Ii£>
`LUCENTIS
`
`PREF!LLED SYR!~~GE
`ADMINISTRATION PREPARATION
`
`1 PREPARE
`0 Make sure that your pc:1ck contains 2:1 ste1·:e
`prefilted syrin9e in a sealed tray
`
`, 1:)eel the Id oft n,e syrinQe t,ay c:rnd, usin(J aseoric
`technique, 1·21-rwve the syringe
`
`2
`
`INSPECT SYRINGE
`, I..UCl::NrlS should be colorl.ess to oate yeti.ow
`, Do riot use the orefiled syringe :f·
`-- The sy,inge cap is tietached frorn the Luer lock
`-- The sy,•inge is damaged
`• Panicul,-,tes, cloui:kess, o,· discolori-,tion are visible
`
`6 EXPEL AIR AND ADJUST DRUG DOSE
`, Hold the sy,inge at eye level. and
`ca,·efully push the plunge,· rod until the
`edge below the dome of t;-e rubber
`stopper· is digr,ed 'Nith the OJJS ml..
`dose marl< (see ii9u1·e 4)
`
`Note: The plunger rod is not
`att;,ched to the rubber stopper----(cid:173)
`this is to prevent air from being
`drawn into the syringe,
`
`7
`
`INJECT
`0 The i"]ecrion p1·ocedure s-houtd be carred out
`unde1· aseptic cud lions
`, 1,-·,s,Yt he ,··,eedle into the i,--,;,:,ction s:te
`unil the rubt)er :.-;topper· r·e;-,ches the
`, I
`bottom of rhe syrin9e to deliver the volu,,,e of OD~i rn ..
`, /\fter injection. do not recao the needle or detach it
`from the sy,•inge. Dispose or the used svringe tcgether
`with the needle in a sharps cis::,csd ccnta ,--,,.,,-_ c,· in
`accoillance win, local. requirements
`
`For !mportarit Safety !r1format!on, please see next
`;.:wge arrd LUCENTIS foH Prnm::ribirrg !nfttrmafa:m,
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`LUCENT!S' PREFILLED SYRINGE: ADMINISTRATION PREPARATION
`
`DEVICE DESCRIPTION
`
`,--1r1QFi
`J,
`
`Cilass l:lar1Ti.
`
`l
`
`HOW TO STORE lUCENTIS:
`, I..UCENTIS sr,ould oe 1·ehigerared at 2°C .9,·c (36°1 --46°F)_
`Do not freeze
`, Do riot use beyonc the expraton dare stamped on the label
`• P··ctect I..UC.:EifflS ::,refi led syrir,ges fr"om ight and stcr·e in the
`,:;r-igin,:il c:;r-ton wdl time of use
`, Do not ooen sealed tuiv until tirne of use
`
`The pr·efilles:: s·ringe is for s:ngle~use cnly The pr·efilles::
`sy,inge is ste1· le. Do riot use product :t the packaging
`is d2nv,ged or lvis been tampe•·ed vvith.
`The opening or the se2led t1·ay and all subsequent steps
`cor,cl itions.
`For the ntr2vitr•e2: injection. a 3D-gauge x 1,2 -:nc1·1 sterile
`injectior, rn-:ecl+ shculc be used (net
`NOTE: The dose must be set to OJJ5 mL
`
`INDICATIONS
`LUCEf\JTIS" lranibZurnab injection) :s, inclicated tor the treatrrent
`of pat ents, vith:
`• Neovas-cut::F (wet) age-related rnacula1· degeneration (f,_MD)
`• M,-,cul,F ,-,clema foJowir,g ··etin,/ ve> occlusion F<'VD)
`• Diabetic r,,acul,Y ede···,·,,-, (Cf.1E)
`• Diabetic retinooathy (DR)
`• Mvoo:c choroid al neovasculal"ization (n·CNV)
`IMPORTANT SAFETY !NFORMAT!ON
`• LUCU\TS s contraindicated :.- patients with ocular or perocular
`infectcons. 01· kriovvn hyoer·s-ensitivity ro ranibizurnab o,- any of the
`exc pents- n I..UCENTIS. Hyperse,,sitivity re::1ctor1S- ,,,2:1y manfest
`as sev,-:--e intr,-,ccular· :r/:arnmation.
