09-J1000-78
`
`Original Effective Date: 12/15/12
`
`Reviewed: 11/10/21
`
`Revised: 04/01/22
`
`Subject: Vascular Endothelial Growth Factor
`Inhibitors for Ocular Neovascularization
`
`THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A
`GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE
`SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT,
`MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE
`RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE
`PROGRAM EXCEPTIONS SECTION.
`
`Dosage/
`Administration
`
`Position Statement
`
`Billing/Coding
`
`Reimbursement
`
`Program Exceptions
`
`Definitions
`
`
`
`Related Guidelines
`
`Other
`
`References
`
`Updates
`
`
`
`DESCRIPTION:
`
`Uncorrectable vision impairment and blindness affect more than 4.2 million individuals in the United
`States older than the age of 40. Age-related macular degeneration (AMD), glaucoma, cataracts, and
`diabetic retinopathy are the most common eye disorders in the U.S. adult population. The number of
`people with AMD is estimated to reach 2.95 million in 2020. AMD is the leading cause of permanent
`impairment of reading and fine or close-up vision among people aged 65 years and older. Vascular
`endothelial growth factor (VEGF) has been implicated in the pathogenesis of a variety of ocular vascular
`conditions characterized by choroidal neovascularization (CNV) and macular edema. VEGF is a protein
`that stimulates the growth, proliferation, and survival of vascular endothelial cells. Several VEGF
`inhibitors for ocular use have been approved for the treatment of various eye diseases. Pegaptanib
`sodium (Macugen) is approved by the US Food and Drug Administration (FDA) for the treatment of
`patients with neovascular (wet) age-related macular degeneration (AMD) [September 2004].
`Ranibizumab (Lucentis) is approved for the treatment of patients with neovascular (wet) AMD [June
`2006], macular edema after retinal vein occlusion (RVO) [June 2010], diabetic macular edema (DME)
`[August 2012], diabetic retinopathy in patients with DME [February 2015], and myopic choroidal
`neovascularization (mCNV) [January 2017]. Aflibercept (Eylea) is approved for the treatment of patient
`with neovascular (Wet) AMD [November 2011], macular edema following central retinal vein occlusion
`(CRVO) [September 2012], DME [July 2014], and macular edema following RVO [October 2014, an
`expansion of CRVO indication]. Aflibercept (Eylea) was granted orphan designation by the FDA for the
`treatment of retinopathy of prematurity in July 2019. Brolucizumab (Beovu) is approved by the FDA for
`the treatment of patient with Neovascular (Wet) AMD [October 2019]. In October 2021, the FDA
`approved a more concentrated formulation of ranibizumab (brand name Susvimo) for use in an ocular
`
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`implant (the Susvimo implant) for the treatment of patients with neovascular (wet) AMD who have
`previously responded to at least two intravitreal injections of a VEGF inhibitor. Susvimo has a
`concentration of 100 mg/mL while Lucentis has a concentration of either 6 mg/mL or 10 mg/mL The
`initial fill and ocular implant insertion, and implant removal procedures (if medically necessary), must be
`performed in an operating room using aseptic technique by a physician experienced in vitreoretinal
`surgery. The refill-exchange procedures are done every 24 weeks (6 months) and must be done by a
`physician experienced in ophthalmic surgery. In a minority of patients (about 5%), supplemental
`treatment with Lucentis 0.5 mg injections may be necessary while the Susvimo implant is in place.
`Susvimo has a boxed warning for endophthalmitis because the implant has been associated with a 3-fold
`higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab.
`
`In April 2017 ranibizumab (Lucentis) became the first VEGF-inhibitor to be FDA-approved for the
`treatment of diabetic retinopathy (DR) in patients without diabetic macular edema (DME). The approval
`was based on a subgroup analysis of a secondary endpoint in the Diabetic Retinopathy Clinical Research
`Network’s (DRCR.net) Protocol S study in which ranibizumab was found to be non-inferior to panretinal
`photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR), including those with
`and without DME. Proliferative DR, as opposed to non-proliferative DR (NPDR), is defined by the
`presence of some degree of retinal neovascularization. The VEGF-inhibitors work by inhibiting
`angiogenesis and neovascularization. At year 2 among patients treated with ranibizumab, 31.7% (13/41)
`and 28.4% (42/148) of eyes in the subgroups with baseline DME and without baseline DME, respectively,
`had ≥3-step improvement from baseline in ETDRS-DRSS (Early Treatment Diabetic Retinopathy Study
`Diabetic Retinopathy Severity Score).
