CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`125156Orig1s110
`
`
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
` LUCENTIS
`
`ranibizumab
`
`Genentech Inc.
`
`October 13, 2016
`
`Lucentis, a vascular endothelial growth factor (VEGF)
`inhibitor, is indicated for the treatment of patients with
`
` •
`
` Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`• Macular Edema Following Retinal Vein Occlusion
`(RVO)
`• Diabetic Macular Edema (DME)
`• Diabetic Retinopathy (DR)
`
`
`Novartis Exhibit 2160.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`125156Orig1s110
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`X
`
`X
`
`X
`
`X
`
`Novartis Exhibit 2160.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`125156Orig1s110
`
`
`APPROVAL LETTER
`
`Novartis Exhibit 2160.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`~Ul VJc,,.
`
`( ~1·"~. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`~+;"'J
`..... (!
`
`Food and Drng Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`BLA 125156/S-11 0
`
`Genentech, Inc.
`Attention: Key Kang, M.Sc.
`Regulato1y Program Management
`1 DNA Way
`South San Francisco, CA 94080-4990
`
`Dear Mr. Kang:
`
`Please refer to your Supplemental Biologics License Application (sBLA), dated June 16, 2016,
`received June 16, 2016, and your amendments, submitted under section 351(a) of the Public
`Health Service Act for Lucentis (ranibizumab injection).
`
`This Prior Approval supplemental biologics application proposes the addition of a Lucentis 0.5
`mg prefilled syringe (PFS).
`
`b)l4
`We also acknowledoe recei t of the
`14 will require a
`------,-----.,------------------------
`lb>
`separate prior approval supplement.
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA
`automated drug registration and listing system (eLIST), the content oflabeling
`[21 CFR 601.14(b)] in stmctured product labeling (SPL) fo1mat, as described at
`http://www.f da. gov/F orindust1y/DataStandards/StmcturedProductLabeling/ default.htm, that is
`identical to the enclosed labeling text for the package inse11 and include the labeling changes
`proposed in any pending "Changes Being Effected" (CBE) supplements. Infonnation on
`submitting SPL files using eLIST may be found in the guidance for industry titled "SPL
`Standard for Content of Labeling Technical Qs and As" at
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 2
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this BLA, including pending “Changes Being Effected” (CBE) supplements, for which FDA
`has not yet issued an action letter, with the content of labeling [21 CFR 601.12(f)] in MS Word
`format that includes the changes approved in this supplemental application.
`
`POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`3134
`
`Perform a shipping study designed to confirm stability of Lucentis drug product
`during shipping under conditions and through a route that are representative of
`commercial drug product shipping. The study will include testing of pre- and
`post-shipping samples for product quality (container closure integrity, purity by
`SEC, nrCE-SDS, IE-HPLC, sub-visible particles, and potency of ranibizumab).
`
`The timetable you submitted on October 10, 2016, states that you will conduct this study
`according to the following schedule:
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`
`12/16
`06/17
`08/17
`
`Submit clinical protocols to your IND 008633 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this BLA.
`In addition, under 21 CFR 601.70 you should include a status summary of each commitment in
`your annual progress report of postmarketing studies to this BLA. The status summary should
`include expected summary completion and final report submission dates, any changes in plans
`since the last annual report, and, for clinical studies/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert(s)
`to:
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 3
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`As required under 21 CFR 601.12(f)(4), you must submit final promotional materials, and the
`package insert(s), at the time of initial dissemination or publication, accompanied by a Form
`FDA 2253. Form FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved BLA (in
`21 CFR 600.80 and in 21 CFR 600.81).
`
`If you have any questions, call Lois Almoza, M.S., Regulatory Health Project Manager, at (301)
`796-1600.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Wiley A. Chambers, M.D.
`Deputy Director
`Division of Transplant and Ophthalmology
` Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`WILEY A CHAMBERS
`10/13/2016
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`125156Orig1s110
`
`
`LABELING
`
`Novartis Exhibit 2160.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 4
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`LUCENTIS safely and effectively. See full prescribing information for
`LUCENTIS.
`
`LUCENTIS® (ranibizumab injection)
`Intravitreal Injection
`Initial U.S. Approval: 2006
`
`--------------------------RECENT MAJOR CHANGES------------------
`Dosage and Administration, Preparation for Administration (2.6) XX/2016
`Dosage and Administration, Administration (2.7)
`XX/2016
`
`--------------------------INDICATIONS AND USAGE-------------------
`LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is
`indicated for the treatment of patients with:
`•
`Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
`•
`•
`Diabetic Macular Edema (DME) (1.3)
`•
`Diabetic Retinopathy in patients with DME (1.4)
`----------------------DOSAGE AND ADMINISTRATION--------------
`For Ophthalmic Intravitreal Injection Only (2.1)
`
`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 days).
