BLA 125156/S106
`Page: 2
`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------------------
`Indications and Usage –
`
`Diabetic Retinopathy in patients with Diabetic Macular Edema (1.4) 2/2015
`
`Dosage and Administration – Diabetic Retinopathy in patients with Diabetic
`
`Macular Edema (2.5)
`2/2015
`
`Warnings and Precautions (5.3)
`2/2015
`
`2/2015
`
`Warnings and Precautions (5.4)
`--------------------------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 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: 02/2015
`_____________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`Clinical Studies Experience
`6.2
`6.3
`Immunogenicity
`1
`INDICATIONS AND USAGE
`6.4
`Postmarketing Experience
`Neovascular (Wet) Age-Related Macular Degeneration
`1.1
`7 DRUG INTERACTIONS
`(AMD)
`8 USE IN SPECIFIC POPULATIONS
`1.2 Macular Edema Following Retinal Vein Occlusion
`Pregnancy
`8.1
`(RVO)
`8.3
`Nursing Mothers
`Diabetic Macular Edema (DME)
`1.3
`8.4
`Pediatric Use
`1.4 Diabetic Retinopathy in patients with DME
`8.5
`Geriatric Use
`2 DOSAGE AND ADMINISTRATION
`10 OVERDOSAGE
`General Dosing Information
`2.1
`11 DESCRIPTION
`2.2
`Neovascular (Wet) Age-Related Macular Degeneration
`12 CLINICAL PHARMACOLOGY
`(AMD)
`12.1 Mechanism of Action
`2.3 Macular Edema Following Retinal Vein Occlusion
`12.2 Pharmacodynamics
`(RVO)
`12.3 Pharmacokinetics
`Diabetic Macular Edema (DME)
`2.4
`13 NONCLINICAL TOXICOLOGY
`2.5
`Diabetic Retinopathy in patients with DME
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`2.6
`Preparation for Administration
`14 CLINICAL STUDIES
`2.7 Administration
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`
`3 DOSAGE FORMS AND STRENGTHS
`(AMD)
`
`4 CONTRAINDICATIONS
`14.2 Macular Edema Following Retinal Vein Occlusion
`
`Ocular or Periocular Infections
`4.1
`(RVO)
`
`4.2
`Hypersensitivity
`14.3 Diabetic Macular Edema (DME)
`5 WARNINGS AND PRECAUTIONS
`14.4 Diabetic Retinopathy in patients with DME
`5.1
`Endophthalmitis and Retinal Detachments
`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: 3698642
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`BLA 125156/S106
`Page: 3
`
`FULL PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
`1
`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)
`
`DOSAGE AND ADMINISTRATION
`
`2
`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).
`
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`BLA 125156/S106
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`
`
`
`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).
`
`2.6 Preparation for Administration
`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 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 vial should only be used for the treatment of a single eye. If the contralateral eye requires
`treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter,
`and injection needles should be changed before 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 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.
`
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`BLA 125156/S106
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`
`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).
`
`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.
`
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`
`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
` 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)].
`
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`
`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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`Table 1
`Ocular Reactions in the DME and DR, AMD, and RVO Studies
`
`DME
`and DR
`2-year
`
`AMD
`2-year
`
`AMD
`1-year
`
`RVO
`6-month
`
`Control
`
`0.5 mg
`
`
`
`LUCENTIS
`
`Control
`
`0.5 mg
`
`
`
`LUCENTIS
`
`Control
`
