BLA 125156/S-117
`
`4
`
`Myopic Choroidal Neovascularization (mCNV) (2.5):
`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)
`-
`6 mg/mL solution (LUCENTIS 0.3 mg) (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) for intravitreal injection
`Initial U.S. Approval: 2006
`--------------------------RECENT MAJOR CHANGES-----------------------­
`Indications and Usage, Diabetic Retinopathy (1.4)
`04/2017
`Dosage and Administration (2)
`03/2018
`Dosage Forms and Strengths (3)
`03/2018
`--------------------------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 (DR) (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.
` Macular Edema Following Retinal Vein Occlusion (RVO) (2.3):
`
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`
`intravitreal injection once a month (approximately 28 days).
`
` Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) (2.4):
`
`LUCENTIS 0.3 mg (0.05 mL) is recommended to be administered by
`
`intravitreal injection once a month (approximately 28 days).
`
`
`-
`
` Single-use glass vial designed to provide 0.05 mL for intravitreal injections:
`-
`10 mg/mL solution (LUCENTIS 0.5 mg) (3)
`-
`6 mg/mL solution (LUCENTIS 0.3 mg) (3)
`------------------------------CONTRAINDICATIONS-------------------­
` Ocular or periocular infections (4.1)
` Hypersensitivity (4.2)
`-----------------------WARNINGS AND PRECAUTIONS-------------­
` Endophthalmitis and retinal detachments may occur following intravitreal
`injections. Patients should be monitored following the injection (5.1).
` Increases in intraocular pressure (IOP) have been noted both pre- and
`post-intravitreal injection (5.2).
` There is a potential risk of arterial thromboembolic events following
`intravitreal use of VEGF inhibitors (5.3).
` Fatal events occurred more frequently in patients with DME and DR at
`baseline, who were treated monthly with LUCENTIS compared with
`control (5.4).
`------------------------------ADVERSE REACTIONS--------------------­
` The most common adverse reactions (reported more frequently in
`
`LUCENTIS-treated subjects than control subjects) are conjunctival
`hemorrhage, eye pain, vitreous floaters, and increased IOP (6.2).
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION.
`Revised: 03/2018
`_____________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`6.2 Clinical Studies Experience
`1
`INDICATIONS AND USAGE
`Immunogenicity
`6.3
`1.1 Neovascular (Wet) Age-Related Macular Degeneration
`6.4
`Postmarketing Experience
`7 DRUG INTERACTIONS
`(AMD)
`8 USE IN SPECIFIC POPULATIONS
`1.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`Pregnancy
`8.1
`1.3 Diabetic Macular Edema (DME)
`8.2
`Lactation
`1.4 Diabetic Retinopathy (DR)
`8.3
`Females and Males of Reproductive Potential
`1.5 Myopic Choroidal Neovascularization (mCNV)
`8.4
`Pediatric Use
`2 DOSAGE AND ADMINISTRATION
`8.5 Geriatric Use
`10 OVERDOSAGE
`2.1 General Dosing Information
`11 DESCRIPTION
`2.2 Neovascular (Wet) Age-Related Macular Degeneration
`12 CLINICAL PHARMACOLOGY
`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion
`12.1 Mechanism of Action
`(RVO)
`12.2 Pharmacodynamics
`2.4 Diabetic Macular Edema (DME) and Diabetic
`
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`Retinopathy (DR)
`
`2.5 Myopic Choroidal Neovascularization (mCNV)
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`Preparation for Administration
`2.6
`2.7 Administration
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`
`3 DOSAGE FORMS AND STRENGTHS
`(AMD)
`
`4 CONTRAINDICATIONS
`14.2 Macular Edema Following Retinal Vein Occlusion
`
`4.1 Ocular or Periocular Infections
`(RVO)
`
`4.2 Hypersensitivity
`14.3 Diabetic Macular Edema (DME)
`5 WARNINGS AND PRECAUTIONS
`14.4 Diabetic Retinopathy (DR)
`Endophthalmitis and Retinal Detachments
`5.1
`14.5 Myopic Choroidal Neovascularization (mCNV)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`5.2
`Increases in Intraocular Pressure
`17 PATIENT COUNSELING INFORMATION
`5.3
`Thromboembolic Events
`5.4
`Fatal Events in Patients with DME and DR at Baseline
`* Sections or subsections omitted from the Full Prescribing Information are
`6 ADVERSE REACTIONS
`not listed.