`
`In May 2019 aflibercept (Eylea) became the second VEGF-inhibitor to be FDA-approved for the
`treatment of diabetic retinopathy (DR) in patients without diabetic macular edema (DME). The approval
`was based on data derived from the VIVID and VISTA studies (patients with DME and DR) and the
`PANORAMA study. A major difference between the aflibercept and ranibizumab approvals is that
`aflibercept was evaluated in a randomized, multi-center, double-masked, controlled study specifically
`looking at patients with moderately-severe to severe nonproliferative diabetic retinopathy (NPDR)
`(ETDRS-DRSS of 47 or 53), without central-involved DME [i.e., PANORAMA trial]. A total of 402
`randomized patients were evaluable for efficacy. Patients were randomly assigned in a 1:1:1 ratio to 1 of
`3 dosing regimens: (1) 3 initial monthly aflibercept 2 mg injections followed by one injection after 8
`weeks and then one injection every 16 weeks (EYLEA 2Q16); (2) 5 monthly aflibercept 2 mg injections
`followed by one injection every 8 weeks (EYLEA 2Q8); and 3) sham treatment. The primary efficacy
`endpoint was the proportion of patients who improved by ≥2 steps on the DRSS from baseline to week
`24 in the combined aflibercept groups and at week 52 in the 2Q16 and 2Q8 groups individually vs. sham.
`A key secondary endpoint was the proportion of patients developing the composite endpoint of
`proliferative diabetic retinopathy or anterior segment neovascularization through week 52. Results are
`seen in Table 1 below.
`
`Table 1
`
`
`
`
`Week 24
`Eylea Combined
`(n=269)
`
`Control
`(n=133)
`
`Eylea 2Q16
`(n=135)
`
`Week 52
`Eylea 2Q8
`(n=134)
`
`Control
`(n=133)
`
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`Patients with a ≥2-step
`improvement on ETDRS-
`DRSS from Baseline
`Composite Endpoint of
`Developing PDR or ASNV
`
`Development of PDR
`
`58%
`
`6%
`
`65%
`
`80%
`
`15%
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`4%
`
`1.6%
`
`2.4%
`
`0%
`
`20.1%
`
`11.9%
`
`PDR = Proliferative Diabetic Retinopathy; ASNV = Anterior Segment Neovascularization
`
`A brief overview of covered products is provided in Table 2.
`
`Table 2
`
`Review of covered products
`
`Product
`
`Notes
`
`Aflibercept (Eylea)
`
` Humanized recombinant fusion protein
`
`Bevacizumab (Avastin)
`and bevacizumab
`biosimilars
`[bevacizumab-awwb
`(Mvasi) and
`bevacizumab-awwb
`(Zirabev)]
`
`Brolucizumab (Beovu)
`
`
`
`Inhibits VEGF-A and placental growth factor
`
` Recombinant humanized monoclonal antibody
`
` Works by binding to and inhibiting the biologic activity of VEGF to
`prevent interaction with receptors on the surface of endothelial cells
`
` Prevents cell proliferation and new blood vessel formation
`
` Produced in a Chinese hamster ovary mammalian cell expression
`system
`
` Recombinant humanized monoclonal single-chain Fv antibody
`fragment
`
` Binds to the three major isoforms of VEGF-A (e.g., VEGF110, VEGF121,
`and VEGF165)
`
` Suppresses endothelial cell proliferation, neovascularization, and
`vascular permeability
`
`Pegaptanib (Macugen)
`
` Pegylated modified oligonucleotide
`
` Selectively binds to extracellular VEGF-165, the major pathological
`VEGF isoform for wet AMD
`
`Ranibizumab (Lucentis)
`
` Recombinant humanized monoclonal antibody – a fragment derived
`from the same parent molecule as bevacizumab
`
` Binds to all active isoforms of VEGF
`
` Reduces endothelial cell proliferation, vascular leakage, and new
`blood vessel formation
`
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`POSITION STATEMENT:
`
`The initiation of aflibercept, bevacizumab (including biosimilars), brolucizumab, pegaptanib, or
`ranibizumab meets the definition of medical necessity for members meeting agent-specific criteria
`outlined in Table 3, AND none of these products are used concurrently in combination with each other
`in the same eye [with the exception of Susvimo and Lucentis, for which Lucentis may be used as periodic
`rescue therapy for breakthrough symptoms in patients receiving treatment with Susvimo], or used in
`combination with dexamethasone (Ozurdex) implant or fluocinolone acetonide (Iluvien, Retisert, Yutiq)
`implant in the same eye as continuous maintenance therapy [with the exception of bevacizumab or
`bevacizumab biosimilars which may be used as rescue therapy for rare members who are refractory to
`the implant]. For Iluvien only, aflibercept, bevacizumab (including biosimilars), brolucizumab,
`pegaptanib, or ranibizumab may be used as periodic rescue therapy for breakthrough symptoms.
