BLA 125156/S-111
`Page 4
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use LUCENTIS
`safely and effectively. See full prescribing information for LUCENTIS.
`
`LUCENTIS® (ranibizumab injection)
`For Intravitreal Injection
`Initial U.S. Approval: 2006
`
`--------------------------RECENT MAJOR CHANGES-----------------­
`Indications and Usage, Myopic Choroidal Neovascularization
`(mCNV) (1.5)
`General Dosing Information (2.1)
`Dosage and Administration, Myopic Choroidal Neovascularization
`(mCNV) (2.6)
`Dosage and Administration, Preparation for Administration (2.7)
`Dosage and Administration, Administration (2.8)
`
`01/2017
`11/2016
`
`01/2017
`11/2016
`10/2016
`
`--------------------------INDICATIONS AND USAGE-----------------------­
`LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is indicated for
`
`the treatment of patients with:
`
` Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`
` Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
`
` Diabetic Macular Edema (DME) (1 3)
`
` Diabetic Retinopathy in patients with DME (1.4)
`
` Myopic Choroidal Neovascularization (mCNV) (1 5)
`
`
`----------------------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.
`
`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).
`
`Myopic Choroidal Neovascularization (mCNV) (2.6)
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be initially administered
`
`by intravitreal injection once a month (approximately 28 days) for up to three
`months. Patients may be retreated if needed.
`
`---------------------DOSAGE FORMS AND STRENGTHS-----------­
`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injections:
`
` 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
`
`
`Single-use glass vial designed to provide 0.05 mL for intravitreal injections:
`
` 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
`
` 6 mg/mL solution (LUCENTIS 0.3 mg) (3)
`
`
`------------------------------CONTRAINDICATIONS-------------------­
` Ocular or periocular infections (4 1)
` Hypersensitivity (4.2)
`
`-----------------------WARNINGS AND PRECAUTIONS-------------­
` Endophthalmitis and retinal detachments may occur following intravitreal
`injections. Patients should be monitored following the injection (5.1).
` Increases in intraocular pressure (IOP) have been noted both pre- and
`post-intravitreal injection (5.2).
` There is a potential risk of arterial thromboembolic events following intravitreal
`use of VEGF inhibitors (5.3).
` Fatal events occurred more frequently in patients with DME and DR at baseline,
`who were treated monthly with LUCENTIS compared with control (5.4).
`------------------------------ADVERSE REACTIONS--------------------­
` The most common adverse reactions (reported more frequently in
`LUCENTIS-treated subjects than control subjects) are conjunctival hemorrhage,
`eye pain, vitreous floaters, and increased IOP (6.2).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`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).
`_____________________________________________________________________________________________________________________________
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 01/2017
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`Neovascular (Wet) Age-Related Macular Degeneration
`1.1
`(AMD)
`1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
`Diabetic Macular Edema (DME)
`1.3
`1.4
`Diabetic Retinopathy in patients with DME
`1.5 Myopic Choroidal Neovascularization (mCNV)
`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)
`Diabetic Macular Edema (DME)
`2.4
`2.5
`Diabetic Retinopathy in patients with DME
`2.6 Myopic Choroidal Neovascularization (mCNV)
`Preparation for Administration
`2.7
`2.8
`Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`Ocular or Periocular Infections
`4.1
`4.2
`Hypersensitivity
`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 Patients with DME and DR at baseline
`6 ADVERSE REACTIONS
`Injection Procedure
`6.1
`6.2
`Clinical Studies Experience
`
`Reference ID: 4037547
`
`Immunogenicity
`6.3
`Postmarketing Experience
`6.4
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`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)
`14.4 Diabetic Retinopathy in patients with DME
`14.5 Myopic Choroidal Neovascularization (mCNV)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the Full Prescribing Information are not
`listed.
`
`Novartis Exhibit 2213.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 5
`
`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)
`
`1.5 Myopic Choroidal Neovascularization (mCNV)
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
`
`Vials: A 5-micron sterile filter needle (19-gauge x 1-1/2 inch), a 1-mL Luer lock syringe and a
`
`30-gauge x ½ inch sterile injection needle are needed but not included.