`0.5 mg
`
`
`
`LUCENTIS
`
`Control
`
`0.3 mg
`
`
`
`LUCENTIS
`
`n=250 n=250
`
`n=379 n=379
`
`n=440 n=441
`
`n=259 n=260
`
`Adverse Reaction
`
`Conjunctival hemorrhage
`
`47% 32% 74% 60% 64% 50% 48% 37%
`
`Eye pain
`
`Vitreous floaters
`
`17% 13% 35% 30% 26% 20% 17% 12%
`
`10% 4% 27% 8% 19% 5% 7% 2%
`
`Intraocular pressure increased
`
`18% 7% 24% 7% 17% 5% 7% 2%
`
`Vitreous detachment
`
`Intraocular inflammation
`
`Cataract
`
`11% 15% 21% 19% 15% 15% 4% 2%
`
`4% 3% 18% 8% 13% 7% 1% 3%
`
`28% 32% 17% 14% 11% 9% 2% 2%
`
`Foreign body sensation in eyes
`
`10% 5% 16% 14% 13% 10% 7% 5%
`
`Eye irritation
`
`Lacrimation increased
`
`Blepharitis
`
`Dry eye
`Visual disturbance or vision
`blurred
`Eye pruritis
`
`Ocular hyperemia
`
`Retinal disorder
`
`Maculopathy
`
`Retinal degeneration
`
`Ocular discomfort
`
`Conjunctival hyperemia
`
`8% 5% 15% 15% 13% 12% 7% 6%
`
`5% 4% 14% 12% 8% 8% 2% 3%
`
`3% 2% 12% 8% 8% 5% 0% 1%
`
`5% 3% 12% 7% 7% 7% 3% 3%
`
`8% 4% 18% 15% 13% 10% 5% 3%
`
`4% 4% 12% 11% 9% 7% 1% 2%
`
`9% 9% 11% 8% 7% 4% 5% 3%
`
`2% 2% 10% 7% 8% 4% 2% 1%
`
`5% 7% 9% 9% 6% 6% 11% 7%
`
`1% 0% 8% 6% 5% 3% 1% 0%
`
`2% 1% 7% 4% 5% 2% 2% 2%
`
`1% 2% 7% 6% 5% 4% 0% 0%
`
`Posterior capsule opacification
`
`4% 3% 7% 4% 2% 2% 0% 1%
`
`Injection site hemorrhage
`
`1% 0% 5% 2% 3% 1% 0% 0%
`
`BLA 125156/S106
`Page: 8
`
`Non-Ocular Reactions
`Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving LUCENTIS for DR, DME,
`AMD, and/or RVO and which occurred at a ≥ 1% 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.
`
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`Table 2
`Non-Ocular Reactions in the DME and DR, AMD and RVO Studies
`
`DME
`and DR
`2-year
`
`AMD
`2-year
`
`AMD
`1-year
`
`RVO
`6-month
`
`Control
`
`0.5 mg
`
`
`
`LUCENTIS
`
`Control
`
`0.5 mg
`
`
`
`LUCENTIS
`
`Control
`
`0.5 mg
`
`
`
`LUCENTIS
`
`Control
`
`0.3 mg
`
`
`
`LUCENTIS
`
`n=25
`0
`
`n=25
`0
`
`n=37
`9
`
`n=37
`9
`
`n=44
`0
`
`n=44
`1
`
`n=25
`9
`
`n=26
`0
`
`12%
`
`11%
`
`6%
`
`16%
`
`13%
`
`10%
`
`9%
`
`8%
`
`9%
`
`7%
`
`6%
`
`8%
`
`4%
`
`5%
`
`9%
`
`3%
`
`5%
`
`5%
`
`1%
`
`1%
`
`4%
`
`1%
`
`2%
`
`Adverse Reaction
`
`Nasopharyngitis
`
`Anemia
`
`BLA 125156/S106
`Page: 9
`
`Nausea
`
`Cough
`
`Constipation
`
`Seasonal allergy
`
`Hypercholesterolemia
`
`Influenza
`
`Renal failure
`
`10%
`
`9%
`
`8%
`
`8%
`
`7%
`
`7%
`
`7%
`
`4%
`
`4%
`
`4%
`
`5%
`
`3%
`
`6%
`
`9%
`
`5%
`
`4%
`
`5%
`
`7%
`
`1%
`
`8%
`
`7%
`
`4%
`
`5%
`
`5%
`
`1%
`
`5%
`
`3%
`
`2%
`
`3%
`
`3%
`
`0%
`
`4%
`
`4%
`
`2%
`
`2%
`
`2%
`
`0%
`
`1%
`
`0%
`
`0%
`
`1%
`
`3%
`
`0%
`
`2%
`
`1%
`
`2%
`
`1%
`
`2%
`
`0%
`
`Upper respiratory tract infection
`
`Gastroesophageal reflux disease
`
`Headache
`
`Edema peripheral
`
`Renal failure chronic
`
`Neuropathy peripheral
`
`7%
`
`6%
`
`6%
`
`6%
`
`6%
`
`5%
`
`7%
`
`4%
`
`8%
`
`4%
`
`2%
`
`3%
`
`9%
`
`4%
`
`12%
`
`3%
`
`0%
`
`1%
`
`8%
`
`6%
`
`9%
`
`5%
`
`1%
`
`1%
`
`5%
`
`3%
`
`6%
`
`2%
`
`0%
`
`1%
`
`5%
`
`4%
`
`5%
`
`3%
`
`0%
`
`0%
`
`2%
`
`1%
`
`3%
`
`0%
`
`0%
`
`0%
`
`3%
`
`2%
`
`0%
`
`3%
`
`1%
`
`0%
`
`0%
`
`2%
`
`Sinusitis
`
`Bronchitis
`
`Atrial fibrillation
`
`Arthralgia
`
`Chronic obstructive pulmonary disease
`
`5%
`
`4%
`
`3%
`
`3%
`
`1%
`
`8%
`
`4%
`
`3%
`
`3%
`
`1%
`
`Wound healing complications
`
`1%
`
`0%
`
`8%
`
`11%
`
`5%
`
`11%
`
`6%
`
`1%
`
`7%
`
`9%
`
`4%
`
`9%
`
`3%
`
`1%
`
`5%
`
`6%
`
`2%
`
`5%
`
`3%
`
`1%
`
`5%
`
`5%
`
`2%
`
`5%
`
`1%
`
`0%
`
`0%
`
`1%
`
`2%
`
`0%
`
`0%
`
`2%
`
`0%
`
`1%
`
`0%
`
`0%
`
`6.3 Immunogenicity
`As with all therapeutic proteins, there is the potential for an immune response in patients treated with
`LUCENTIS. The immunogenicity data reflect the percentage of patients whose test results were
`considered positive for antibodies to LUCENTIS in immunoassays and are highly dependent on the
`sensitivity and specificity of the assays.