`
`Table 3
`
`Criteria for use
`
`Product
`
`Aflibercept (Eylea)
`
`Bevacizumab (Avastin)
`and bevacizumab
`biosimilars
`[bevacizumab-awwb
`(Mvasi) and
`
`Criteria
`
`Use is a medical necessity for the following indications in members
`without ocular or periocular infections and dosage does not exceed 2 mg
`to each eye every 28 days (except retinopathy of prematurity which is a
`single dose only per eye):
`
`1. Neovascular (wet) age-related macular degeneration (ARMD/AMD)
`
`2. Macular edema following central retinal vein occlusion (CRVO)
`
`3. Macular edema following branch retinal vein occlusion (BRVO)
`
`4. Diabetic macular edema (DME)
`
`5. Diabetic retinopathy (DR) in members with DME
`
`6. Moderately-severe to severe non-proliferative diabetic retinopathy
`(NPDR) (with or without macular edema) – the member’s Early
`Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy
`Severity Scale score demonstrating at least moderately-severe disease
`(i.e., 47 or greater) must be provided
`
`7. Proliferative diabetic retinopathy (PDR) as defined by the presence of
`retinal neovascularization (with or without macular edema)
`
`8. Retinopathy of prematurity when first-line treatment with laser
`photocoagulation is not possible (e.g., opaque cornea or lens, poor
`pupillary dilation) and treatment is given as a single dose
`
`Use is a medical necessity for the below listed non-FDA labeled*
`indications in members without ocular or periocular infections:
`
`1. Neovascular (wet) age-related macular degeneration (ARMD/AMD)
`
`2. Macular edema following branch retinal vein occlusion (BRVO)
`
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`bevacizumab-awwb
`(Zirabev)]
`
`Brolucizumab (Beovu)
`
`Pegaptanib (Macugen)
`
`3. Macular edema following central retinal vein occlusion (CRVO)
`
`4. Diabetic macular edema (DME)
`
`5. Diabetic retinopathy (DR)
`
`6. Neovascularization of the iris (NVI) (rubeosis iridis)
`
`7. Polypoidal choroidal vasculopathy (PCV)
`
`8. Proliferative diabetic retinopathy (PDR) as defined by the presence of
`retinal neovascularization (with or without macular edema)
`
`9. Proliferative diabetic retinopathy requiring treatment with retinal
`laser photocoagulation or vitrectomy as a single preoperative dose
`
`10. Secondary angle-closure glaucoma resulting from neovascularization
`(i.e., neovascular glaucoma)
`
`11. Radiation retinopathy
`
`12. Retinopathy of prematurity when first-line treatment with laser
`photocoagulation is not possible (e.g., opaque cornea or lens, poor
`pupillary dilation) and treatment is given as a single dose
`
`13. Choroidal neovascularization secondary to ANY of the following:
`
`a. Pathologic myopia (i.e., myopic choroidal neovascularization)
`
`b. Ocular histoplasmosis syndrome (OHS)
`
`c. Angioid streaks/pseudoxanthoma elasticum
`
`*Physicians should provide appropriate informed consent with respect to
`the off-label use of bevacizumab.