`• lntr,-,'./treal injectior,s. :r,c us::ing those vvith l..UCE\JTIS, have
`been associated vvith enccphthal1-r1:t:s, retind Cetdchrnent, ,-rnd
`i2t-·ogen c traumatic cataract,
`• lnueases :.- intraocular· f.)1·esSlll"e have been noted bot1·1 f.)1·e-(cid:173)
`injection and post-injecton vvith LUCE\lTIS
`
`IMPORTANT SAFETY INFORMATION
`• :\lthough F,ere was a lovv 1·2:1te of arterial thr-omooernbot:c events
`(/',Jl::s) observec n the L.UCl:NTS clinical n-ials, there is 2:1 potent al
`1·is-k of ATEs fol.lowing dravn-eal use of VEG;: in>bito,s. AITs
`are s::efinecl as nonfatal. stroke, ···,onfatd mycc:;rdi,-,1 :rJarctio·\ or
`vascul,:;r death (including deaths of lJl"l[,:r,own cause).
`• Fatal events occurred rnore freque···,t:y in p,-,tients w-:t> DVIE and
`DR at basel ne treated rnont·ly w:u· LJJCEHTS mm pared w th
`contrnl. i'dhough the •·ate of fatal events was lovv and included
`causes of tie a th typica I of p2:1t ents win, ativ::1,,ced di::1 oetic
`complications. a potential relatio,,ship t;etween these events anti
`i ntr,-,'./trea I use of VEC:,r:' inhib,tcr·s cannot be ex duded.
`• In the I..UCENTS ::>hase L: cli···,ical h,Js, the ,--.-,ost co1-r11-r1cn ccular· sice
`effects inclui:k:d ccn)urn:tv,J he1-r1w··hage, eye ;,a\1, vitr·,-,ous float,-:i-;:;,
`,:-ncl inu,-,;-ises:: :r1traocul,:;r wessur,-,, T,e r,,ost cormmn no···,~ocul,-,1·
`side effects ncluded nasop;-aryng:tis. anemia. nausea. and rnugh.
`For M:lditionat S<lfety !nformath:m, ple,,me set LUCENT!S foH
`Prm,aE::i rrg !nfornmtion,
`You mav report side effects tc t1·1e FD/\ at (BOO) FD/\--1 OBS or
`,v\vw.fda.gov/niec1-vatch. You n1ay also r·epoi-t sice effects to
`Genentech at wsm tl3j--25~i 1:i
`
`Genentech (:i) 20'18 G0nentt:ch U:?,}\ :::i:. ~ DN:~ V\idy; SO'.Jth S2:: F:dl'ICiSL::i: Cl':... 94-GSD-4/;C)Q
`
`/':...J riqh~s rt:s{:,rved. LUC/G51·116/0G43Q(2) 04/ 18
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`HIGHLIGHTS OF' PRESCRll:HNG INF'ORMATION
`These highlights do not include all the information needed to use
`LlJCENTIS safely and effectively. See full prescribing information for
`LVCENTIS.
`
`LIJCENTIS'" (ranibizumab in_jedion) for intrnvitreal in_jedion
`Initial U.S. Approval: 2006
`
`··············································RECENT MA.JOR CHANGES··········································
`04/2017
`Indications and Usage, Diabetic Retinopathy (l .4)
`Dosage and Administration (2)
`03/2018
`03/2018
`Dosage Forms and Strengths (3)
`
`--------------------------IND ICA TIO NS AND FSAGE-----------------------(cid:173)
`LUCENTIS, a vascular endothelial growth factor {VEGF) inhibitor, is
`indicated for the treatment of patients with:
`• Neovascular (Wet) Age-Related Macular Degeneration (AMD) (l .I)
`• Macular Edema Following Retinal Vein Ocdusion (RVO) (1.2)
`• Diabetic Macular Edema (DME) (1.3)
`• Diabetic Retinopathy (DR) (l.4)
`• Myopic Choroidal Neovascularization (mCNV) (1.5)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------(cid:173)
`For ophthalmic intravitreal ir;jection only (2. I)
`
`• Neovascular (Wet) Age-Related Macular Degeneration (AMD) (2.2):
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 ,lays).
`
`Although not as effective, patients may be treated with 3 monthly doses
`followed by less frequent dosing with regular assessment
`Although not as effective, patients may also be treated with one dose
`every 3 months afler 4 monthly doses. Patients should be assessed
`regularly.
`
`• Macular Edema Following Retinal Vein Occlusion (RVO) (2.3):
`LUCENTlS 0.5 mg (0.05 rnL) is recomrnended to be administered by
`intravitreal ir;jection once a rnonth (approximately 28 days).
