaceuticals, Inc.
`777 Old Saw Mill River Road
`Tarrytown, NY 10591-6707
`U.S. License Number 1760
`EYLEA is a registered trademark of Regeneron Pharmaceuticals, Inc.
`© 2012, Regeneron Pharmaceuticals, Inc.
`All rights reserved.
`Issue Date: September 21, 2012
`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
`
`Exhibit 2136
`Page 02 of 02
`
`