`
`Use is a medical necessity for the following indication(s) in members
`without ocular or periocular infections and dosage does not exceed 6 mg
`to each eye every 4 weeks (28 days) for the first three doses, and then
`every 8 weeks (56 days) for subsequent doses:
`
`1. Neovascular (wet) age-related macular degeneration (ARMD/AMD)
`
`Use is a medical necessity for the following indications in members
`without ocular or periocular infections and dosage does not exceed 0.3
`mg to each eye every 6 weeks (45 days):
`
`1. Neovascular (wet) age-related macular degeneration (ARMD/AMD)
`
`2. Diabetic macular edema (DME)
`
`Ranibizumab (Lucentis)
`
`[6 mg/ml and 10 mg/mL
`solution]
`
`Use is a medical necessity for the following indications in members
`without ocular or periocular infections:
`
`1. Neovascular (wet) age-related macular degeneration (ARMD/AMD)
`and dosage does not exceed 0.5 mg to each eye every 28 days
`
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`2. Macular edema following branch retinal vein occlusion (BRVO) and
`dosage does not exceed 0.5 mg to each eye every 28 days
`
`3. Macular edema following central retinal vein occlusion (CRVO) and
`dosage does not exceed 0.5 mg every to each eye 28 days
`
`4. Diabetic macular edema (DME) and dosage does not exceed 0.3 mg to
`each eye every 28 days
`
`5. Diabetic retinopathy (DR) in members with DME and dosage does not
`exceed 0.3 mg to each eye every 28 days
`
`6. Proliferative diabetic retinopathy (PDR) as defined by the presence of
`retinal neovascularization (with or without macular edema) and
`dosage does not exceed 0.3 mg to each eye every 28 days
`
`7. Choroidal neovascularization secondary to ANY of the following and
`dosage does not exceed 0.5 mg to each eye every 28 days:
`
`a. Pathologic myopia (i.e., myopic choroidal neovascularization)
`
`b. Ocular histoplasmosis syndrome (OHS)
`
`c. Angioid streaks/pseudoxanthoma elasticum
`
`8. Retinopathy of prematurity when first-line treatment with laser
`photocoagulation is not possible (e.g., opaque cornea or lens, poor
`pupillary dilation) and treatment is given as a single dose that does
`not exceed 0.3 mg to each eye
`
`Ranibizumab for Ocular
`Implant (Susvimo)
`
`[100 mg/mL solution]
`
`Use is a medical necessity for the following indication(s) in members
`without ocular or periocular infections, without active intraocular
`inflammation, and dosage does not exceed 2 mg to each eye every 24
`weeks:
`
`1. Neovascular (wet) age-related macular degeneration (ARMD/AMD)
`AND the member has previously responded to at least TWO
`intravitreal injections of a VEGF inhibitor medication
`
`Approval duration: 1 year (except retinopathy of prematurity and pre-operative use for diabetic
`retinopathy requiring treatment with retinal laser photocoagulation or vitrectomy; for these indications
`only a single dose will be approved)
`
`Continuation of aflibercept, bevacizumab (including biosimilars), brolucizumab, pegaptanib, or
`ranibizumab meets the definition of medical necessity for members meeting all of the following criteria
`(“1” to “6”):
`
`1. An authorization or reauthorization has been previously approved by Florida Blue or another health
`plan in the past two years for an indication listed in Table 3 [except for the use of aflibercept or
`bevacizumab (including biosimilars) for retinopathy of prematurity or as a single preoperative dose –
`see initiation criteria], OR the member has previously met all indication-specific initiation criteria
`
`2. Member has had improvement or stabilization of visual function as compared to before treatment
`
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`3. The dosage does not exceed the drug- and indication-specific limit listed in Table 3
`
`4. Member is without ocular or periocular infections, and, for Susvimo only, member is without active
`intraocular inflammation
`
`5. None of the agents are used in combination with each other in the same eye [with the exception of
`Susvimo and Lucentis, for which Lucentis may be used as periodic rescue therapy for breakthrough
`symptoms in patients receiving treatment with Susvimo]
`
`6. Beovu, Eylea, Lucentis, Macugen, or Susvimo are not used as continuous maintenance therapy in
`combination with dexamethasone (Ozurdex) implant or fluocinolone acetonide (Iluvien, Retisert,
`Yutiq) implant in the same eye*
`
`*Beovu, Eylea, Lucentis, or Macugen may be used as periodic rescue therapy for breakthrough
`symptoms in patients receiving treatment with a fluocinolone acetonide (Iluvien) implant.
`
`Approval duration: 1 year
`
`DOSAGE/ADMINISTRATION:
`
`THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING
`PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING
`INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL
`DECISIONS REGARDING ITS USAGE.
`
`Dosage and administration vary considerably with each product. A brief overview of selected products is
`provided in Table 3, but it is strongly recommended the prescriber reference the product-specific
`labeling for complete dosing and administration instructions.