`
`• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) (2.4):
`LlJCENTIS 0.3 mg (0.05 mL) is recommended to be adrninistered by
`intravitreal injection once a month (approximately 28 days).
`
`F'ULL PRESCRIBING IN.FORMATION: CONTENTS*
`J
`INDICATIONS AND USAGE
`l. J
`Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`I.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`L\
`Diabetic Macular Edema (!Yv1E)
`Diabetic Retinopathy (DR)
`l "-
`1.5 Myopic Choroidal Neovascularization (mCNV)
`2 DOSAGE ANU ADMINISTRATION
`2. J
`General Dosing Information
`2.2
`Neovascular (Wet) Age-Related Macular Degeneration
`{AMD)
`2.3 Macular Ederna Following Retinal Vein Occlusion
`(RVO)
`Diabetic Macular Edema (DME) and Diabetic
`Retinopathy (DR)
`2.5 Myopic Choroidal Neovascularization (mCNV)
`Preparation for Administration
`2.6
`2.7
`Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`4.1
`Ocular or Periocular Infections
`4.2
`Hypersensitivity
`5 WARNINGS AND PRECAUTIONS
`5.1
`Endophthalmitis and Retinal Detachments
`5.2
`Increases in Intraocular Pressure
`5.3
`Tbrnmboembolic Events
`Fatal Events in Patients with DME and DR at Baseline
`5.4
`6 ADVERSE REACTIONS
`6.1
`Injection Procedure
`
`• Myopic Choroidal Neovascularization (mCNV) (2.5):
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be initially administered
`by intravitreal in_1ection once a month (approximately 28 days) for up to
`three months. Patients may be retreated if needed.
`
`---------------------DOSAGE J,'ORMS AND STRENGTHS------------
`• Single-use prefilled syringe designed to provide 0.05 mL for intravitreal
`injections:
`10 mgimL solution (LUCENTIS 0.5 mg) (3)
`6 mg/mL solution {LUCENTIS Cl.3 mg) (3)
`
`• Single-use glass vial designed to provide 0.05 mL for intravitreal injections:
`10 mgimL solution (LUCENTIS 0.5 mg) (3)
`6 mg/mL solution {LUCENTIS Cl.3 mg) (3)
`
`------------------------------CONTRAINDICATIONS--------------------
`• Ocular or periocular infections (4. J)
`• Hypersensitivity ( 4.2)
`
`-----------------------WAR.t'\/IN GS AND PREC A IJTIO NS--------------
`• Endophthalmitis arid retinal detaclnnents may occur following intravitreal
`injections. Patients should be monitored following the injection (5.1).
`• Increases in intraocular pressure (IOP) have been noted both pre- and
`post-intravitreal injection (5.2).
`• There is a potential risk of arterial thromboembolic events following
`intravitreal use ofVEGF inhibitors (5.3).
`• Fatal events occurred more frequenlly in patients with DME and DR at
`baseline, who were treated monthly with LlJCENTIS cornpared with
`control (5.4).
`
`· ·········································· ·········ADVERSE REAC'HONS•····································
`• The most common adverse reactions (reported more frequently in
`LUCENTIS-treated subjects than control subjects) are conjuncti val
`hemorrhage, eye pain, vitreous floaters, and increased TOP (6.2).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`J .. 333 .. 335 .. 2555 or :FDA at J .. soo .. FDA .. J088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COlJNSEUNG IN"FORMATION.
`
`Revised: 03/2018
`
`Clinical Studies Experience
`6.2
`lmnmnogenici1y
`6.3
`Postmarketing Experience
`6.4
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`K 2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`Geriatric Use
`8.5
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 MecbanismofAction
`12.2 Pharmacodynamics
`12.3 Pbannacokinetics
`B NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, J\1:utagenesis, hnpainneni of F~1tility
`14 CLINICAL STlJlnES
`14.J Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`14.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`14 .3 Diabetic Macular Edema (DME)
`14.4 Diabetic Retinopathy (DR)
`14.5 Myopic Choroidal Neovascularization (mCNV)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INF'ORMATION
`
`* Sections or subsections ornitted from the Full Prescribing Information are
`oot listed.
