` BLA 125156/S-111
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` Page 4
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use LUCENTIS
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` safely and effectively. See full prescribing information for LUCENTIS.
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` LUCENTIS® (ranibizumab injection)
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`For Intravitreal Injection
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`Initial U.S. Approval: 2006
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`--------------------------RECENT MAJOR CHANGES-----------------­
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`Indications and Usage, Myopic Choroidal Neovascularization
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`(mCNV) (1.5)
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`General Dosing Information (2.1)
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`Dosage and Administration, Myopic Choroidal Neovascularization
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`(mCNV) (2.6)
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`Dosage and Administration, Preparation for Administration (2.7)
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`Dosage and Administration, Administration (2.8)
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`01/2017
`11/2016
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`01/2017
`11/2016
`10/2016
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`--------------------------INDICATIONS AND USAGE-----------------------­
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`LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is indicated for
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`the treatment of patients with:
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` Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
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` Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
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` Diabetic Macular Edema (DME) (1.3)
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` Diabetic Retinopathy in patients with DME (1.4)
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` Myopic Choroidal Neovascularization (mCNV) (1.5)
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`----------------------DOSAGE AND ADMINISTRATION-------------­
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`For Ophthalmic Intravitreal Injection Only (2.1)
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`Neovascular (Wet) Age-Related Macular Degeneration (AMD) (2.2)
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`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by intravitreal
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`injection once a month (approximately 28 days).
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`Although not as effective, patients may be treated with 3 monthly doses followed
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`by less frequent dosing with regular assessment.
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`Although not as effective, patients may also be treated with one dose every 3
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`months after 4 monthly doses. Patients should be assessed regularly.
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`Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in patients
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`with Diabetic Macular Edema (2.4, 2.5)
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`LUCENTIS 0.3 mg (0.05 mL) is recommended to be administered by
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`
`intravitreal injection once a month (approximately 28 days).
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`Myopic Choroidal Neovascularization (mCNV) (2.6)
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`LUCENTIS 0.5 mg (0.05 mL) is recommended to be initially administered
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`by intravitreal injection once a month (approximately 28 days) for up to three
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`months. Patients may be retreated if needed.
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`---------------------DOSAGE FORMS AND STRENGTHS-----------­
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`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injections:
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` 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
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`Single-use glass vial designed to provide 0.05 mL for intravitreal injections:
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` 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
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` 6 mg/mL solution (LUCENTIS 0.3 mg) (3)
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`------------------------------CONTRAINDICATIONS-------------------­
` Ocular or periocular infections (4.1)
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` Hypersensitivity (4.2)
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`-----------------------WARNINGS AND PRECAUTIONS-------------­
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` Endophthalmitis and retinal detachments may occur following intravitreal
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`injections. Patients should be monitored following the injection (5.1).
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` Increases in intraocular pressure (IOP) have been noted both pre- and
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`post-intravitreal injection (5.2).
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` There is a potential risk of arterial thromboembolic events following intravitreal
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`use of VEGF inhibitors (5.3).
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` Fatal events occurred more frequently in patients with DME and DR at baseline,
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`who were treated monthly with LUCENTIS compared with control (5.4).
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`------------------------------ADVERSE REACTIONS--------------------­
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` The most common adverse reactions (reported more frequently in
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`LUCENTIS-treated subjects than control subjects) are conjunctival hemorrhage,
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`eye pain, vitreous floaters, and increased IOP (6.2).
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`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
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`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`Macular Edema Following Retinal Vein Occlusion (RVO) (2.3)
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` LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
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`intravitreal injection once a month (approximately 28 days).
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`_____________________________________________________________________________________________________________________________
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`See 17 for PATIENT COUNSELING INFORMATION.