`
`Table 4
`
`Dosage and administration
`
`Product
`
`Dosing/Administration
`
`Aflibercept (Eylea)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
` 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks
`(monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05
`mL) via intravitreal injection once every 8 weeks (2 months)
`
` May be dosed as frequently as 2 mg every 4 weeks (monthly);
`however, additional efficacy was not demonstrated in most patients
`when dosed every 4 weeks compared to every 8 weeks. Some patients
`may need every 4 week (monthly) dosing after the first 12 weeks (3
`months). Although not as effective as the recommended every 8 week
`dosing regimen, patients may also be treated with one dose every 12
`weeks after one year of effective therapy. Patients should be assessed
`regularly.
`
`Macular Edema Following Retinal Vein Occlusion (RVO) – includes both
`central and branch RVO (CRVO and BRVO)
`
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` 2 mg (0.05 mL) administered by intravitreal injection once every 4
`weeks (monthly)
`
`Diabetic Macular Edema (DME) or Diabetic Retinopathy (DR)
`
` 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks
`(monthly) for the first five injections, followed by 2 mg (0.05 mL) via
`intravitreal injection once every 8 weeks (2 months)
`
` May be dosed as frequently as 2 mg every 4 weeks (monthly);
`however, additional efficacy was not demonstrated in most patients
`when dosed every 4 weeks compared to every 8 weeks. Some patients
`may need every 4 week (monthly) dosing after the first 20 weeks (5
`months).
`
`Off-label dosing recommendations
`
` 1.25 mg (0.05 mL) administered by intravitreal injection
`
`Bevacizumab (Avastin)
`and bevacizumab
`biosimilars
`[bevacizumab-awwb
`(Mvasi) and
`bevacizumab-awwb
`(Zirabev)]
`
`Brolucizumab (Beovu)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
` 6 mg (0.05 mL) administered by intravitreal injection monthly
`(approximately every 25 to 31 days) for the first three doses, followed
`by one dose of 6 mg (0.05 mL) every 8 to 12 weeks.
`
`Pegaptanib (Macugen)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
` 0.3 mg should be administered once every six weeks by intravitreous
`injection into the eye to be treated
`
`Ranibizumab (Lucentis) Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`
` 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 three monthly
`doses followed by less frequent dosing with regular assessment. In the
`nine months after three initial monthly doses, less frequent dosing
`with 4-5 doses on average is expected to maintain visual acuity while
`monthly dosing may be expected to result in an additional average 1-2
`letter gain. Patients should be assessed regularly
`
` Although not as effective, patients may also be treated with one dose
`every 3 months after 4 monthly doses. Compared to continued
`monthly dosing, dosing every 3 months over the next 9 months will
`lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on
`average. Patients should be assessed regularly
`
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`Macular Edema Following Retinal Vein Occlusion (RVO) – includes both
`central and branch RVO (CRVO and BRVO)
`
` 0.5 mg (0.05 mL of 10 mg/mL solution) administered by intravitreal
`injection once a month (approximately 28 days)
`
`Diabetic Macular Edema (DME) or Diabetic Retinopathy (DR)
`
` 0.3 mg (0.05 mL of 6 mg/mL solution) administered by intravitreal
`injection once a month (approximately 28 days)
`
`Myopic Choroidal Neovascularization (mCNV)
`
` 0.5 mg (0.05 mL of 10 mg/mL solution) administered by intravitreal
`injection once a month (approximately 28 days) for up to 3 months.
`May retreat if needed.
`
`Ranibizumab for Ocular
`Implant (Susvimo)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD) in patients
`who have previously responded to at least two intravitreal injections of
`a VEGF inhibitor medication
`
` 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the
`Susvimo ocular implant with refills administered every 24 weeks
`(approximately 6 months)
`
`o The initial fill and ocular implant insertion and implant
`removal procedures must be performed under aseptic
`conditions in an operating room by a physician experienced in
`vitreoretinal surgery
`
`o The refill-exchange procedures must be performed under
`aseptic conditions by a physician experienced in ophthalmic
`surgery
`
`
`
`Supplemental treatment with 0.5 mg (0.05 mL of 10 mg/mL)
`intravitreal ranibizumab injection (Lucentis) may be administered in
`the affected eye while the implant is in place and if clinically necessary
`
`PRECAUTIONS:
`Specific precautions and warnings are highlighted in Table 5.
