` sBLA 125156/S-069
`
` sBLA 125156/S-076
`Page 6
`
`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
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`• Indications and Usage, Diabetic Macular Edema (DME) (1.3)
`08/2012
`
`• Dosage and Administration, Diabetic Macular Edema
`08/2012
`
`(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 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 less effective, treatment may be reduced to one injection every
`
`
`
`3 months after the first four injections if monthly injections are not feasible.
`
`
`
`Compared to continued monthly dosing, dosing every 3 months will lead to
`
`an approximate 5-letter (1-line) loss of visual acuity benefit, on average,
`
`over the following 9 months. Patients should be treated 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: 08/2012
`
`
`
`
`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
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`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
`
`Reference ID: 3172875
`
`Regeneron Exhibit 1202.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Diabetic Macular Edema (DME)
`
`DOSAGE AND ADMINISTRATION
`
`
`Neovascular (Wet) Age-Related Macular Degeneration
`
`
`
`Neovascular (Wet) Age-Related Macular Degeneration
`
`
` sBLA 125156/S-069
`
` sBLA 125156/S-076
`Page 7
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`LUCENTIS is indicated for the treatment of patients with:
`
`1.1
`(AMD)
`
`1.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`
`1.3
`2
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
`
`
`2.2
`(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 less effective, treatment may be reduced to one injection
`every 3 months after the first four injections if monthly injections
`
`are not feasible. Compared to continued monthly dosing, dosing
`every 3 months will lead to an approximate 5-letter (1-line) loss of
`
`visual acuity benefit, on average, over the following 9 months.
`
`Patients should be treated 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.
`
`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
`
`
`CONTRAINDICATIONS
`
`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
`
`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
`
`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.
`
`
`
`
`Reference ID: 3172875
`
`Regeneron Exhibit 1202.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` sBLA 125156/S-069
`
` sBLA 125156/S-076
`Page 8
`
`
`
`
`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) with 0.5 mg LUCENTIS and
`10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was
`
`4.8% (12 of 249) with 0.5 mg LUCENTIS and 2.0% (5 of 250)
`
`
`
`
`with 0.3 mg LUCENTIS.
`
`Fatal Events in DME Patients
`5.4
`
`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.
`
`Ocular Reactions
`Table 1 shows frequently reported ocular adverse reactions in
`LUCENTIS-treated patients compared with the control group.
`
`
`
`Dry eye
`Visual
`
`disturbance or
`vision blurred
`Eye pruritis
`
`Ocular hyperemia
`
`Retinal disorder
`
`5%
`
`8%
`
`4%
`
`9%
`
`2%
`
`3%
`
`12%
`
`7%
`
`7%
`
`4%
`
`18% 15% 13% 10%
`
`5%
`
`3%
`
`4%
`
`12% 11%
`
`9%
`
`7%
`
`9%
`
`11%
`
`8%
`
`7%
`
`4%
`
`2%
`
`10%
`
`7%
`
`8%
`
`4%
`
`1%
`
`5%
`
`2%
`
`2%
`
`3%
`
`1%
`
`7%
`
`0%
`
`2%
`
`0%
`
`1%
`
`0%
`
`5%
`
`1%
`
`2%
`
`1%
`
`7%
`
`0%
`
`1%
`
`2%
`
`9%
`
`8%
`
`7%
`
`7%
`
`9%
`
`6%
`
`4%
`
`6%
`
`6%
`
`6%
`
`11%
`
`5%
`
`3%
`
`1%
`
`5%
`
`2%
`
`5%
`
`4%
`
`2%
`
`0%
`
`Maculopathy
`Retinal
`degeneration
`
`Ocular discomfort
`Conjunctival
`hyperemia
`Posterior capsule
`opacification
`Injection site
`hemorrhage
`
`Non-Ocular Reactions
`
`Non-ocular adverse reactions with an incidence of ≥ 5% in patients
`
`receiving LUCENTIS for DME, AMD, and/or RVO and which
`
`4%
`
`3%
`
`7%
`
`4%
`
`2%
`
`2%
`
`0%
`
`1%
`
`0%
`
`5%
`
`2%
`
`3%
`
`1%
`
`0%
`
`
`
`Reference ID: 3172875
`
`Regeneron Exhibit 1202.003
`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%
`
`10%
`
`5%
`
`16% 14% 13% 10%
`
`8%
`
`5%
`
`5%
`
`15% 15% 13% 12%
`
`4%
`
`14% 12%
`
`8%
`
`8%
`
`3%
`
`2%
`
`12%
`
`8%
`
`8%
`
`5%
`
`7%
`
`2%
`
`7%
`
`7%
`
`2%
`
`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
`
`

`

`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.