`
`Reference ID: 3698642
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`IPR2021-00816
`
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`The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5% across treatment groups.
`After monthly dosing with LUCENTIS for 6 to 24 months, antibodies to LUCENTIS were detected in
`approximately 1%-9% of patients.
`
`The clinical significance of immunoreactivity to LUCENTIS is unclear at this time. Among neovascular
`AMD patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis.
`Intraocular inflammation was not observed in patients with DME and DR at baseline, or RVO patients
`with the highest levels of immunoreactivity.
`
`6.4 Postmarketing Experience
`The following adverse reactions have been identified during post-approval use of LUCENTIS. Because
`these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
`reliably estimate their frequency or establish a causal relationship to drug exposure.
` Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD
`
`DRUG INTERACTIONS
`7
`Drug interaction studies have not been conducted with LUCENTIS.
`
`LUCENTIS intravitreal injection has been used adjunctively with verteporfin photodynamic
`therapy (PDT). Twelve (12) of 105 (11%) patients with neovascular AMD developed serious
`intraocular inflammation; in 10 of the 12 patients, this occurred when LUCENTIS was administered
`7 days (± 2 days) after verteporfin PDT.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`There are no studies of LUCENTIS in pregnant women. An embryo-fetal developmental toxicity study
`
`was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of
`ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at doses of 0, 0.125, and 1
`mg/eye. Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull,
`vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in
`fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye dose resulted in trough serum
`ranibizumab levels up to 13 times higher than predicted Cmax levels with single eye treatment in humans.
`No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough
`exposures equivalent to single eye treatment in humans. No effect on the weight or structure of the
`placenta, maternal toxicity, or embryotoxicity was observed.
`
`Animal reproduction studies are not always predictive of human response. It is also not known whether
`ranibizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction
`capacity. Based on the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology
`(12.1)], treatment with LUCENTIS may pose a risk to embryo-fetal development (including
`teratogenicity) and reproductive capacity. LUCENTIS should be given to a pregnant woman only if
`clearly needed.
`
`Reference ID: 3698642
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`IPR2021-00816
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`8.3 Nursing Mothers
`It is not known whether ranibizumab is excreted in human milk. Because many drugs are excreted in
`human milk, and because the potential for absorption and harm to infant growth and development exists,
`caution should be exercised when LUCENTIS is administered to a nursing woman.
`
`8.4 Pediatric Use
`The safety and effectiveness of LUCENTIS in pediatric patients have not been established.
`
`8.5 Geriatric Use
`In the clinical studies, approximately 79% (2387 of 3005) of patients randomized to treatment with
`LUCENTIS were ≥ 65 years of age and approximately 54% (1636 of 3005) were ≥ 75 years of age [see
`Clinical Studies (14)]. No notable differences in efficacy or safety were seen with increasing age in
`these studies. Age did not have a significant effect on systemic exposure.
`
`10 OVERDOSAGE
`More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients.
`No additional unexpected adverse reactions were seen.
`
`11 DESCRIPTION
`LUCENTIS (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal
` antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity
`
`of human vascular endothelial growth factor A (VEGF-A). Ranibizumab, which lacks an Fc region, has
`a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a
`nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final
`product.
`
`LUCENTIS is a sterile, colorless to pale yellow solution in a single-use glass vial. LUCENTIS is
`supplied as a preservative-free, sterile solution in a single-use glass vial designed to deliver 0.05 mL of
`10 mg/mL LUCENTIS (0.5 mg dose vial) or 6 mg/mL LUCENTIS (0.3 mg dose vial) aqueous solution
`with 10 mM histidine HCl, 10% α,α-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically
`active, cleaved form of this molecule, VEGF110. VEGF-A has been shown to cause neovascularization
`and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to
`pathophysiology of neovascular AMD, macular edema following RVO, DR and DME. The binding of
`ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and
`VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage,
`and new blood vessel formation.
