`
` sBLA 125156/S-081
`Page 3
`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
`
`08/2012
`
`08/2012
`08/2012
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`• Indications and Usage, Diabetic Macular Edema (DME) (1.3)
`08/2012
`
`• Dosage and Administration, Neovascular (Wet) Age-Related
`02/2013
`
`Macular Degeneration (AMD) (2.2)
`• Dosage and Administration, Diabetic Macular Edema
`
`(DME) (2.4)
`• Dosage and Administration, Administration (2.6)
`
`
`• Warnings and Precautions, Endophthalmitis and Retinal
`
`
`
`Detachments (5.1)
`• Warnings and Precautions, Increases in Intraocular Pressure (5.2)
`08/2012
`
`• Warnings and Precautions, Thromboembolic Events (5.3)
`08/2012
`
`
`• Warnings and Precautions, Fatal Events in DME Patients (5.4)
`08/2012
`
`--------------------------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)
`
`----------------------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 three monthly doses
`
`followed by less frequent dosing with regular assessment. In the nine months
`after three initial monthly doses, less frequent dosing with 4-5 doses on
`
`average is expected to maintain visual acuity while monthly dosing may be
`
`expected to result in an additional average 1-2 letter gain. Patients should be
`
`assessed regularly.
`
`Although not as effective, patients may also be treated with one dose every 3
`months after 4 monthly doses. Compared to 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.
`
`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). In the RVO
`clinical studies, 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.
`
`
`
`Diabetic Macular Edema (DME) (2.4)
`• 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 DME patients 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: 02/2013
`
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
` sBLA 125156/S-081
`Page 4
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`
`1.1 Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`1.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`1.3 Diabetic Macular Edema (DME)
`2 DOSAGE AND ADMINISTRATION
`
` General Dosing Information
`2.1
`2.2 Neovascular (Wet) Age-Related Macular Degeneration
`
`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`2.4 Diabetic Macular Edema (DME)
`Preparation for Administration
`2.5
`2.6 Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`4.1 Ocular or Periocular Infections
`
` Hypersensitivity
`4.2
`5 WARNINGS AND PRECAUTIONS
`Endophthalmitis and Retinal Detachments
`5.1
`5.2
`Increases in Intraocular Pressure
`5.3
` Thromboembolic Events
`5.4
`Fatal Events in DME Patients
`6 ADVERSE REACTIONS
`6.1
` Injection Procedure
`6.2 Clinical Studies Experience
`
`
`
`
`6.3
` Immunogenicity
`
`6.4
`Postmarketing Experience
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`
` Nursing Mothers
`8.3
`8.4
` Pediatric Use
`8.5
` Geriatric Use
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`
`
`
`(AMD)
`
`14.2 Macular Edema Following Retinal Vein Occlusion
`
`(RVO)
`
`14.3 Diabetic Macular Edema (DME)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the Full Prescribing Information are
`
`not listed.
`
`FULL PRESCRIBING INFORMATION
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
`
`Diabetic Macular Edema (DME)
`
`DOSAGE AND ADMINISTRATION
`
`
`INDICATIONS AND USAGE
`1
`LUCENTIS is indicated for the treatment of patients with:
`
`1.1
`
`1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
`
`1.3
`2
`
`General Dosing Information
`2.1
`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 three monthly doses followed by less frequent dosing with regular assessment. In the nine
`months after three initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly
`dosing may be expected to result in an additional average 1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1)].
`
`
`Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Compared to 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).
`
`
`Preparation for Administration
`2.5
`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.
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
` sBLA 125156/S-081
`Page 5
`
`CONTRAINDICATIONS
`
`
`Administration
`2.6
`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
`njection [see Warnings and Precautions (5.1)].
`i
`
`
`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
`
`Ocular or Periocular Infections
`4.1
`LUCENTIS is contraindicated in patients with ocular or periocular infections.
`
`
`4.2
`Hypersensitivity
`
`LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity
`
`reactions may manifest as severe intraocular inflammation.
`5
`WARNINGS AND PRECAUTIONS
`
`Endophthalmitis and Retinal Detachments
`5.1
`Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal detachments. Proper aseptic
`injection technique should always be used when administering LUCENTIS. In addition, patients should be monitored following the injection to
`permit early treatment should an infection occur [see Dosage and Administration (2.5, 2.6) and Patient Counseling Information (17)].