`
`• Ocular: Tear of retinal pigment epithelium among patients
`
`with neovascular AMD
`
`
` sBLA 125156/S-069
`
` sBLA 125156/S-076
`Page 9
`
` 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.
`
`
`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
`
`Adverse
`Reaction
`
`
`
`n=25
`0
`
`n=25
`0
`
`n=37
`9
`
`n=37
`9
`
`n=44
`0
`
`n=44
`1
`
`n=25
`9
`
`n=26
`0
`
`Nasopharyngitis
`
`12%
`
`
`
` 6%
`
`
`
` 16%
`
`13%
`
`Anemia
`
`11%
`
`
`10%
`
`
`8%
`
`9%
`
`7%
`
`6%
`
`
`
` 8%
`
`4%
`
`
`
`
` 9%
`
`3%
`
`
`
`
` 5%
`
`1%
`
`
`
`
` 4%
`
`1%
`
`
`
`Nausea
`
`Cough
`
`
`Constipation
`
`
`Seasonal allergy
`
`Hypercholesterole
`
`mia
`
`Influenza
`
`Renal failure
`
`
`10%
`
`9%
`
`8%
`
`8%
`
`7%
`
`7%
`
`7%
`
`9%
`
`4%
`
`4%
`
`4%
`
`5%
`
`3%
`
`6%
`
`9%
`
`5%
`
`4%
`
`5%
`
`7%
`
`1%
`
`8%
`
`7%
`
`4%
`
`5%
`
`5%
`
`1%
`
`
`5%
`
`
`5%
`
`
`3%
`
`
`2%
`
`
`3%
`
`
`3%
`
`
`5%
`
`
`4%
`
`
`4%
`
`
`2%
`
`
`2%
`
`
`2%
`
`
`1%
`
`
`1%
`
`
`0%
`
`
`0%
`
`
`2%
`
`
`2%
`
`
`1%
`
`
`2%
`
`
`1%
`
`
`1%
`
`
`3%
`
`
`2%
`
`
`0%
`
`
`Upper respiratory
`tract infection
`
`Gastroesophageal
`reflux disease
`
`Headache
`
`
`Edema peripheral
`
`Renal failure
`chronic
`
`
`Neuropathy
`peripheral
`
`
`0%
`
`
`0%
`
`
`0%
`
`USE IN SPECIFIC POPULATIONS
`
`7%
`
`7%
`
`9%
`
`8%
`
`
`5%
`
`
`5%
`
`
`2%
`
`
`2%
`
`6%
`
`4%
`
`4%
`
`6%
`
`6%
`
`
`8%
`
`4%
`
`6%
`
`2%
`
`
`12%
`
`3%
`
`0%
`
`6%
`
`9%
`
`5%
`
`1%
`
`
`3%
`
`
`4%
`
`
`1%
`
`
`0%
`
`
`6%
`
`
`2%
`
`
`5%
`
`
`3%
`
`
`3%
`
`
`0%
`
`
`3%
`
`
`1%
`
`
`0%
`
`
`0%
`
`
`0%
`
`
`0%
`
`5%
`
`3%
`
`1%
`
`1%
`
`
`1%
`
`
`0%
`
`
`0%
`
`
`0%
`
`
`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 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. In a study of placental and embryo-fetal
`
`
`development in pregnant cynomolgus monkeys, skeletal
`
`abnormalities were seen in fetuses at the highest dose tested of 1
`mg/eye which resulted in trough exposures up to 13 times higher
`
`than predicted Cmax levels with single eye treatment in humans
`[see Nonclinical Toxicology (13.2)]. Skeletal abnormalities were
`
`not seen in monkeys at 0.125 mg/eye, a dose which resulted in
`
`trough exposures equivalent to single eye treatment in humans.