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`FULL PRESCRIBING INFOR!VIA TION
`
`IND I CA TIO NS AND USAGE
`l
`LUCENTIS is indicated for the treatment of patients with:
`
`1.1
`
`Neovascular (\Vet) Age-Related Macular Degeneration (AMD)
`
`1.2 Macular Edema F'oUowing Retinal Vein Occlusion (RVO)
`1.3
`Diabetic Macular Edema (DME)
`1.4
`Diabetic Retinopathy (DR)
`
`1.5 Myopic Choroidal Neovascuhuization (mCNV)
`2
`DOSAGE AND ADMINISTRATION
`2.1
`General Dosing Information
`FOR OPl-:ITHALMIC INTRA VITREAL INJECTION.
`Vials: A 5-micron sterile filter needle (19-gauge x 1-1/2 inch), a 1-mL Luer lock syringe and a
`30-gauge x ½ inch sterile injection needle are needed but not included.
`2.2
`Neovascular (\Vet) Age-Related Macular Degeneration (AMD)
`LUCENTJS 0.5 mg (0.05 mL of l O mg/mL solution) is recommended to be administered by intravitreal
`injection once a month (approximately 28 days).
`
`Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with
`regular assessment. In the 9 months after three initial monthly doses, less frequent dosing with 4-5 doses on
`average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional
`average 1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1)].
`
`Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses.
`Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an
`approximate 5-letter (I-line) loss of visual acuity benefit, on average. Patients should be assessed regularly [see
`Clinical Studies (14.1)].
`2.3 Macular Edema FoHowing Retinal Vein Occlusion (RVO)
`LUCENTJS 0.5 mg (0.05 mL of l O mg/mL solution) is recommended to be administered by intravitreal
`injection once a month (approximately 28 days).
`
`In Studies RVO-1 and RVO-2, patients received monthly injections of LUCENTIS for 6 months. ln spite of
`being guided by optical coherence tomography and visual acuity re-treatment criteria, patients who were then
`not treated at Month 6 experienced on average, a loss of visual acuity at Month 7, whereas patients who were
`treated at Month 6 did not. Patients should be treated monthly [see Clinical Studies (] 4.2)].
`2.4
`Diabetic Macular Edema (DME) and Diabetic RetinoJ)athy (DR)
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection
`once a month (approximately 28 days).
`
`2.5 Myopic Choroidal Neovascufa.rization (mCNV)
`LUCENTlS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be initially administered
`by intravitreal injection once a month (approximately 28 days) for up to 3 months. Patients may be retreated if
`needed [(see Clinical Studies 14.5)].
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.6
`
`Preparation for Administration
`
`Prejilled Syringe:
`
`The prefilled syringe is sterile and is for single use only. Do not use the product
`if the packaging is damaged or has been tampered with.
`
`To prepare lUCENTIS for intravitreal administration, please adhere to these
`instructions for use. Read all the instructions carefully before using the prefilled
`syringe.
`
`The opening of the sealed tray and all subsequent steps should be done under
`aseptic conditions.
`
`For the intravitreal injection, a 30-gauge x ½ inch sterile injection needle should
`be used (not provided).
`Note: the dose must be set to a.as ml.
`
`Device description
`
`LUCENTIS prefilled syringes are available in 2 dose strengths:
`
`• LUCENTIS 0.5 mg prefilled syringe with a CLEAR finger
`grip.
`
`• LUCENTIS 0.3 mg prefilled syringe with an ORANGE finger
`grip.
`
`Check the labels on the LUCENTIS carton, syringe tray and
`prefilled syringe to make sure you have the correct dose strength.
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Hncer Grip
`k _,
`
`Luer L.ock
`
`OC(i rnL Dose t/ark
`
`Step 1: Prepare
`
`• Make sure that your pack contains a sterile prefilled syringe in a
`sealed tray.
`
`•
`
`Peel the lid off the syringe tray and, using aseptic technique,
`remove the syringe.
`
`Step 2: Inspect syringe
`
`•
`
`•
`
`LUCENTIS should be colorless to pale yellow.
`
`Do not use the prefilled syringe if:
`the syringe cap is detached from the Luer lock.
`the syringe is damaged.
`particulates, cloudiness, or discoloration are visible.
`
`Step 3: Remove syringe cap
`
`Snap off (do not turn or twist)
`the syringe cap (see Figure 2).
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Step 4: Attach needle
`
`•
`
`Attach a 30G x ½ inch sterile
`injection needle firmly onto the
`syringe by screwing it tightly
`onto the Luer lock (see Figure
`3).
`
`•
`
`Carefully remove the needle cap
`by pulling it straight off.