`
`
`Increases in Intraocular Pressure
`5.2
`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 (2.6)].
`
`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 of the study during the first year were similar to rates observed in 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
`
`In a pooled analysis of Studies DME-1 and DME-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)
`
`
`
`
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
` sBLA 125156/S-081
`Page 6
`
`
`
`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 DME Patients
`A pooled analysis of Studies DME-1 and DME-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 DME Patients
`
`
`
`Injection Procedure
`6.1
`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.
`
`
`Clinical Studies Experience
`6.2
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be
`
`directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.
`
`
`The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with neovascular AMD in Studies AMD-1, AMD-2, and AMD-3, and
`259 patients with macular edema following RVO. The data also reflect exposure to 0.3 mg LUCENTIS in 250 patients with DME [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.
`
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Table 1
`
`Ocular Reactions in the DME, AMD, and RVO Studies
`
`DME
`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
`
`47% 32% 74% 60% 64% 50% 48% 37%
`
`17% 13% 35% 30% 26% 20% 17% 12%
`
`10%
`
`4%
`
`27%
`
`8%
`
`19%
`
`5%
`
`18%
`
`7%
`
`24%
`
`7%
`
`17%
`
`5%
`
`7%
`
`7%
`
`2%
`
`2%
`
`11% 15% 21% 19% 15% 15%
`
`4%
`
`2%
`
`4%
`
`3%
`
`18%
`
`8%
`
`13%
`
`7%
`
`1%
`
`3%
`
`28% 32% 17% 14% 11%
`
`9%
`
`2%
`
`10%
`
`5%
`
`16% 14% 13% 10%
`
`7%
`
`8%
`
`5%
`
`5%
`
`15% 15% 13% 12%
`
`7%
`
`4%
`
`14% 12%
`
`8%
`
`8%
`
`2%
`
`3%
`
`2%
`
`12%
`
`8%
`
`8%
`
`5%
`
`0%
`
`3%
`
`2%
`
`5%
`
`6%
`
`3%
`
`1%
`
`3%
`
`Adverse Reaction
`
`
`Conjunctival
`hemorrhage
`Eye pain
`
`
`
`Vitreous floaters
`Intraocular
`pressure
`increased
`Vitreous
`detachment
`Intraocular
`inflammation
`Cataract
`
`Foreign body
`sensation in eyes
`Eye irritation
`Lacrimation
`increased
`Blepharitis
`
`
`
` sBLA 125156/S-081
`Page 7
`
`Dry eye
`Visual
`
`disturbance or
`vision blurred
`Eye pruritis
`
`Ocular hyperemia
`
`Retinal disorder
`
`Maculopathy
`Retinal
`degeneration
`
`Ocular discomfort
`Conjunctival
`hyperemia
`Posterior capsule
`opacification
`Injection site
`hemorrhage
`
`5%
`
`8%
`
`4%
`
`9%
`
`2%
`
`5%
`
`1%
`
`2%
`
`1%
`
`3%
`
`12%
`
`7%
`
`7%
`
`7%
`
`4%
`
`18% 15% 13% 10%
`
`5%
`
`3%
`
`4%
`
`12% 11%
`
`9%
`
`9%
`
`11%
`
`8%
`
`2%
`
`10%
`
`7%
`
`7%
`
`0%
`
`1%
`
`2%
`
`9%
`
`8%
`
`7%
`
`7%
`
`9%
`
`6%
`
`4%
`
`6%
`
`7%
`
`8%
`
`6%
`
`5%
`
`5%
`
`5%
`
`7%
`
`4%
`
`4%
`
`1%
`
`5%
`
`2%
`
`2%
`
`3%
`
`1%
`
`6%
`
`11%
`
`7%
`
`3%
`
`1%
`
`0%
`
`2%
`
`4%
`
`2%
`
`0%
`
`2%
`
`0%
`
`4%
`
`3%
`
`7%
`
`4%
`
`2%
`
`2%
`
`0%
`
`1%
`
`1%
`
`0%
`
`5%
`
`2%
`
`3%
`
`1%
`
`0%
`
`0%
`
`
`Non-Ocular Reactions
`
`
`Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving LUCENTIS for 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.