`
`Table 5
`
`Precautions and warnings
`
`Product
`
`Precautions/Warnings
`
`Aflibercept (Eylea)
`
`Contraindications
`
` Ocular or periocular infection
`
` Active intraocular inflammation
`
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` Hypersensitivity to aflibercept or any of the excipients. Hypersensitivity
`reactions may manifest as rash, pruritus, urticaria, severe
`anaphylactic/anaphylactoid reactions, or severe intraocular
`inflammation.
`
`Precautions/Warnings
`
` Endophthalmitis and Retinal Detachments - Intravitreal injections,
`including those with aflibercept, have been associated with
`endophthalmitis and retinal detachments. Proper aseptic injection
`technique must always be used when administering. Patients should be
`instructed to report any symptoms suggestive of endophthalmitis or
`retinal detachment without delay and should be managed
`appropriately.
`
`
`
`Increases in Intraocular Pressure - Increases in intraocular pressure
`have been seen within 60 minutes of an intravitreal injection.
`Sustained increases in intraocular pressure have also been reported
`after repeated intravitreal dosing with vascular endothelial growth
`factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the
`optic nerve head should be monitored and managed appropriately.
`
` Thromboembolic Events - There is a potential risk of arterial
`thromboembolic events following intravitreal use of VEGF inhibitors.
`
`Brolucizumab (Beovu)
`
`Contraindications
`
` Ocular or periocular infections
`
` Active intraocular inflammation
`
` Hypersensitivity to brolucizumab or any other excipient in this product
`
`Precautions/Warnings
`
` Endophthalmitis and Retinal Detachments - Intravitreous injections,
`including those with brolucizumab, have been associated with
`endophthalmitis and retinal detachments. Proper aseptic injection
`technique must always be used when administering. Patients should be
`instructed to report any symptoms suggestive of endophthalmitis or
`retinal detachment without delay and should be managed
`appropriately.
`
` Retinal Vasculitis and/or Retinal Vascular Occlusion - Retinal vasculitis
`and/or retinal vascular occlusion, typically in the presence of
`intraocular inflammation, have been reported with the use. Patients
`should be instructed to report any change in vision without delay.
`
`
`
`Increase in Intraocular Pressure - Acute increases in intraocular
`pressure (IOP) have been seen within 30 minutes of an intravitreal
`injection. Sustained IOP increases have also been reported. Both IOP
`and perfusion of the optic nerve head must be monitored and
`managed appropriately.
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` Thromboembolic Events - Although there was a low rate of arterial
`thromboembolic events (ATEs) observed in the brolucizumab 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). The ATE rate in the two controlled 96-week
`neovascular AMD studies (HAWK and HARRIER) during the first 96-
`weeks was 4.5% (33 of 730) in the pooled brolucizumab arms
`compared with 4.7% (34 of 729) in the pooled aflibercept arms.
`
`Pegaptanib (Macugen)
`
`Contraindications
`
` Ocular or periocular infection
`
` Hypersensitivity to pegaptanib sodium or any other excipient in this
`product
`
`Precautions/Warnings
`
` Endophthalmitis - Intravitreous injections, including those with
`pegaptanib, have been associated with endophthalmitis. Proper
`aseptic injection technique should always be utilized when
`administering. In addition, patients should be monitored during the
`week following the injection to permit early treatment, should an
`infection occur.
`
`
`
`Increases in Intraocular Pressure - Increases in intraocular pressure
`have been seen within 30 minutes of an intravitreal injection.
`Therefore, intraocular pressure as well as the perfusion of the optic
`nerve head should be monitored and managed appropriately.
`
` Anaphylaxis - Rare cases of anaphylaxis/anaphylactoid reactions,
`including angioedema, have been reported in the postmarketing
`experience following the pegaptanib intravitreal administration
`procedure.
`
`Ranibizumab (Lucentis) Contraindications
`
` Ocular or periocular infection
`
` Hypersensitivity to ranibizumab or any of the excipients.
`Hypersensitivity reactions may manifest as severe intraocular
`inflammation.
`
`Precautions/Warnings
`
` Endophthalmitis and Retinal Detachments - Intravitreal injections,
`including those with ranibizumab, have been associated with
`endophthalmitis and retinal detachments. Proper aseptic injection
`technique should always be used when administering. In addition,
`patients should be monitored following the injection to permit early
`treatment should an infection occur.