`
`Note: Do not wipe the needle at any
`time.
`
`~ LJ
`
`Flgur-e 3
`
`•
`
`•
`
`•
`
`Step 5: Dislodge air bubbles
`
`Hold the syringe with the needle
`pointing up.
`
`If there are any air bubbles,
`gently tap the syringe with your
`finger until the bubbles rise to
`the top (see Figure 4).
`
`Fnure 4
`
`Step 6: Expel air and adjust drug dose
`
`Hold the syringe at eye level, and
`carefully push the plunger rod
`until the edge below the dome of
`the rubber stopper is aligned
`with the 0.05 ml dose mark
`(see Figure 5).
`
`Note: The plunger rod is not attached
`to the rubber stopper - this is
`to prevent air being drawn
`into the syringe.
`
`Figure 5
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Step 7: Inject
`
`•
`
`•
`
`•
`
`•
`
`The injection procedure should be carried out under aseptic conditions.
`
`Insert the needle into the injection site.
`
`Inject slowly until rubber stopper reaches the bottom of the syringe to
`deliver the volume of 0.05 ml.
`
`After injection, do not recap the needle or detach it from the syringe.
`Dispose of the used syringe together with the needle in a sharps disposal
`container or in accordance with local requirements.
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Vial:
`Using aseptic technique, all of the LUCENTJS vial contents are withdrawn through a 5-micron (19-gauge
`x l-l/2 inch), sterile filter needle attached to al mL syringe (not included). The filter needle should be
`discarded after withdrawal of the vial contents and should not be used for intravitreal injection. The filter
`needle should be replaced with a sterile 30-gauge x ½ inch needle for the intravitreal injection.
`
`Use aseptic technique to can-y out the following preparation steps:
`
`Prepare for intravitreal injection with the following medical devices for single use (not included):
`" a 5-rnicron sterile filter needle ( 19-gauge x 1-1 /2 inch)
`" al mL sterile Luer lock syringe (with marking to measure 0.05 mL)
`• a sterile injection needle (30-gauge x 1 /2-inch)
`
`Before withdrawal, disinfect the outer part of the rnbber stopper of the vial.
`
`Place a 5-micron filter needle ( 19-gauge x 1-1/2 inch) onto a 1 mL Luer lock syringe using aseptic
`technique.
`
`Push the filter needle into the center of the vial stopper until the needle touches the bottom edge of the
`vial.
`
`\Vithdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease
`
`2.
`
`3.
`
`4.
`
`5.
`
`complete withdrawal. u
`
`1······11·
`l'f
`
`1111
`
`fl
`!IA I
`Jill•
`,, j/
`tJ I
`fl
`I : :
`
`•
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`6.
`
`Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely
`empty the filter needle.
`
`7.
`
`The filter needle should be discarded after withdrawal of the vial contents and must not be used for the
`intravitreal injection.
`
`8. Attach a 30-gauge x 1/2-inch sterile injection needle firmly onto the syringe by screwing it tightly onto the
`Luer lock Carefully remove the needle cap by pulling it straight off Do not wipe the needle at any time.
`
`9. Hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your
`finger until the bubbles rise to the top.
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(CH)00002720
`
`Novartis Exhibit 2118.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`10. Hold the syringe at eye level, and carefully push the plunger rod until the plunger tip is aligned with the
`line that marks 0.05 mL on the syringe.
`
`O.OSml~
`
`Administration
`2. 7
`The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the
`use of sterile gloves, a sterile drape, and a sterile eyelid speculum ( or equivalent). Adequate anesthesia and a
`broad-spectmm microbicide should be given prior to the injection.
`
`Prior to and 30 minutes following the intravitreal injection, patients should be monitored for elevation in
`intraocular pressure using tonometry. Monitoring may also consist of a check for perfusion of the optic nerve
`head immediately after the injection [see VVarnings and Precautions (5.2)]. Patients should also be monitored
`for and instructed to report any symptoms suggestive of endophthalmitis without delay following the injection
`[see Warnings and Precautions (5.1)].
`
`Each prefilled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye
`requires treatment, a new prefilled syringe or vial should be used and the sterile field, syringe, gloves, drapes,
`eyelid speculum, filter needle (vial only), and injection needles should be changed before LUCENTIS is
`administered to the other eye.
`
`No special dosage modification is required for any of the populations that have been studied (e.g., gender,
`elderly).