`Injection Procedure
`6.1
`
`Reference ID: 4235732
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`5
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`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 (DR)
`1.5 Myopic Choroidal Neovascularization (mCNV)
`2
`DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`FOR OPHTHALMIC INTRAVITREAL INJECTION.
`
`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 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 9 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 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 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) and Diabetic Retinopathy (DR)
`LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection
`once a month (approximately 28 days).
`2.5 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 3 months. Patients may be retreated if
`needed [(see Clinical Studies 14.5)].
`
`Reference ID: 4235732
`
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`2.6
`
`Preparation for Administration
`
`6
`
`Prefilled Syringe:
` The prefilled syringe is sterile and is for single use only. Do not use the
`
`
`
` product if the packaging is damaged or has been tampered with.
`To prepare LUCENTIS for intravitreal administration, please adhere to
`
` these instructions for use. Read all the instructions carefully before using
`the prefilled syringe.
` 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
`
`LUCENTIS prefilled syringes are available in 2 dose strengths:
`
` LUCENTIS 0.5 mg prefilled syringe with a CLEAR finger
`
`
`grip.
`
`
`
`
`
`  LUCENTIS 0.3 mg prefilled syringe with an ORANGE finger
`grip.
`
` Check the labels on the LUCENTIS carton, syringe tray and
`
`
` prefilled syringe to make sure you have the correct dose strength.
`
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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
`
` Attach a 30G x ½ inch sterile
`injection needle firmly onto
`
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`
`8
`
`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.
`Insert the needle into the injection site.
`
`
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`
`9
`
`
`
`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.
`
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`10
`
`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 included):
`1.
` 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 aseptic
`3.
`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.
`
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`11
`
`
`6.
`
`Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely
`empty the filter needle.
`
`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.
`
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`
`12
`
`
`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.
`
`Administration
`2.7
`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.
`No special dosage modification is required for any of the populations that have been studied (e.g., gender,
`elderly).
`3
`DOSAGE FORMS AND STRENGTHS
`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injection.
` Colorless to pale yellow 10 mg/mL solution ( LUCENTIS 0.5 mg)
` Colorless to pale yellow 6 mg/mL solution ( LUCENTIS 0.3 mg)
`Single-use glass vial designed to provide 0.05 mL for intravitreal injection.
` Colorless to pale yellow 10 mg/mL solution (LUCENTIS 0.5 mg)
` Colorless to pale yellow 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.
`
`Reference ID: 4235732
`
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`BLA 125156/S-117
`
`13
`
`
`WARNINGS AND PRECAUTIONS
`5
`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 (2.6, 2.7) and Patient Counseling Information (17)].
`5.2
`Increases in Intraocular Pressure
`Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60 minutes) while
`being treated with LUCENTIS. Monitor intraocular pressure prior to and following intravitreal injection with
`LUCENTIS and manage appropriately [see Dosage and Administration (2.7)].
`5.3
`Thromboembolic Events
`Although there was a low rate of arterial thromboembolic events (ATEs) observed in the LUCENTIS clinical
`trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. Arterial thromboembolic
`events are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of
`unknown cause).
`Neovascular (Wet) Age-Related Macular Degeneration
`
`The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3) during the first year
`was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared
`with 1.1% (5 of 441) in patients from the control arms [see Clinical Studies (14.1)]. In the second year of
`
`Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated
`patients compared with 2.9% (10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates
`observed in the 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1,
`AMD-2, and AMD-3.