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`Revised: 01/2017
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`INDICATIONS AND USAGE
`1
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`Neovascular (Wet) Age-Related Macular Degeneration
`1.1
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`(AMD)
`1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
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`Diabetic Macular Edema (DME)
`1.3
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`Diabetic Retinopathy in patients with DME
`1.4
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`1.5 Myopic Choroidal Neovascularization (mCNV)
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`2 DOSAGE AND ADMINISTRATION
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`General Dosing Information
`2.1
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`Neovascular (Wet) Age-Related Macular Degeneration
`2.2
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`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
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`Diabetic Macular Edema (DME)
`2.4
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`Diabetic Retinopathy in patients with DME
`2.5
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`2.6 Myopic Choroidal Neovascularization (mCNV)
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`Preparation for Administration
`2.7
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`Administration
`2.8
`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
`Ocular or Periocular Infections
`4.1
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`Hypersensitivity
`4.2
`5 WARNINGS AND PRECAUTIONS
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`Endophthalmitis and Retinal Detachments
`5.1
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`Increases in Intraocular Pressure
`5.2
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`Thromboembolic Events
`5.3
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`Fatal Events in Patients with DME and DR at baseline
`5.4
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`6 ADVERSE REACTIONS
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`Injection Procedure
`6.1
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`Clinical Studies Experience
`6.2
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`Reference ID: 4037547
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`6.3
`Immunogenicity
`6.4
`Postmarketing Experience
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`7 DRUG INTERACTIONS
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`8 USE IN SPECIFIC POPULATIONS
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`Pregnancy
`8.1
`8.2
`Lactation
`Females and Males of Reproductive Potential
`8.3
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`Pediatric Use
`8.4
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`Geriatric Use
`8.5
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`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`14.1 Neovascular (Wet) Age-Related Macular Degeneration
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`(AMD)
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`14.2 Macular Edema Following Retinal Vein Occlusion (RVO)
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`14.3 Diabetic Macular Edema (DME)
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`14.4 Diabetic Retinopathy in patients with DME
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`14.5 Myopic Choroidal Neovascularization (mCNV)
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`* Sections or subsections omitted from the Full Prescribing Information are not
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`listed.
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`Regeneron Exhibit 1201.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 5
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` FULL PRESCRIBING INFORMATION
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` INDICATIONS AND USAGE
`1
` LUCENTIS is indicated for the treatment of patients with:
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` 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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` 1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
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` 1.3 Diabetic Macular Edema (DME)
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` 1.4 Diabetic Retinopathy (Non Proliferative Diabetic Retinopathy (NPDR), Proliferative Diabetic Retinopathy
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` (PDR)) in patients with Diabetic Macular Edema (DME)
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` 1.5 Myopic Choroidal Neovascularization (mCNV)
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`2
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` DOSAGE AND ADMINISTRATION
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` 2.1 General Dosing Information
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` FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
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`Vials: A 5-micron sterile filter needle (19-gauge x 1-1/2 inch), a 1-mL Luer lock syringe and a
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` 30-gauge x ½ inch sterile injection needle are needed but not included.
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` 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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` LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with
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` regular assessment. In the nine months after 3 initial monthly doses, less frequent dosing with 4-5 doses on
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` average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional
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` average 1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1)].
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` Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses.
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` Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an
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` approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly [see
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` Clinical Studies (14.1)].
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` 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
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` intravitreal injection once a month (approximately 28 days).
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` In Studies RVO-1 and RVO-2, patients received monthly injections of LUCENTIS for 6 months. In spite of
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` being guided by optical coherence tomography and visual acuity re-treatment criteria, patients who were then
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` not treated at Month 6 experienced on average, a loss of visual acuity at Month 7, whereas patients who were
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` treated at Month 6 did not. Patients should be treated monthly [see Clinical Studies (14.2)].
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` 2.4 Diabetic Macular Edema (DME)
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`Reference ID: 4037547
`
`Regeneron Exhibit 1201.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 6
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` LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` 2.5 Diabetic Retinopathy in Patients with Diabetic Macular Edema (DME)
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` LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` 2.6 Myopic Choroidal Neovascularization (mCNV)
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` LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be initially administered
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` by intravitreal injection once a month (approximately 28 days) for up to three months. Patients may be retreated
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` if needed [(see Clinical Studies 14.5)].
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` 2.7 Preparation for Administration
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` Prefilled Syringe:
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` To prepare LUCENTIS for intravitreal administration, please adhere to
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` the prefilled syringe.
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` How to store LUCENTIS:
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` 1. LUCENTIS should be refrigerated at 2º-8ºC (36º-46ºF). Do not freeze.
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` 2. Do not use beyond the expiration date stamped on the label.
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` 4. Do not open the sealed tray until time of use.
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` The prefilled syringe is for single use only. The prefilled syringe is sterile.
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` Do not use the product if the packaging is damaged or has been
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` For the intravitreal injection, a 30-gauge x ½ inch sterile injection needle
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` Note: the dose must be set to 0.05 mL.
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`______________________________________________________________________________
` Device description
`
`______________________________________________________________________________
`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 7
`
`______________________________________________________________________________
` Step 1: Prepare
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`______________________________________________________________________________
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` Make sure that your pack contains a sterile prefilled syringe
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`in a sealed tray.