`3
`DOSAGE FORMS AND STRENGTHS
`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injection.
`"' Colorless to pale yellow l 0 mg/mL solution ( LUCENTIS 0.5 mg)
`I "' Colorless to pale yellow 6 mg/mL solution ( LUCENTIS 0.3 mg)
`Single-use glass vial designed to provide 0JJ5 mL for intravitreal injection.
`"' Colorless to pale yellow 10 mg/mL solution (LUCENTIS 0.5 mg)
`"' Colorless to pale yellow 6 mg/mL solution (LUCENTIS 0.3 mg)
`4
`CONTRAINDICATIONS
`
`Ocular or Periocufar Infections
`4.1
`LUCENTIS is contraindicated in patients with ocular or periocular infections.
`4.2
`Hypersensitivity
`LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients
`in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular inflammation.
`
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`5
`
`W ARl'lINGS AND PRECAUTIONS
`
`Endophthalmitis and Retinal Detachments
`5.1
`Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal
`detachments. Proper aseptic injection technique should always be used when administering LUCENTJS. In
`addition, patients should be monitored following the injection to permit early treatment should an infection
`occur [see Dosage and Administration (2. 6, 2. 7) and Patient C'ounseling l!?fhrmation (17)].
`5.2
`Increases in IntraocuJar Pressure
`Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60 minutes) while
`being treated with LUCENTIS. Monitor intraocular pressure prior to and following intravitreal injection with
`LUCENTIS and manage appropriately [see Dosage and Administration (2. 7)],
`
`Thrornboernbolic Events
`5.3
`Although there was a low rate of arterial thromboembolic events (A TEs) observed in the LUCENTIS clinical
`trials, there is a potential risk of ATEs following intravitreal use ofVEGF inhibitors. Arterial thromboembolic
`events are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of
`unknown cause).
`
`Neovascu!ar (FVet) Age-Related Macular Degeneration
`The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3) during the first year
`was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared
`with 1. 1 % (5 of 441) in patients from the control arms [see Clinical Studies(] 4.1)]. ln the second year of
`Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of721) in the combined group ofLUCENTlS-treated
`patients compared with 2.9% ( 10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates
`observed in the 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1,
`AMD-2, and AMD-3.
`
`In a pooled analysis of 2-year controlled studies [AMD-1, AMD-2, and a study ofLUCENTlS used
`adjunctively with verteporfin photodynamic therapy (PDT)], the stroke rate (including both ischemic and
`hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg LUCENTIS compared to l.1 % (5 of
`435) in patients in the control arms [odds ratio 2.2 (95% confidence interval (0.8-7. l)].
`
`A1acular Edema Following Retinal Vein Occlusion
`The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the LUCENTIS
`and control arms of the studies ( 4 of 525 in the combined group of patients treated with 0.3 mg or 0.5 mg
`LUCENTIS and 2 of 260 in the control arms) [see Clinical Studies (14.2)]. The stroke rate was 0.2% (1 of 525)
`in the combined group of LUCENT IS-treated patients compared to 0.4%) ( 1 of 260) in the control arms.
`
`Diabetic Macular Edema and Diabetic Retinopathy
`Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at baseline [ see
`Clinical Studies (14.3, 1-:f..4)].
`
`In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], the A TE rate at 2 years was 7.2% ( 18
`of 250) with 0.5 mg LUCENTIS, 5.6% (14 of250) with 0.3 mg LUCENTIS, and 5.2% (13 of250) with control.
`The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg LUCENTIS, 1.2% (3 of 250) with 0.3 mg
`LUCENTJS, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of249) with 0.5 mg
`LUCENTIS and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with 0.5 mg
`LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS.
`
`Fatal Events in Patients with Diabetic MacuJar Edema and Diabetic Retinopathy at Baseline
`5.4
`Diabetic }vfacular Edema and Diabetic Retinopathy
`Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at baseline [see
`Clinical Studies (14.3, 14.4)].
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`A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (l-1.3)], showed that fatalities in the first 2 years
`occurred in 4.4% (1 l of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8% (7 of 250) of patients treated
`with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control patients. Over 3 years, fatalities occurred in 6.4%
`(16 of 249) of patients treated with 0.5 mg LUCENTIS and in 4.4% (l 1 of 250) of patients treated with 0.3 mg
`LUCENTIS. Although the rate of fatal events was low and included causes of death typical of patients with
`advanced diabetic complications, a potential relationship between these events and intravitreal use ofVEGF
`inhibitors cannot be excluded.