`
`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 after 4 monthly doses. Patients should be assessed regularly.
`
`Macular Edema Following Retinal Vein Occlusion (RVO) (2.3)
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`•
`intravitreal injection once a month (approximately 28 days).
`
`Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in
`patients with Diabetic Macular Edema (2.4, 2.5)
`LUCENTIS 0.3 mg (0.05 mL) is recommended to be administered by
`•
`intravitreal injection once a month (approximately 28 days).
`
`---------------------DOSAGE FORMS AND STRENGTHS------------
`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal
`injections:
`• 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
`
`Single-use glass vial designed to provide 0.05 mL for intravitreal injections:
`• 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
`• 6 mg/mL solution (LUCENTIS 0.3 mg) (3)
`
`------------------------------CONTRAINDICATIONS--------------------
`•
`Ocular or periocular infections (4.1)
`•
`Hypersensitivity (4.2)
`-----------------------WARNINGS AND PRECAUTIONS--------------
`•
`Endophthalmitis and retinal detachments 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 of VEGF inhibitors (5.3).
`Fatal events occurred more frequently in patients with DME and DR at
`•
`baseline, who were treated monthly with LUCENTIS compared with
`control (5.4).
`------------------------------ADVERSE REACTIONS---------------------
`•
`The most common adverse reactions (reported more frequently in
`LUCENTIS-treated subjects than control subjects) are conjunctival
`hemorrhage, eye pain, vitreous floaters, and increased IOP (6.2).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`Revised: XX/2016
`_____________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`6.2 Clinical Studies Experience
`1
`INDICATIONS AND USAGE
`6.3
`Immunogenicity
`1.1 Neovascular (Wet) Age-Related Macular Degeneration
`6.4
`Postmarketing Experience
`7 DRUG INTERACTIONS
`(AMD)
`8 USE IN SPECIFIC POPULATIONS
`1.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`8.1
`Pregnancy
`1.3 Diabetic Macular Edema (DME)
`8.3 Nursing Mothers
`1.4 Diabetic Retinopathy in patients with DME
`8.4
`Pediatric Use
`2 DOSAGE AND ADMINISTRATION
`8.5 Geriatric Use
`10 OVERDOSAGE
`2.1 General Dosing Information
`11 DESCRIPTION
`2.2 Neovascular (Wet) Age-Related Macular Degeneration
`12 CLINICAL PHARMACOLOGY
`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion
`12.1 Mechanism of Action
`(RVO)
`12.2 Pharmacodynamics
`2.4 Diabetic Macular Edema (DME)
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`2.5 Diabetic Retinopathy in patients with DME
`2.6
`Preparation for Administration
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`2.7 Administration
`3 DOSAGE FORMS AND STRENGTHS
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`4 CONTRAINDICATIONS
`(AMD)
`4.1 Ocular or Periocular Infections
`14.2 Macular Edema Following Retinal Vein Occlusion
`4.2 Hypersensitivity
`(RVO)
`5 WARNINGS AND PRECAUTIONS
`14.3 Diabetic Macular Edema (DME)
`5.1
`Endophthalmitis and Retinal Detachments
`14.4 Diabetic Retinopathy in patients with DME
`16 HOW SUPPLIED/STORAGE AND HANDLING
`5.2
`Increases in Intraocular Pressure
`17 PATIENT COUNSELING INFORMATION
`5.3
`Thromboembolic Events
`5.4
`Fatal Events in Patients with DME and DR at baseline
`6 ADVERSE REACTIONS
`6.1
`Injection Procedure
`
`* Sections or subsections omitted from the Full Prescribing Information are
`not listed.
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 5
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`LUCENTIS is indicated for the treatment of patients with:
`
`1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
`
`1.3 Diabetic Macular Edema (DME)
`
`1.4 Diabetic Retinopathy (Non Proliferative Diabetic Retinopathy (NPDR), Proliferative Diabetic
`Retinopathy (PDR)) in patients with Diabetic Macular Edema (DME)
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
`
`2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS 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 nine months after 3 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 (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly [see
`Clinical Studies (14.1)].
`
`2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
`LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS 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. In 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 (14.2)].
`
`2.4 Diabetic Macular Edema (DME)
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`2.5 Diabetic Retinopathy in patients with Diabetic Macular Edema
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 6
`
`2.6 Preparation for Administration
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`2.6 Preparation for Administration
`Prefilled Syringe:
`
`To prepare LUCENTIS for intravitreal administration, please adhere to
`these instructions for use. Read all the instructions carefully before using
`the prefilled syringe.