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` Peel the lid off the syringe tray and, using aseptic technique,
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`remove the syringe.
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`______________________________________________________________________________
` Step 2: Inspect syringe
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`______________________________________________________________________________
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`
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`LUCENTIS should be colorless to pale yellow.
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` Do not use the prefilled syringe if:
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`the syringe cap is detached from the Luer lock.
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` Step 3: Remove syringe cap
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`Snap off (do not turn or twist)
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`the syringe cap (see Figure 2).
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`______________________________________________________________________________
` Step 4: Attach needle
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`______________________________________________________________________________
`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`Page 8
`
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`  Attach a 30G x ½ inch sterile
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` injection needle firmly onto
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` tightly onto the Luer lock (see
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` Figure 3).
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`  Carefully remove the needle
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` cap by pulling it straight off.
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` Note: Do not wipe the needle at
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`______________________________________________________________________________
` Step 5: Dislodge air bubbles
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` Hold the syringe with the
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`needle pointing up.
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`If there are any air bubbles,
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`gently tap the syringe with
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`your finger until the bubbles
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`rise to the top (see Figure 4).
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`______________________________________________________________________________
` Step 6: Expel air and adjust drug dose
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`Hold the syringe at eye level,
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`plunger rod until the edge
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`rubber stopper is aligned
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`with the 0.05 mL dose mark
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`(see Figure 5).
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`Note: The plunger rod is not
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`attached to the rubber
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`stopper – this is to
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`prevent air being drawn into the syringe.
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`______________________________________________________________________________
` Step 7: Inject
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`______________________________________________________________________________
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`
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`The injection procedure should be carried out under aseptic
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`conditions.
`
`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 9
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`
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`
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` Insert the needle into the injection site.
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` Inject slowly until rubber stopper reaches the bottom of the syringe
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` to deliver the volume of 0.05 mL.
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`  After injection, do not recap the needle or detach it from the syringe.
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` Dispose of the used syringe together with the needle in a sharps
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`Vial:
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`Using aseptic technique, all of the LUCENTIS vial contents are withdrawn through a 5-micron
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`(19-gauge x 1-1/2 inch), sterile filter needle attached to a 1 mL syringe (not included). The
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`filter needle should be discarded after withdrawal of the vial contents and should not be used
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`for intravitreal injection. The filter needle should be replaced with a sterile 30-gauge x ½ inch
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`needle for the intravitreal injection.
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`Use aseptic technique to carry out the following preparation steps.
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`Prepare for intravitreal injection with the following medical devices for single use (not
`1.
`included):
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` a 5-micron sterile filter needle (19-gauge x 1-1/2 inch)
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` a 1 mL sterile Luer lock syringe (with marking to measure 0.05 mL)
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` a sterile injection needle (30-gauge x 1/2-inch)
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`2. Before withdrawal, disinfect the outer part of the rubber stopper of the vial.
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`3.
`Place a 5-micron filter needle (19-gauge x 1-1/2 inch) onto a 1 mL Luer lock syringe using
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`aseptic technique.
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`Push the filter needle into the center of the vial stopper until the needle touches the bottom
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`5. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly
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`inclined to ease complete withdrawal.
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`4.
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`6.
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`Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to
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`completely empty the filter needle.
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`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 10
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` 7.
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` The filter needle should be discarded after withdrawal of the vial contents and must not be
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` 8. Attach a 30-gauge x 1/2-inch sterile injection needle firmly onto the syringe by screwing it
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` tightly onto the Luer lock. Carefully remove the needle cap by pulling it straight off. Do
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` not wipe the needle at any time.
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`9. Hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the
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`syringe with your finger until the bubbles rise to the top.
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`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 11
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` 10. Hold the syringe at eye level, and carefully push the plunger rod until the plunger tip is
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`2.8 Administration
`The intravitreal injection procedure should be carried out under controlled aseptic conditions,
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`which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or
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`equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the
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`injection.
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`Prior to and 30 minutes following the intravitreal injection, patients should be monitored for
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`elevation in intraocular pressure using tonometry. Monitoring may also consist of a check for
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`perfusion of the optic nerve head immediately after the injection [see Warnings and Precautions
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`(5.2)]. Patients should also be monitored for and instructed to report any symptoms suggestive
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`of endophthalmitis without delay following the injection [see Warnings and Precautions (5.1)].