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Table 2
`Non-Ocular Reactions in the DME, AMD and RVO Studies
`
`DME
`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
`
`
`Nasopharyngitis
`
`Anemia
`
`
`12%
`
`
`11%
`
`6%
`
`
`10%
`
`9%
`
`
`16%
`
`13%
`
`
`8%
`
`
`9%
`
`7%
`
`6%
`
`
`8%
`
`4%
`
`5%
`
`
`9%
`
`3%
`
`5%
`
`
`5%
`
`
`1%
`
`
`1%
`
`
`4%
`
`
`1%
`
`
`2%
`
`
`
` sBLA 125156/S-081
`Page 8
`
`
`
`
`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%
`
`7%
`
`
`9%
`
`8%
`
`5%
`
`5%
`
`
`2%
`
`
`2%
`
`6%
`
`6%
`
`6%
`
`6%
`
`5%
`
`4%
`
`
`8%
`
`4%
`
`2%
`
`3%
`
`
`4%
`
`
`12%
`
`
`3%
`
`
`0%
`
`
`1%
`
`6%
`
`9%
`
`5%
`
`1%
`
`1%
`
`3%
`
`6%
`
`2%
`
`0%
`
`1%
`
`5%
`
`4%
`
`5%
`
`3%
`
`0%
`
`0%
`
`5%
`
`
`1%
`
`
`3%
`
`
`0%
`
`
`0%
`
`
`0%
`
`
`0%
`
`
`3%
`
`
`1%
`
`
`0%
`
`
`0%
`
`
`Sinusitis
`
`
`Bronchitis
`
`
`
`Atrial fibrillation
`
`
`Arthralgia
`
`Chronic obstructive
`pulmonary disease
`
`Wound healing
`
`complications
`
`5%
`
`4%
`
`3%
`
`3%
`
`1%
`
`8%
`
`
`4%
`
`3%
`
`
`3%
`
`1%
`
`
`8%
`
`
`11%
`
`
`5%
`
`
`11%
`
`
`6%
`
`7%
`
`9%
`
`4%
`
`9%
`
`3%
`
`6%
`
`2%
`
`5%
`
`3%
`
`5%
`
`2%
`
`5%
`
`1%
`
`
`3%
`
`
`0%
`
`
`1%
`
`
`2%
`
`
`0%
`
`
`2%
`
`
`2%
`
`
`0%
`
`
`1%
`
`
`0%
`
`
`1%
`
`
`0%
`
`
`1%
`
`1%
`
`1%
`
`0%
`
`
`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.
`
`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%-8% 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 DME or RVO patients with the highest
`
`
`levels of immunoreactivity.
`
`Postmarketing Experience
`6.4
`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.
`
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
` sBLA 125156/S-081
`Page 9
`
`Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD
`
`•
`
`
`7
`DRUG INTERACTIONS
`
`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
`
`Pregnancy
`8.1
`Pregnancy Category C. 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.
`
`
`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.
`
`Pediatric Use
`8.4
`
`The safety and effectiveness of LUCENTIS in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`
`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.
`
`DESCRIPTION
`11
`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
`
`
`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, 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.
`
`Pharmacodynamics
`12.2
`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 following RVO, and DME. Leakage from choroidal neovascularization (CNV) as
`
`assessed by fluorescein angiography (FA) is associated with neovascular AMD.
`
`
`USE IN SPECIFIC POPULATIONS
`
`CLINICAL PHARMACOLOGY
`
`
`
`Reference ID: 3256868
`
`Regeneron Exhibit 1239.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
` sBLA 125156/S-081
`Page 10
`
`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 12 in both arms. 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 DME-1 and DME-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)].
`
`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, maximum ranibizumab serum concentrations were low
`(0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit
`
`
`the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay. The maximum observed serum concentration
`
`was dose proportional over the dose range of 0.05 to 1 mg/eye. Serum ranibizumab concentrations in RVO and DME patients were similar to
`
`those observed in neovascular AMD patients.
`
`
`
`Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations of 1.5 ng/mL 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
`
`
`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)].
`
`CLINICAL STUDIES
`14
`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 through Month 24. Patients treated with LUCENTIS in Study AMD-1
`received a mean of 2