`
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`
`
`Increases in Intraocular Pressure - Increases in intraocular pressure
`have been noted both pre-injection and post-injection (at 60 minutes)
`while being treated. Monitor intraocular pressure prior to and
`following intravitreal injection and manage appropriately.
`
` Thromboembolic Events - Although there was a low rate of arterial
`thromboembolic events (ATEs) observed in the 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).
`
` Fatal Events in Patients with Diabetic Macular Edema and Diabetic
`Retinopathy at Baseline - Fatal events occurred more frequently in
`patients with DME and DR at baseline, who were treated monthly with
`ranibizumab as compared with control. 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.
`
`Ranibizumab for Ocular
`Implant (Susvimo)
`
`Boxed Warning:
`
`WARNING: ENDOPHTHALMITIS
`
` The Susvimo implant has been associated with a 3-fold higher rate of
`endophthalmitis than monthly intravitreal injections of ranibizumab.
`Many of these events were associated with conjunctival retractions or
`erosions. Appropriate conjunctiva management and early detection
`with surgical repair of conjunctival retractions or erosions may reduce
`the risk of endophthalmitis. In clinical trials, 2% of patients receiving a
`ranibizumab implant experienced at least one episode of
`endophthalmitis.
`
`Contraindications
`
` Ocular or periocular infection
`
` Hypersensitivity to ranibizumab products or any of the excipients in
`Susvimo
`
` Active intraocular inflammation
`
`Precautions/Warnings
`
` Endophthalmitis – see boxed warning
`
` Rhegmatogenous Retinal Detachment - Rhegmatogenous retinal
`detachments have occurred in clinical trials and may result in vision
`loss. Rhegmatogenous retinal detachments should be promptly treated
`with an intervention (e.g., pneumatic retinopexy, vitrectomy, or laser
`photocoagulation). Refill-exchanges should be delayed in the presence
`of a retinal detachment or retinal break. Careful evaluation of the
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`retinal periphery is recommended to be performed, and any suspected
`areas of abnormal vitreo-retinal adhesion or retinal breaks should be
`treated before inserting the implant in the eye.
`
`
`
`Implant Dislocation - In clinical trials, the device has
`dislocated/subluxated into the vitreous cavity or has extended outside
`the vitreous cavity into or beyond the subconjunctival space. Device
`dislocation requires urgent surgical intervention. Strict adherence to
`the scleral incision length and appropriate targeting of the pars plana
`during laser ablation may reduce the risk of implant dislocation.
`
` Vitreous Hemorrhage - Vitreous hemorrhages may result in temporary
`vision loss. Vitrectomy may be needed in the case of a non-clearing
`vitreous hemorrhage. In clinical trials, including extension phases,
`vitreous hemorrhages were reported in 5.2% (23/443) of patients. The
`majority of these hemorrhages occurred within the first post-operative
`month following surgical implantation and the majority of vitreous
`hemorrhages resolved spontaneously. Patients on antithrombotic
`medication (e.g., oral anticoagulants, aspirin, nonsteroidal anti-
`inflammatory drugs) may be at increased risk of vitreous hemorrhage.
`Antithrombotic medications are recommended to be temporarily
`interrupted prior to the implant insertion procedure. Refill-exchanges
`should be delayed in the event of sight-threatening vitreous
`hemorrhage. The use of pars plana laser ablation and scleral
`cauterization should be performed to reduce the risk of vitreous
`hemorrhage.
`
` Conjunctival Erosion or Retraction - Conjunctival erosion is a full
`thickness degradation or breakdown of the conjunctiva in the area of
`the implant flange. A conjunctival retraction is a recession or opening
`of the limbal and/or radial peritomy. Conjunctival erosions or
`retractions have been associated with an increased risk of
`endophthalmitis, especially if the implant becomes exposed. Surgical
`intervention (e.g., conjunctival/Tenon’s capsule repair) is
`recommended to be performed in case of conjunctival erosion or
`retraction with or without exposure of the implant flange. In clinical
`trials, including extension phases, 3.6% (16/443) of patients reported
`conjunctival erosion and 1.6% (7/443) of patients reported conjunctival
`retraction in the study eye. Appropriate intraoperative handling of
`conjunctiva and Tenon’s capsule to preserve tissue integrity and secure
`closure of peritomy while ensuring placement of sutures away from
`im