`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.
`
`
`
`
`Sinusitis
`
`
`Bronchitis
`
`
`
`Atrial fibrillation
`
`
`Arthralgia
`
`Chronic
`obstructive
`pulmonary disease
`
`5%
`
`4%
`
`3%
`
`3%
`
`8%
`
`
`4%
`
`3%
`
`
`3%
`
`8%
`
`
`11%
`
`5%
`
`
`11%
`
`7%
`
`9%
`
`4%
`
`9%
`
`
`5%
`
`
`6%
`
`
`2%
`
`
`5%
`
`
`5%
`
`
`5%
`
`
`2%
`
`
`5%
`
`
`3%
`
`
`0%
`
`
`1%
`
`
`2%
`
`
`2%
`
`
`2%
`
`
`0%
`
`
`1%
`
`1%
`
`1%
`
`6%
`
`3%
`
`
`3%
`
`
`1%
`
`
`0%
`
`
`0%
`
`1%
`
`1%
`
`
`1%
`
`
`0%
`
`
`0%
`
`
`0%
`
`1%
`
`
`0%
`
`Wound healing
`
`complications
`
`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
`
`
`
`Reference ID: 3172875
`
`Regeneron Exhibit 1202.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` sBLA 125156/S-069
`
` sBLA 125156/S-076
`Page 10
`
`Geriatric Use
`8.5
`
`In the clinical studies, approximately 72% (1366 of 1908) of
`patients randomized to treatment with LUCENTIS were ≥ 65 years
`
`of age and approximately 43% (822 of 1908) 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
`Planned initial single doses of ranibizumab injection 1 mg were
`associated with clinically significant intraocular inflammation in
`2 of 2 neovascular AMD patients injected. With an escalating
`regimen of doses beginning with initial doses of ranibizumab
`injection 0.3 mg, doses as high as 2 mg were tolerated in 15 of
`20 neovascular AMD patients.
`
`
`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 center point thickness (CPT) 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.
`
`Neovascular (Wet) Age-Related Macular Degeneration
`In Study AMD-3, CPT was assessed by OCT in 118 of 184
`patients. 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. CPT data did not provide
`
`
`information useful in influencing treatment decisions [see Clinical
`Studies (14.1)].
`
`
`CLINICAL PHARMACOLOGY
`
`In patients treated with LUCENTIS, the area of vascular leakage,
`on average, decreased by Month 3 as assessed by FA. The area of
`
`vascular 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)].
`
`
`
`NONCLINICAL TOXICOLOGY
`
`
`
`Reference ID: 3172875
`
`Regeneron Exhibit 1202.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Table 3
`
`Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-1
`
`
`Outcome Measure Month
`
`Loss of <15 letters in
`visual acuity (%)
`
`Gain of ≥15 letters in
`visual acuity (%)
`
`Mean change in
`visual acuity (letters)
`(SD)
`
`12
`
`24
`
`12
`
`24
`
`12
`
`24
`
`Sham
`
`n=229
`
`60%
`
`56%
`
`6%
`
`4%
`
`91%
`
`89%
`
`31%
`
`30%
`
`−11.0 (17.9
`)
`
`−15.0 (19.7
`)
`
`
`+6.3 ( 14.1)
`
`+5.5 ( 15.9)
`
`LUCENTIS
`0.5 mg
`
`n=230
`
`Estimated
`Difference
`(95% CI)a
`
`
`30%
`(23%, 37%)
`
`33%
`(26%, 41%)
`
`25%
`(18%, 31%)
`
`25%
`(18%, 31%)
`
`17.1
`
`(14.2, 20.0)
`
`20.1
`
`(16.9, 23.4)
`
`
` sBLA 125156/S-069
`
` sBLA 125156/S-076
`Page 11
`
` 13.2 Animal Toxicology and/or Pharmacology
`
`
`
` 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.
`
`
` 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 22 total
`treatments out of a possible 24 from Day 0 to Month 24.
`
`
`
`In Study AMD-2, patients with predominantly classic CNV lesions
`received one of the following: 1) monthly LUCENTIS 0.3 mg
`
`intravitreal injections and sham PDT; 2) monthly LUCENTIS
`
`0.5 mg intravitreal injections and sham PDT; or 3) s