`
`In a pooled analysis of 2-year controlled studies [AMD-1, AMD-2, and a study of LUCENTIS used
`adjunctively with verteporfin photodynamic therapy (PDT)], 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.
`Fatal Events in Patients with Diabetic Macular Edema and Diabetic Retinopathy at Baseline
`5.4
`Diabetic Macular Edema and Diabetic Retinopathy
`
`Reference ID: 4235732
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`BLA 125156/S-117
`
`14
`
`
`
`
` 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.
`ADVERSE REACTIONS
`6
`
`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)]
`
`
`
`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.
`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 224 patients with mCNV, as well as Studies AMD-4 and D-3, 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: 4235732
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`BLA 125156/S-117
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`15
`
`Table 1
`Ocular Reactions in the DME and DR, AMD, and RVO Studies
`
`DME
`and DR
`2-year
`
`AMD
`2-year
`
`AMD
`1-year
`
`RVO
`6-month
`
`Control
`
`0.5 mg
`
`LUCENTIS
`
`Control
`0.5 mg
`
`LUCENTIS
`
`Control
`0.5 mg
`
`LUCENTIS
`
`Control
`0.3 mg
`
`LUCENTIS
`
`n=250 n=250
`
`n=379 n=379
`
`n=440 n=441
`
`n=259 n=260
`
`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%
`
`28% 32% 17% 14% 11% 9%
`
`10% 5% 16% 14% 13% 10%
`
`8% 5% 15% 15% 13% 12%
`
`5% 4% 14% 12% 8%
`
`8%
`
`2%
`
`7%
`
`7%
`
`2%
`
`2%
`
`5%
`
`6%
`
`3%
`
`8%
`
`5%
`
`0%
`
`1%
`
`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
`
`3% 2% 12% 8%
`
`5% 3% 12% 7%
`
`7%
`
`7%
`
`8% 4% 18% 15% 13% 10%
`
`4% 4% 12% 11% 9%
`
`9% 9% 11% 8%
`
`Dry eye
`Visual
`disturbance or
`vision blurred
`Eye pruritis
`Ocular
`hyperemia
`Retinal disorder 2% 2% 10% 7%
`Maculopathy
`5% 7% 9% 9%
`Retinal
`degeneration
`Ocular
`discomfort
`Conjunctival
`hyperemia
`Posterior
`capsule
`opacification
`Injection site
`hemorrhage
`
`1% 0% 8% 6%
`
`2% 1% 7% 4%
`
`1% 2% 7% 6%
`
`4% 3% 7% 4%
`
`1% 0% 5% 2%
`
`Reference ID: 4235732
`
`3%
`
`5%
`
`1%
`
`5%
`
`2%
`
`11%
`
`1%
`
`3%
`
`3%
`
`2%
`
`3%
`
`1%
`
`7%
`
`0%
`
`7%
`
`4%
`
`4%
`
`6%
`
`3%
`
`7%
`
`8%
`
`6%
`
`5%
`
`5%
`
`2%
`
`2%
`
`2%
`
`5%
`
`4%
`
`0%
`
`0%
`
`2%
`
`2%
`
`0%
`
`1%
`
`3%
`
`1%
`
`0%
`
`0%
`
`Regeneron Exhibit 2033
`Page 12 of 28
`
`

`

`BLA 125156/S-117
`
`16
`
`
`Non-Ocular Reactions
`Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving LUCENTIS for DR, DME, AMD,
`
`and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with LUCENTIS compared to
`
`control are shown in Table 2. Though less common, wound healing complications were also observed in some
`
`studies.