`
`12.2 Pharmacodynamics
`Increased retinal thickness (i.e., center point thickness (CPT) or central foveal thickness (CFT)), as
`assessed by optical coherence tomography (OCT) is associated with neovascular AMD, macular edema
`
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`following RVO, and DME. Leakage from choroidal neovascularization (CNV) as assessed by
`fluorescein angiography (FA) is associated with neovascular AMD. Microvascular retinal changes and
`neovascularization, as assessed by color fundus photography, are associated with diabetic retinopathy.
`
`Neovascular (Wet) Age-Related Macular Degeneration
`In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TD-OCT
`measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with
`LUCENTIS, CPT decreased, on average, more than in the sham group from baseline through Month 12.
`CPT decreased by Month 1 and decreased further at Month 3, on average. In this study, CPT data did
`not provide information useful in influencing treatment decisions [see Clinical Studies (14.1)].
`
`In Study AMD-4, CFT was assessed by spectral domain (SD)-OCT in all patients; on average, CFT
`reductions were observed beginning at Day 7 following the first LUCENTIS injection through Month
`24. CFT data did not provide information capable of predicting final visual acuity results [see Clinical
`Studies (14.1)].
`
`In patients treated with LUCENTIS, the area of CNV leakage, on average, decreased by Month 3 as
`assessed by FA. The area of CNV leakage for an individual patient was not correlated with visual
`acuity.
`
`Macular Edema Following Retinal Vein Occlusion
`On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following
`the first LUCENTIS injection through Month 6. CPT was not evaluated as a means to guide treatment
`decisions [see Clinical Studies (14.2)].
`
`Diabetic Macular Edema
`On average, CPT reductions were observed in Studies D-1 and D-2 beginning at Day 7 following the
`first LUCENTIS injection through Month 36. CPT data did not provide information useful in
`influencing treatment decisions [see Clinical Studies (14.3)].
`
`Diabetic Retinopathy in patients with Diabetic Macular Edema
`Improvements from baseline in DR severity as assessed on fundus photography were observed in
`Studies D-1 and D-2 at Month 3 (first scheduled DR photographic assessment after randomization)
`through Month 36 [see Clinical Studies (14.4)].
`
`12.3 Pharmacokinetics
`In animal studies, following intravitreal injection, ranibizumab was cleared from the vitreous with a
`half-life of approximately 3 days. After reaching a maximum at approximately 1 day, the serum
`concentration of ranibizumab declined in parallel with the vitreous concentration. In these animal
`studies, systemic exposure of ranibizumab was more than 2000-fold lower than in the vitreous.
`
`In patients with neovascular AMD, following monthly intravitreal administration of 0.5 mg LUCENTIS,
`mean (±SD) maximum ranibizumab serum concentrations were 1.7 (± 1.1) ng/mL. These concentrations
`were below the concentration range of ranibizumab (11 to 27 ng/mL) that was necessary to inhibit the
`biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay (based on
`human umbilical vein endothelial cells (HUVEC)). No significant change from baseline was observed in
`
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`the mean plasma VEGF concentrations following three monthly 0.5 mg intravitreal injections. The
`maximum observed serum concentration was dose proportional over the dose range of 0.05 to 2 mg/eye.
`Serum ranibizumab concentrations in RVO and DME and DR patients were similar to those observed in
`neovascular AMD patients.
`
`Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum
`concentrations are predicted to be reached at approximately 1 day after monthly intravitreal
`administration of LUCENTIS 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the
`estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum
`concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum
`ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal
`concentrations.
`
`In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild,
`11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these
`patients are not considered clinically significant, no dosage adjustment is needed based on renal
`impairment status.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No carcinogenicity or mutagenicity data are available for ranibizumab injection in animals or humans.
`
`No studies on the effects of ranibizumab on fertility have been conducted. Although systemic exposure
`following ocular administration is expected to be low, effects on female fertility are possible due to the
`anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1)].
`
`14 CLINICAL STUDIES
`Unless otherwise noted, visual acuity was measured at a distance of 4 meters.
`
`14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`The safety and efficacy of LUCENTIS were assessed in three randomized, double-masked, sham- or
`active-controlled studies in patients with neovascular AMD. A total of 1323 patients (LUCENTIS 879,
`control 444) were enrolled in the three studies.
`
`Studies AMD-1 and AMD-2
`In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received
`monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are
`available th