`
`How to store LUCENTIS:
`LUCENTIS should be refrigerated at 2º-8ºC (36º-46ºF). Do not freeze.
`•
`• Do not use beyond the expiration date stamped on the label.
`LUCENTIS prefilled syringes should be protected from light and
`•
`stored in a dark place.
`• Do not open the sealed tray until time of use.
`
`The prefilled syringe is for single use only. The prefilled syringe is sterile.
`Do not use the product if the packaging is damaged or has been
`tampered with.
`
`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 0.05 mL.
`______________________________________________________________________________
`Device description
`
`
`
`Syringe ca1
`
`Rubbef opper
`
`Finger Grip
`1
`
`Luer Lock
`
`0.05 ml Dose Mark
`
`Plunger Rod
`
`Figure 1
`
`______________________________________________________________________________
`Step 1: Prepare
`______________________________________________________________________________
`
`• Make sure that your pack contains a sterile prefilled syringe
`in a sealed tray.
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 7
`
`• 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).
`
`Figure 2
`
`______________________________________________________________________________
`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.
`______________________________________________________________________________
`Step 5: Dislodge air bubbles
`______________________________________________________________________________
`
`Figu re 3
`
`• 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).
`
`Reference ID: 3998669
`
`Figure 4
`
`Novartis Exhibit 2160.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 8
`
`______________________________________________________________________________
`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.
`______________________________________________________________________________
`Step 7: Inject
`______________________________________________________________________________
`
`Figure 5
`
`•
`
`•
`
`•
`
`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 require-
`ments.
`
`Vial:
`Using aseptic technique, all of the LUCENTIS vial contents are withdrawn through a 5-micron, 19-gauge filter
`needle attached to a 1-cc tuberculin syringe. 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 1/2-inch needle for the intravitreal injection. The contents should be expelled until the plunger tip is
`aligned with the line that marks 0.05 mL on the syringe.
`
`2.7 Administration
`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-spectrum 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
`
`Reference ID: 3998669
`
`Novartis Exhibit 2160.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-110
`Page 9
`
`head immediately after the injection [see Warnings 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).
`
`DOSAGE FORMS AND STRENGTHS
`3
`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injection.
`10 mg/mL solution (LUCENTIS 0.5 mg)
`•
`Single-use glass vial designed to provide 0.05 mL for intravitreal injection.
`10 mg/mL solution (LUCENTIS 0.5 mg)
`•
`6 mg/mL solution (LUCENTIS 0.3 mg)
`•
`
`4
`
`CONTRAINDICATIONS
`
`4.1 Ocular or Periocular Infections
`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.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Endophthalmitis and Retinal Detachments
`Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal
`detachments. Proper aseptic injection technique should always be used when administering LUCENTIS. 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 Counseling Information (17)].
`
`5.2 Increases in Intraocular 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)].
`
`5.3 Thromboembolic Events
`Although there was a low rate of arterial thromboembolic events (ATEs) observed in the LUCENTIS clinical
`trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as
`nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).
`
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`BLA 125156/S-110
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`
`Neovascular (Wet) 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 (14.1)]. In the second year of
`Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-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 of LUCENTIS used
`adjunctively with verteporfin photodynamic therapy), 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 1.1% (5 of 435) in
`patients in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))).
`
`Macular 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 LUCENTIS-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, 14.4)].
`
`In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], the ATE rate at 2 years was 7.2% (18
`of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 5.2% (13 of 250) 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
`LUCENTIS, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) 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.
`
`5.4 Fatal Events in Patients with DME and DR at baseline
`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, 14.4)].
`
`A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], showed that fatalities in the first 2 years
`occurred in 4.4% (11 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% (11 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 of VEGF
`inhibitors cannot be excluded.
`
`6 ADVERSE REACTIONS
`The following adverse reactions are discussed in greater detail in the Warnings and Precautions (5) section of
`the label:
`• Endophthalmitis and Retinal Detachments
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`BLA 125156/S-110
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`
`• Increases in Intraocular Pressure
`• Thromboembolic Events
`• Fatal Events in patients with DME and DR at baseline
`
`6.1 Injection Procedure
`Serious adverse reactions related to the injection procedure have occurred in < 0.1% of intravitreal injections,
`including endophthalmitis [see Warnings and Precautions (5.1)], rhegmatogenous retinal detachment, and
`iatrogenic traumatic cataract.