`
`
`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)
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 6
`
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`2.5 Diabetic Retinopathy in Patients with Diabetic Macular Edema (DME)
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`2.6 Myopic Choroidal Neovascularization (mCNV)
`LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be initially administered
`by intravitreal injection once a month (approximately 28 days) for up to three months. Patients may be retreated
`if needed [(see Clinical Studies 14.5)].
`
`2.7 Preparation for Administration
`Prefilled Syringe:
`
`To prepare LUCENTIS for intravitreal administration, please adhere to
`these instructions for use. Read all the instructions carefully before using
`the prefilled syringe.
`
`How to store LUCENTIS:
`1. LUCENTIS should be refrigerated at 2º-8ºC (36º-46ºF). Do not freeze.
`2. Do not use beyond the expiration date stamped on the label.
`3. Protect LUCENTIS prefilled syringes from light and store in the
`original carton until time of use.
`4. Do not open the sealed tray until time of use.
`
`The prefilled syringe is for single use only. The prefilled syringe is sterile.
`Do not use the product if the packaging is damaged or has been
`tampered with.
`
`The opening of the sealed tray and all subsequent steps should be done
`under aseptic conditions.
`
`For the intravitreal injection, a 30-gauge x ½ inch sterile injection needle
`should be used (not provided).
`
`Note: the dose must be set to 0.05 mL.
`______________________________________________________________________________
`Device description
`______________________________________________________________________________
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 7
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`
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`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`______________________________________________________________________________
`Step 1: Prepare
`______________________________________________________________________________
`
` Make sure that your pack contains a sterile prefilled syringe
`in a sealed tray.
`
` Peel the lid off the syringe tray and, using aseptic technique,
`remove the syringe.
`______________________________________________________________________________
`Step 2: Inspect syringe
`______________________________________________________________________________
`
`
`
`LUCENTIS should be colorless to pale yellow.
`
` Do not use the prefilled syringe if:
`the syringe cap is detached from the Luer lock.
`-
`the syringe is damaged.
`-
`particulates, cloudiness, or discoloration are visible.
`-
`______________________________________________________________________________
`Step 3: Remove syringe cap
`______________________________________________________________________________
`
`
`
`Snap off (do not turn or twist)
`the syringe cap (see Figure 2).
`
`______________________________________________________________________________
`Step 4: Attach needle
`______________________________________________________________________________
`
`
`
`
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 8
`
` Attach a 30G x ½ inch sterile
`
`injection needle firmly onto
`
`the syringe by screwing it
`
`tightly onto the Luer lock (see
`
`Figure 3).
`
`
` Carefully remove the needle
`
`cap by pulling it straight off.
`
`
`Note: Do not wipe the needle at
`
`any time.
`
`
`
`
`
`
`______________________________________________________________________________
`Step 5: Dislodge air bubbles
`______________________________________________________________________________
`
` Hold the syringe with the
`
`needle pointing up.
`
`
`
`
`If there are any air bubbles,
`
`gently tap the syringe with
`
`your finger until the bubbles
`
`rise to the top (see Figure 4).
`
`
`
`
`
`
`______________________________________________________________________________
`Step 6: Expel air and adjust drug dose
`______________________________________________________________________________
`
`Hold the syringe at eye level,
`
`and carefully push the
`
`plunger rod until the edge
`
`below the dome of the
`
`rubber stopper is aligned
`
`with the 0.05 mL dose mark
`
`(see Figure 5).
`
`
`Note: The plunger rod is not
`
`attached to the rubber
`
`stopper – this is to
`
`prevent air being drawn into the syringe.
`
`______________________________________________________________________________
`Step 7: Inject
`______________________________________________________________________________
`
`
`
`
`
`
`
`The injection procedure should be carried out under aseptic
`
`conditions.
`
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 9
`
`
`
`
`
`Insert the needle into the injection site.
`
`Inject slowly until rubber stopper reaches the bottom of the syringe
`to deliver the volume of 0.05 mL.
`
` After injection, do not recap the needle or detach it from the syringe.
`Dispose of the used syringe together with the needle in a sharps
`disposal container or in accordance with local requirements.
`
`Vial:
`Using aseptic technique, all of the LUCENTIS vial contents are withdrawn through a 5-micron
`(19-gauge x 1-1/2 inch), sterile filter needle attached to a 1 mL syringe (not included). 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 ½ inch
`needle for the intravitreal injection.