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`Each prefilled syringe or vial should only be used for the treatment of a single eye. If the
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`contralateral eye requires treatment, a new prefilled syringe or vial should be used and the sterile
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`field, syringe, gloves, drapes, eyelid speculum, filter needle (vial only), and injection needles
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`should be changed before LUCENTIS is administered to the other eye.
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`
`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 12
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` No special dosage modification is required for any of the populations that have been studied
` (e.g., gender, elderly).
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`3
` DOSAGE FORMS AND STRENGTHS
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` Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injection.
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`  10 mg/mL solution ( LUCENTIS 0.5 mg)
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` Single-use glass vial designed to provide 0.05 mL for intravitreal injection.
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` 10 mg/mL solution (LUCENTIS 0.5 mg)
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` 6 mg/mL solution (LUCENTIS 0.3 mg)
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`4
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`CONTRAINDICATIONS
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`4.1 Ocular or Periocular Infections
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`LUCENTIS is contraindicated in patients with ocular or periocular infections.
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`4.2 Hypersensitivity
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`LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of
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`the excipients in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular
`inflammation.
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Endophthalmitis and Retinal Detachments
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`Intravitreal injections, including those with LUCENTIS, have been associated with
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`endophthalmitis and retinal detachments. Proper aseptic injection technique should always be
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`used when administering LUCENTIS. In addition, patients should be monitored following the
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`injection to permit early treatment should an infection occur [see Dosage and Administration
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`(2.7, 2.8) and Patient Counseling Information (17)].
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`5.2 Increases in Intraocular Pressure
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`Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60
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`minutes) while being treated with LUCENTIS. Monitor intraocular pressure prior to and
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`following intravitreal injection with LUCENTIS and manage appropriately [see Dosage and
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`Administration (2.8)].
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`5.3 Thromboembolic Events
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`Although there was a low rate of arterial thromboembolic events (ATEs) observed in the
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`LUCENTIS clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF
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`inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death
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`(including deaths of unknown cause).
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`Neovascular (Wet) Age-Related Macular Degeneration
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`The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3)
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`during the first year was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg
`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 13
`
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` or 0.5 mg LUCENTIS compared with 1.1% (5 of 441) in patients from the control arms [see
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` Clinical Studies (14.1)]. In the second year of Studies AMD-1 and AMD-2, the ATE rate was
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` 2.6% (19 of 721) in the combined group of LUCENTIS-treated patients compared with 2.9% (10
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` of 344) in patients from the control arms. In Study AMD-4, the ATE rates observed in the
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` 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1,
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` AMD-2, and AMD-3.
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` In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of LUCENTIS
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` used adjunctively with verteporfin photodynamic therapy), the stroke rate (including both
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` ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg
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` LUCENTIS compared to 1.1% (5 of 435) in patients in the control arms (odds ratio 2.2 (95%
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` confidence interval (0.8-7.1))).
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` Macular Edema Following Retinal Vein Occlusion
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` The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the
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` LUCENTIS and control arms of the studies (4 of 525 in the combined group of patients treated
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` with 0.3 mg or 0.5 mg LUCENTIS and 2 of 260 in the control arms) [see Clinical Studies
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` (14.2)]. The stroke rate was 0.2% (1 of 525) in the combined group of LUCENTIS-treated
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` patients compared to 0.4% (1 of 260) in the control arms.
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` Diabetic Macular Edema and Diabetic Retinopathy
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` 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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` In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], the ATE rate at 2 years
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` was 7.2% (18 of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and
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` 5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg
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` LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with control. At 3
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` years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS and 10.8% (27 of 250) with
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` 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with 0.5 mg LUCENTIS and 2.0% (5
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` of 250) with 0.3 mg LUCENTIS.
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` 5.4 Fatal Events in Patients with DME and DR at baseline
` Diabetic Macular Edema and Diabetic Retinopathy
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` 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 (14.3)], showed that fatalities in
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` the first 2 years occurred in 4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in
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` 2.8% (7 of 250) of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control
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` patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated with 0.5 mg
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` LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 mg LUCENTIS. Although the
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` rate of fatal events was low and included causes of death typical of patients with advanced
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` diabetic complications, a potential relationship between these events and intravitreal use of
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` VEGF inhibitors cannot be excluded.