`
`6.2 Clinical Studies Experience
`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, and 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 (14)].
`
`Safety data observed in Study AMD-4 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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`BLA 125156/S-110
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`
`Table 1
`Ocular Reactions in the DME and DR, AMD, and RVO Studies
`
`DME
`and DR
`2-vear
`
`Cl)
`
`~ .. 0
`E
`J:,
`Ul "' C
`u 0
`0
`u
`;::,
`.....:i
`
`AMD
`2-year
`
`AMD
`I-year
`
`RVO
`6-month
`
`~ .. 0
`
`Cl)
`
`E
`.,.,
`Ul
`u 0
`;::,
`.....:i
`
`~ .. 0
`
`Cl)
`
`E
`.,.,
`Ul
`u 0
`;::,
`.....:i
`
`J:,
`C
`0
`u
`
`~ .. 0
`
`Cl)
`
`E
`.,.,
`Ul
`u 0
`;::,
`.....:i
`
`J:,
`C
`0
`u
`
`J:,
`C
`0
`u
`
`n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260
`
`47% 32% 74% 60% 64% 50% 48% 37%
`
`17% 13% 35% 30% 26% 20% 17% 12%
`
`10% 4% 27% 8% 19% 5% 7% 2%
`
`18% 7% 24% 7% 17% 5% 7% 2%
`
`11% 15% 21% 19% 15% 15% 4% 2%
`
`4% 3% 18% 8% 13% 7%
`
`1% 3%
`
`Adverse Reaction
`
`Conjllllctival
`hemon-b.age
`
`Eye pain
`
`Vitreous
`floaters
`Intraocular
`pressure
`increased
`Vitreous
`detachment
`Intraocular
`inflammation
`
`Cataract
`
`28% 32% 17% 14% 11% 9% 2% 2%
`
`Foreign body
`sensation in
`eyes
`
`10% 5% 16% 14% 13% 10% 7%
`
`5%
`
`Eye in-itation
`
`8%
`
`5% 15% 15% 13% 12% 7% 6%
`
`Lac1-imation
`increased
`
`Blepharitis
`
`5% 4% 14% 12% 8%
`
`8% 2% 3%
`
`3% 2% 12% 8%
`
`8%
`
`5% 0%
`
`1%
`
`D1yeye
`
`5% 3% 12% 7% 7% 7% 3% 3%
`
`Visual
`disturbance or
`vision bhm·ed
`
`Eye pnu-itis
`
`Ocular
`hyperemia
`
`8% 4% 18% 15% 13% 10% 5% 3%
`
`4% 4% 12% 11% 9% 7%
`
`1% 2%
`
`9% 9% 11% 8% 7% 4%
`
`5% 3%
`
`Retinal disorder 2% 2% 10% 7%
`
`8% 4% 2%
`
`1%
`
`Maculopathy
`
`5% 7% 9% 9% 6% 6% 11% 7%
`
`Retinal
`degeneration
`Ocular
`discomfort
`Conjllllctival
`hyperemia
`Posterior
`capsule
`opacification
`Injection site
`hemon-b.age
`
`1% 0%
`
`8% 6%
`
`5% 3%
`
`1% 0%
`
`2%
`
`1% 7% 4%
`
`5% 2% 2% 2%
`
`1% 2% 7% 6%
`
`5% 4% 0% 0%
`
`4% 3% 7% 4% 2% 2% 0%
`
`1%
`
`1% 0%
`
`5% 2% 3%
`
`1% 0% 0%
`
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`

`BLA 125156/S-110
`Page 13
`
`Non-Ocular Reactions
`
`Non-ocular adverse reactions with an incidence of2::: 5% in patients receiving LUCENTIS for DR, DME, AMD,
`and/or RVO and which occmTed at a 2::: I% higher frequency in patients treated with LUCENTIS 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
`andDR
`2-year
`
`AMD
`2-year
`
`AMD
`I-year
`
`RVO
`6-month
`
`(/)
`
`(/)
`
`(/)
`
`]
`C
`0
`<.>
`
`(/)
`
`i::: 00
`@ a
`.,...
`<.>
`;:::i 0
`...:i
`
`]
`C
`0
`<.>
`
`Adverse Reaction
`
`N asopharyngjtis
`
`Anemia
`
`Nausea
`
`]
`C
`0
`<.>
`
`]
`C
`0
`<.>
`
`i::: 00
`i::: 00
`i::: 00
`a'j a
`a'j a
`a'j a
`.,...
`.,...
`<'>
`<.>
`<.>
`<.>
`:3 0
`:3 0
`:3 0
`n