`
`Table 2
`Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies
`
`DME
`and DR
`2-year
`
`AMD
`2-year
`
`AMD
`1-year
`
`RVO
`6-month
`
`Control
`
`0.5 mg
`
`LUCENTIS
`
`Control
`
`0.5 mg
`
`LUCENTIS
`
`Control
`
`0.5 mg
`
`LUCENTIS
`
`Control
`
`0.3 mg
`
`LUCENTIS
`
`Adverse Reaction
`
`n=250 n=250
`
`n=379 n=379
`
`n=440 n=441
`
`n=259 n=260
`
`Nasopharyngitis
`
`Anemia
`
`Nausea
`
`12%
`
`11%
`
`10%
`
`6%
`
`16%
`
`13%
`
`10%
`
`9%
`
`8%
`
`9%
`
`7%
`
`6%
`
`8%
`
`4%
`
`5%
`
`9%
`
`3%
`
`5%
`
`5%
`
`1%
`
`1%
`
`1%
`
`4%
`
`1%
`
`2%
`
`2%
`
`Cough
`
`Constipation
`
`Seasonal allergy
`
`Hypercholesterolemia
`
`Influenza
`
`Renal failure
`
`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%
`
`0%
`
`0%
`
`1%
`
`3%
`
`0%
`
`2%
`
`1%
`
`2%
`
`1%
`
`2%
`
`0%
`
`2%
`
` Upper respiratory
`
`tract infection
`
` Gastroesophageal
`
`reflux disease
`
`Headache
`
`Edema peripheral
`
`Renal failure chronic
`
`Neuropathy
`peripheral
`
`7%
`
`7%
`
`9%
`
`8%
`
`5%
`
`5%
`
`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%
`
`4%
`
`5%
`
`3%
`
`0%
`
`0%
`
`1%
`
`3%
`
`0%
`
`0%
`
`0%
`
`3%
`
`0%
`
`3%
`
`1%
`
`0%
`
`0%
`
`2%
`
`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%
`
`5%
`
`6%
`
`2%
`
`5%
`
`3%
`
`5%
`
`5%
`
`2%
`
`5%
`
`1%
`
`0%
`
`1%
`
`2%
`
`0%
`
`2%
`
`0%
`
`1%
`
`0%
`
`1%
`
`0%
`
`1%
`
`1%
`
`1%
`
`0%
`
`0%
`
`0%
`
`Reference ID: 4235732
`
`Regeneron Exhibit 2033
`Page 13 of 28
`
`

`

`BLA 125156/S-117
`
`17
`
`
`Immunogenicity
`6.3
`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.
`Postmarketing Experience
`6.4
`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
`7
`DRUG INTERACTIONS
`Drug interaction studies have not been conducted with LUCENTIS.
`LUCENTIS intravitreal injection has been used adjunctively with 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 PDT.
`8
`USE IN SPECIFIC POPULATIONS
`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 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
`
`Reference ID: 4235732
`
`Regeneron Exhibit 2033
`Page 14 of 28
`
`

`

`BLA 125156/S-117
`
`18
`
`
`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 child from ranibizumab.
`8.3
`Females and Males of Reproductive Potential
`Infertility
`
`No studies on the effects of ranibizumab on fertility have been conducted and it is not known whether
`
`ranibizumab can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab,
`
`treatment with LUCENTIS may pose a risk to reproductive capacity.
`
`8.4
`Pediatric Use
`The safety and effectiveness of LUCENTIS in pediatric patients have not been established.
`8.5 Geriatric Use
`In the clinical studies, approximately 76% (2449 of 3227) of patients randomized to treatment with LUCENTIS
`were ≥ 65 years of age and approximately 51% (1644 of 3227) were ≥ 75 years of age [see Clinical Studies
`(14)]. No notable differences in efficacy or safety were seen with increasing age in these studies. Age did not
`have a significant effect on systemic exposure.
`10
`OVERDOSAGE
`More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients. No
`additional unexpected adverse reactions were seen.
`11
`DESCRIPTION
`LUCENTIS (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody
`fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human
`vascular endothelial growth factor A (VEGF-A). Ranibizumab, which lacks an Fc region, has a molecular
`weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium
`containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.
`LUCENTIS is a sterile, colorless to pale yellow solution in a single-use prefilled syringe or a single-use glass
`vial. LUCENTIS is supplied as a preservative-free, steril