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`
`
`Reference ID: 4037547
`
`Regeneron Exhibit 1201.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

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` BLA 125156/S-111
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` Page 14
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` 6 ADVERSE REACTIONS
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` The following adverse reactions are discussed in greater detail in other sections of the label:
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`  Endophthalmitis and Retinal Detachments [see Warnings and Precautions (5.1)]
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`  Increases in Intraocular Pressure [see Warnings and Precautions (5.2)]
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`  Thromboembolic Events [see Warnings and Precautions (5.3)]
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`  Fatal Events in patients with DME and DR at baseline [see Warnings and Precautions
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` (5.4)]
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` 6.1 Injection Procedure
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` Serious adverse reactions related to the injection procedure have occurred in < 0.1% of
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` intravitreal injections, including endophthalmitis [see Warnings and Precautions (5.1)],
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` rhegmatogenous retinal detachment, and iatrogenic traumatic cataract.
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` 6.2 Clinical Studies Experience
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` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
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` observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials
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` of the same or another drug and may not reflect the rates observed in practice.
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` The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with neovascular AMD in
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` Studies AMD-1, AMD-2, and AMD-3; in 259 patients with macular edema following RVO. The
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` data also reflect exposure to 0.3 mg LUCENTIS in 250 patients with DME and DR at baseline
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` [see Clinical Studies (14)].
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` Safety data observed in Study AMD-4 and in 224 patients with mCNV were consistent with
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` these results. On average, the rates and types of adverse reactions in patients were not
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` significantly affected by dosing regimen.
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` Ocular Reactions
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` Table 1 shows frequently reported ocular adverse reactions in LUCENTIS-treated patients
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` compared with the control group.
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`Reference ID: 4037547
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`Regeneron Exhibit 1201.011
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 15
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` Table 1
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`Ocular Reactions in the DME and DR, AMD, and RVO Studies
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` DME
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` and DR
`2-year
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`AMD
`2-year
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`AMD
`1-year
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`RVO
`6-month
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`Control
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`0.5 mg
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`LUCENTIS
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`Control
`0.5 mg
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`LUCENTIS
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`Control
`0.5 mg
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`LUCENTIS
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`Control
`0.3 mg
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`LUCENTIS
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`n=250 n=250
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`n=379 n=379
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`n=440 n=441
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`n=260
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`n=25
`9
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`47% 32% 74% 60% 64% 50% 48% 37%
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`17% 13% 35% 30% 26% 20% 17% 12%
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`10% 4% 27% 8% 19% 5% 7%
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`2%
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`18% 7% 24% 7% 17% 5% 7%
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`2%
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`11% 15% 21% 19% 15% 15% 4%
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`2%
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`4% 3% 18% 8% 13% 7% 1%
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`3%
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`28% 32% 17% 14% 11% 9% 2%
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`10% 5% 16% 14% 13% 10% 7%
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`8% 5% 15% 15% 13% 12% 7%
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`5% 4% 14% 12% 8%
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`8% 2%
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`3% 2% 12% 8% 8%
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`5% 0%
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`5% 3% 12% 7% 7%
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`7% 3%
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`8% 4% 18% 15% 13% 10% 5%
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` Adverse Reaction
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` Conjunctival
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`hemorrhage
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` Eye pain
` Vitreous
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`floaters
` Intraocular
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` pressure
`increased
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` Vitreous
`detachment
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` Intraocular
`inflammation
`Cataract
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` Foreign body
` sensation in
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`eyes
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` Eye irritation
` Lacrimation
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`increased
`Blepharitis
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`2%
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`5%
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`6%
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`3%
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`1%
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`3%
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`3%
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`2%
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`3%
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`1%
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`7%
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`0%
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`7% 1%
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`4% 5%
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`4% 2%
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`6% 11%
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`3% 1%
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`2% 2%
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`2%
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`4% 0%
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`0%
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`2% 0%
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`1%
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` Dry eye
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` Visual
` disturbance or
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` vision blurred
` Eye pruritis
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` Ocular
`hyperemia
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` Retinal disorder 2% 2% 10% 7% 8%
`Maculopathy
`5% 7% 9% 9% 6%
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` Retinal
`degeneration
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` Ocular
`discomfort
` Conjunctival
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`hyperemia
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` Posterior
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` capsule
`opacification
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`4% 4% 12% 11% 9%
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`9% 9% 11% 8% 7%
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`1% 0% 8% 6% 5%
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`2% 1% 7% 4% 5%
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`1% 2% 7% 6% 5%
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`4% 3% 7% 4% 2%
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`Reference ID: 4037547
`
`Regeneron Exhibit 1201.012
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-111
`
` Page 16
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` Injection site
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`hemorrhage
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`1% 0% 5% 2% 3%
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