`
`Use aseptic technique to carry out the following preparation steps.
`Prepare for intravitreal injection with the following medical devices for single use (not
`1.
`included):
` a 5-micron sterile filter needle (19-gauge x 1-1/2 inch)
` a 1 mL sterile Luer lock syringe (with marking to measure 0.05 mL)
` a sterile injection needle (30-gauge x 1/2-inch)
`2. Before withdrawal, disinfect the outer part of the rubber stopper of the vial.
`Place a 5-micron filter needle (19-gauge x 1-1/2 inch) onto a 1 mL Luer lock syringe using
`3.
`aseptic technique.
`Push the filter needle into the center of the vial stopper until the needle touches the bottom
`edge of the vial.
`5. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly
`inclined to ease complete withdrawal.
`
`4.
`
`6.
`
`Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to
`completely empty the filter needle.
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 10
`
`7.
`
`The filter needle should be discarded after withdrawal of the vial contents and must not be
`used for the intravitreal injection.
`8. Attach a 30-gauge x 1/2-inch sterile injection needle firmly onto the syringe by screwing it
`tightly onto the Luer lock. Carefully remove the needle cap by pulling it straight off. Do
`not wipe the needle at any time.
`
`9. Hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the
`syringe with your finger until the bubbles rise to the top.
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 11
`
`10. Hold the syringe at eye level, and carefully push the plunger rod until the plunger tip is
`aligned with the line that marks 0.05 mL on the syringe.
`
`
`
`2.8 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 prefilled syringe or vial should only be used for the treatment of a single eye. If the
`contralateral eye requires treatment, a new prefilled syringe or vial should be used and the sterile
`field, syringe, gloves, drapes, eyelid speculum, filter needle (vial only), and injection needles
`should be changed before LUCENTIS is administered to the other eye.
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 12
`
`No special dosage modification is required for any of the populations that have been studied
`(e.g., gender, elderly).
`
`DOSAGE FORMS AND STRENGTHS
`3
`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injection.
`
` 10 mg/mL solution ( LUCENTIS 0.5 mg)
`
`
`Single-use glass vial designed to provide 0.05 mL for intravitreal injection.
`
` 10 mg/mL solution (LUCENTIS 0.5 mg)
`
` 6 mg/mL solution (LUCENTIS 0.3 mg)
`
`
`4
`
`CONTRAINDICATIONS
`
`4.1 Ocular or Periocular Infections
`LUCENTIS is contraindicated in patients with ocular or periocular infections.
`
`4.2 Hypersensitivity
`LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of
`the excipients in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular
`inflammation.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Endophthalmitis and Retinal Detachments
`Intravitreal injections, including those with LUCENTIS, have been associated with
`endophthalmitis and retinal detachments. Proper aseptic injection technique should always be
`used when administering LUCENTIS. In addition, patients should be monitored following the
`injection to permit early treatment should an infection occur [see Dosage and Administration
`(2.7, 2.8) 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 (2.8)].
`
`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
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 13
`
`or 0.5 mg LUCENTIS compared with 1.1% (5 of 441) in patients from the control arms [see
`Clinical Studies (14.1)]. In the second year of Studies AMD-1 and AMD-2, the ATE rate was
`2.6% (19 of 721) in the combined group of LUCENTIS-treated patients compared with 2.9% (10
`of 344) in patients from the control arms. In Study AMD-4, the ATE rates observed in the
`0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1,
`AMD-2, and AMD-3.
`
`In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of LUCENTIS
`used adjunctively with verteporfin photodynamic therapy), the stroke rate (including both
`ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg
`LUCENTIS compared to 1.1% (5 of 435) in patients in the control arms (odds ratio 2.2 (95%
`confidence interval (0.8-7.1))).
`
`Macular Edema Following Retinal Vein Occlusion
`The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the
`LUCENTIS and control arms of the studies (4 of 525 in the combined group of patients treated
`with 0.3 mg or 0.5 mg LUCENTIS and 2 of 260 in the control arms) [see Clinical Studies
`(14.2)]. The stroke rate was 0.2% (1 of 525) in the combined group of LUCENTIS-treated
`patients compared to 0.4% (1 of 260) in the control arms.