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in greater detail in other sections of the label:
`• Endophthalmitis and Retinal Detachments [see FVamings and Precautions (5.1)]
`• Increases in Intraocular Pressure [see Warnings and Precautions (5.2)]
`• Thromboembolic Events [see FVarnings and Precautions (5.3)]
`• Fatal Events in patients with DME and DR at baseline /see Warnings and Precautions (5.4)}
`
`Injection Procedure
`6.1
`Serious adverse reactions related to the injection procedure have occurred in< 0.1 % of intravitreal injections,
`including endophthalmitis [see FVamings and Precautions (5.1)], rhegmatogenous retinal detachment, and
`iatrogenic traumatic cataract.
`
`Clinical Studies Experience
`6.2
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one
`clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug
`and may not reflect the rates observed in practice.
`
`The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with neovascular AMD in Studies
`AMD-1, AMD-2, and AMD-3; in 259 patients with macular edema following RVO. The data also reflect
`exposure to 0.3 mg LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (I 4)].
`
`Safety data observed in 224 patients with mCNV, as well as Studies AMD-4 and D-3, were consistent with
`these results. On average, the rates and types of adverse reactions in patients were not significantly affected by
`dosing regimen.
`
`Ocular Reactions
`Table 1 shows frequently reported ocular adverse reactions in LUCENTIS-treated patients compared with the
`control group.
`
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`
`

`

`Table 1
`Ocular Reactions in the DME and DR, AMD, and RVO Studies
`
`DME
`and DR
`2-year
`
`AMD
`2-year
`
`AMD
`I-year
`
`RVO
`6-month
`
`~
`f:-i El 2
`z
`'1
`i.Q
`u
`0
`u
`::, 6
`,..i
`
`!"'!")
`
`bO
`
`~
`f:-i
`z s
`.,-,
`i.Q
`u
`::, 0
`,..i
`
`~
`bO 2
`,. z s
`c-<
`0
`'1
`'1
`~ .,-,
`u
`0
`0
`u
`u
`j 0
`
`bO
`
`~
`f:-i
`z s
`.,-,
`i.Q
`u
`::, 0
`,..i
`
`0
`,_,
`~
`0
`u
`
`n~250 JF'.250 JF}79 JF}79 n~440 JF44! JF'.259 n~260
`
`47% 32% 74% 60% 64% 50% 48% 37%
`
`Adverse Reaction
`
`Conjunctival
`hemorrhage
`
`Eye pain
`
`17(~/ct 13'1/i, 35'1/i, 30'1/i, 26(~/ct
`
`20'1/i,
`
`17%,
`
`12 1!-{J
`
`10% 4% 27~'o 8% 19%
`
`5'1/i,
`
`1o,;o
`
`21!,{J
`
`18°1,, TVo
`
`24'1/i, TVo
`
`17(~/ct
`
`S~'o
`
`TVo
`
`2%
`
`11% 15% 21 ~j} 19% 15% 15%
`
`4%
`
`'"'10!'.
`L, /0
`
`4%
`
`301
`,0
`
`18% go;
`"'o
`
`13% 7%
`
`JOI
`,0
`
`3o/O
`
`28% 32% 17% 14% 11% 9%
`
`2%
`
`'"'10!'.
`L, /0
`
`10% 5~'o
`
`16% 14% 13% 10%
`
`701 ,0
`
`5%
`
`Vitreous
`floaters
`In traocular
`pressure
`increased
`Vitreous
`detachment
`Intraocular
`inflammation
`
`Cataract
`
`Foreign body
`sensation in
`eyes
`
`Eye irritation
`
`Lacrimation
`increased
`
`Blepharitis
`
`8%
`
`5% 15% 15% 13% 12%
`
`7%
`
`5~j}
`
`401
`,0
`
`14% 12%
`
`8~j}
`
`8~j}
`
`'"'10!'.