`
`Diabetic Macular Edema and Diabetic Retinopathy
`Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at
`baseline [see Clinical Studies (14.3, 14.4)].
`
`In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], the ATE rate at 2 years
`was 7.2% (18 of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and
`5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg
`LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with control. At 3
`years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS and 10.8% (27 of 250) with
`0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with 0.5 mg LUCENTIS and 2.0% (5
`of 250) with 0.3 mg LUCENTIS.
`
`5.4 Fatal Events in Patients with DME and DR at baseline
`Diabetic Macular Edema and Diabetic Retinopathy
`Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at
`baseline [see Clinical Studies (14.3, 14.4)].
`
`A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], showed that fatalities in
`the first 2 years occurred in 4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in
`2.8% (7 of 250) of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control
`patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated with 0.5 mg
`LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 mg LUCENTIS. Although the
`rate of fatal events was low and included causes of death typical of patients with advanced
`diabetic complications, a potential relationship between these events and intravitreal use of
`VEGF inhibitors cannot be excluded.
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 14
`
`6 ADVERSE REACTIONS
`The following adverse reactions are discussed in greater detail in other sections of the label:
` Endophthalmitis and Retinal Detachments [see Warnings and Precautions (5.1)]
` Increases in Intraocular Pressure [see Warnings and Precautions (5.2)]
` Thromboembolic Events [see Warnings and Precautions (5.3)]
` Fatal Events in patients with DME and DR at baseline [see Warnings and Precautions
`(5.4)]
`
`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; in 259 patients with macular edema following RVO. The
`data also reflect exposure to 0.3 mg LUCENTIS in 250 patients with DME and DR at baseline
`[see Clinical Studies (14)].
`
`Safety data observed in Study AMD-4 and in 224 patients with mCNV 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: 4037547
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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
`
`05 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=260
`
`n=25
`9
`
`47% 32% 74% 60% 64% 50% 48% 37%
`
`17% 13% 35% 30% 26% 20% 17% 12%
`
`10% 4% 27% 8% 19% 5% 7%
`
`2%
`
`18% 7% 24% 7% 17% 5% 7%
`
`2%
`
`11% 15% 21% 19% 15% 15% 4%
`
`2%
`
`4% 3% 18% 8% 13% 7% 1%
`
`3%
`
`Adverse Reaction
`
`Conjunctival
`hemorrhage
`Eye pain
`Vitreous
`floaters
`Intraocular
`pressure
`increased
`Vitreous
`detachment
`Intraocular
`inflammation
`Cataract
`Foreign body
`sensation in
`eyes
`Eye irritation
`Lacrimation
`increased
`Blepharitis
`
`Reference ID: 4037547
`
`28% 32% 17% 14% 11% 9% 2%
`
`10% 5% 16% 14% 13% 10% 7%
`
`8% 5% 15% 15% 13% 12% 7%
`
`5% 4% 14% 12% 8%
`
`8% 2%
`
`3% 2% 12% 8% 8%
`
`5% 0%
`
`5% 3% 12% 7% 7%
`
`7% 3%
`
`8% 4% 18% 15% 13% 10% 5%
`
`Dry eye
`Visual
`disturbance or
`vision blurred
`Eye pruritis
`Ocular
`hyperemia
`Retinal disorder 2% 2% 10% 7% 8%
`Maculopathy
`5% 7% 9% 9% 6%
`Retinal
`degeneration
`Ocular
`discomfort
`Conjunctival
`hyperemia
`Posterior
`capsule
`opacification
`
`4% 4% 12% 11% 9%
`
`9% 9% 11% 8% 7%
`
`1% 0% 8% 6% 5%
`
`2% 1% 7% 4% 5%
`
`1% 2% 7% 6% 5%
`
`4% 3% 7% 4% 2%
`
`2%
`
`5%
`
`6%
`
`3%
`
`1%
`
`3%
`
`3%
`
`2%
`
`3%
`
`1%
`
`7%
`
`0%
`
`7% 1%
`
`4% 5%
`
`4% 2%
`
`6% 11%
`
`3% 1%
`
`2% 2%
`
`2%
`
`4% 0%
`
`0%
`
`2% 0%
`
`1%
`
`Novartis Exhibit 2213.012
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`
`Injection site|jo, 2%|3% 1% 10%9% 15% 0%
`
`
`
`
`
`hemorrhage
`
`Non-Ocular Reactions
`Non-ocular adverse reactions with an incidence of 2 5% in patients recetving LUCENTISfor
`DR, DME, AMD,and/or RVO and which occurred at a 2 1% higher frequencyin patients
`treated with LUCENTIS comparedto control are shown in Table 2. Though less common,
`woundhealing complications were also observed in somestudies.
`
`Table 2
`Non-Ocular Reactions in the DME and DR, AMD,and RVOStudies
`
`LUCENTIS
`
`LUCENTIS
`
`LUCENTIS
`
`LUCENTIS
`
`a
`
`
`5
`a
`a
`aa
`a
`of
`od
`of
`of
`of
`
`12% 6%|16% 13%} 8% 9% 5% 4%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8% T%|4% 3% 1% 1%
`
`
`
`9%
`
`9%
`
`6%
`
`8%
`
`5%
`
`5%
`
`5%
`
`4%
`
`1%
`
`1%
`
`2%
`
`2%
`
`%
`
`
`
`
`
`8% 4%|5% TM%|3% 4%|0% 1%
`
`
`
`
`
`}Seasonalallergy|8% 4%|4% 4%|2% 2%|0% 2%
`
`
`
`
`
`3
`5%
`5%
`5%
`3%
`2%
`1%
`1%
`|lesterolemi
`luenza
`Inf
`
`T%
`
`3%
`
`T%
`
`5%
`
`3%
`
`2%
`
`3%
`
`2%
`
`
`
`
`
`
`
`
`
`me 1%|0% 0%|0%1% 0%
`
`2 89= 5%|2%5% 2%
`
`
`
`3a
`
`Upper respiratory
`1%
`tract infection
`
`
`
`Gastroesophageal
`
`0%
`
`1%
`
`6% 3%|2% 3%|0%4% 3% 1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`) 2%|0% 1%|0% 0%|0% 0%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5% 0%|0%3% 1% 1% 1% 0%
`
`
`
`
`
`5%
`
`8%
`
`8%
`
`™%
`
`5%
`
`5%
`
`3%
`
`2%
`
`4% 4%|11% 5%|0%M% 6% 2%
`
`
`
`
`
`
`
`3% 3%|S% 4%|2% 2% 1% 0%
`
`
`
`
`
`
`
`
`
`
`
`
`
`we2 3%|11% 9% 5% 5% 2%
`
`
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.013
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`
`
`
`
`4%
`
`12%
`
`6%
`
`9%
`
`3%
`
`6%
`
`4%
`
`5%
`
`i}es
`
`3%
`
`3%
`
`Novartis Exhibit 2213.013
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`

`BLA 125156/S-111
`Page 17
`
`Chronic obstructive
`pulmonary disease
`
`Wound healing
`complications
`
`1%
`
`1%
`
`6%
`
`3%
`
`3%
`
`1%
`
`0%
`
`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%-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 reaction has been identified during post-approval use of LUCENTIS.
`Because this reaction was reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate the 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.
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Risk Summary
`There are no adequate and well-controlled studies of LUCENTIS administration in pregnant
`women.
`
`Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis
`resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted
`human exposure (based on maximal serum trough levels [Cmax]) after a single eye treatment at
`the recommended clinical dose. No skeletal abnormalities were observed at serum trough levels
`
`Reference ID: 4037547
`
`Novartis Exhibit 2213.014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 125156/S-111
`Page 18
`
`equivalent to the predicted human exposure after a single eye treatment at the recommended
`clinical dose [see Animal Data].
`
`Animal reproduction studies are not always predictive of human response, and it is not known
`whether ranibizumab can cause fetal harm when administered to a pregnant woman. Based on
`the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1)],
`treatment with LUCENTIS may pose a risk to human embryofetal development.
`
`LUCENTIS should be given to a pregnant woman only if clearly needed.
`
`Data
`Animal Data
`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.
`
`8.2 Lactation
`Risk Summary
`There are no data available on the presence of ranibizumab in human milk, the effects of
`ranibizumab on the breastfed infant or the effects of ranibizumab on milk production/excretion.
`
`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.
`
`The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for LUCENTIS and any potential adverse effects on the breastfed chil