`L, /0
`
`3~/o
`
`2% 12% 8%
`
`8%
`
`5%
`
`0%
`
`Dry eye
`
`5~j}
`
`301 ,0 12% 701 ,0
`
`7%
`
`7%
`
`301 ,0
`
`6~'o
`
`3o/O
`
`JOI ,0
`
`3o/O
`
`301 ,0
`
`Visual
`disturbance or
`vision blurTCd
`
`Eye prurilis
`
`Ocular
`hyperemi8
`
`8%
`
`4% 18% 15% 13% 10%
`
`5%
`
`4%,
`
`40/ /0
`
`12 1!/iJ 11'% 9%,
`
`7'%
`
`Io/ /0
`
`2'¾,
`
`9';1.,
`
`9% 11%, 8%
`
`/<!,{)
`
`4%
`
`5%
`
`10/
`-· /0
`
`Retinal disorder
`
`2%,
`
`20/ /0
`
`10% 70/ /0
`
`gt/(}
`
`4%,
`
`20/ /0
`
`1%
`
`Maculopathy
`
`5%
`
`7%
`
`9%
`
`9%
`
`6%
`
`6%
`
`11%,
`
`7(}0
`
`Retinal
`degeneration
`Ocular
`discomfort
`Conjunctival
`hyperemia
`Posterior
`capsule
`opacification
`Injection site
`hemorrrrnge
`
`1%,
`
`0%
`
`go/
`/0
`
`60/
`/0
`
`5{/0
`
`3%,
`
`Io/
`/0
`
`0%
`
`2~/o
`
`1%
`
`7%
`
`4%
`
`5%
`
`2~/o
`
`2%
`
`'"'10!'.
`L, /0
`
`1%
`
`201 ,0
`
`701 ,0
`
`6~'o
`
`5~j}
`
`4%
`
`()0/
`- ,0
`
`0%
`
`4%
`
`3%
`
`7%
`
`4%
`
`2~/o
`
`2~/o
`
`0%
`
`JOI ,0
`
`1%,
`
`0%
`
`51:}0
`
`20/ /0
`
`3%,
`
`1%,
`
`0%
`
`0%
`
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`Non-Ocular Reactions
`Non-ocular adverse reactions with an incidence of :2: 5% in patients receiving LUCENTIS for DR, DME, AMD,
`and/or RVO and which occurred at a :2: l (% higher frequency in patients treated with LUCENTlS compared to
`control are shown in Table 2. Though less common, wound healing complications were also observed in some
`studies.
`
`Table 2
`Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies
`
`DME
`
`and DR
`2-year
`
`AMD
`2-year
`
`AMD
`]-year
`
`RVO
`6-rnonth
`
`lfl
`~ Of)
`z I::
`l"1
`•n
`v
`6
`~
`..-1
`
`0 ,_,
`~
`0 v
`
`lfl
`~ Of)
`z I::
`l"1
`•n
`v
`6
`~
`..-1
`
`0 >,
`§
`v
`
`Adverse Reaction
`
`Nasopharyngitis
`
`16%
`
`13?'o
`
`11%
`
`10%
`9()/ ;O
`
`Anemia
`
`Nausea
`
`Cough
`
`Constipation
`
`Seasonal allergy
`
`Hypercholesterolemia
`
`7%
`
`9()/ ;O
`
`8%
`
`5%
`
`7%
`
`7%
`
`0()/ ;O
`
`Influenza
`
`Renal failure
`
`Upper respiratory
`tract infection
`
`Ciastroesophageal
`reflux disease
`
`Headache
`
`Edema peripheral
`
`Renal failure chronic
`
`Neuropathy
`peripheral
`
`Sinusitis
`
`Bronchitis
`
`Atrial fibrillation
`
`Arthralgia
`
`Chronic obstructive
`pulmonary disease
`
`Wound healing
`complications
`
`1()/ ;O
`
`1%
`
`3%
`
`0%
`
`4%
`
`2%
`
`2%
`
`2%
`
`0%
`
`4%
`
`1%
`
`2%
`
`1 ?'o
`
`2?'o
`
`2%
`
`3%
`
`1%
`
`0%
`
`O?'o
`
`1%
`
`O?'o
`
`0%
`
`6%
`
`4%
`
`4%
`
`1%
`
`1%
`
`0%
`
`5%
`
`4%
`
`8%i
`
`11 (_'..·O
`
`S?'o
`
`11%
`
`10.'
`,O
`
`1%
`
`6?,,0
`
`10.'
`,O
`
`0%
`
`1 ?'o
`
`7o/o
`
`9\%
`
`4%J
`
`9~/o
`
`3?'o
`
`1%
`
`3%
`
`0%
`
`1 ?'o
`
`5%
`
`1%
`
`O?'o
`
`ImmunogenkHy
`6.3
`As with all therapeutic proteins, there is the potential for an immune response in patients treated with
`LUCENTlS. The i