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`
`Mylan v. Regeneron
`IPR2021-00881
`U.S. Pat. 9,254,338
`
`Exhibit 2213
`
`Exhibit 2213
`Page 01 of 07
`
`

`

`STN BL 125156/053
`
`
`Page 6
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`
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`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`INDICATIONS AND USAGE
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`LUCENTISis indicated for the treatment ofpatients with:
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`1.1
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`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`1.2
`2
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`Macular Edema Following Retinal Vein Occlusion (RVO)
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`DOSAGE AND ADMINISTRATION
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`2.1
`General Dosing Information
`
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`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
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`2.2
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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`LUCENTIS0.5 mg (0.05 mL) is recommendedto be administered by
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`intravitreal injection once a month (approximately 28 days).
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`Althoughless effective, treatment may be reduced to one injection every
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`three monthsafter the first four injections if monthly injections are not
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`feasible. Compared to continued monthly dosing, dosing every 3 months
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`will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on
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`average, overthe following 9 months. Patients should be treated regularly
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`[see Clinical Studies (14.2)].
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`2.3
`Macular Edema Following Retinal Vein Occlusion (RVO)
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`LUCENTIS0.5 mg (0.05 mL) is recommendedto be administered by
`
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`intravitreal injection once a month (approximately 28 days).
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`In Studies RVO-1 and RVO-2,patients received monthly injections of
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`LUCENTISforsix months.
`In spite of being guided by optical coherence
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`tomographyand visual acuity re-treatmentcriteria, patients who were then
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`not treated at Month 6 experienced on average, a loss of visual acuity at
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`Month 7, whereas patients who were treated at Month 6 did not. Patients
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`should be treated monthly [see Clinical Studies (14. 2)].
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`.
`2.4
`Preparation for Administration
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`Using aseptic technique,all (0.2 mL) of the LUCENTISvial contents are
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`withdrawn through a 5-micron, 19-gaugefilter needle attached to a l-cc
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`tuberculin syringe. Thefilter needle should be discarded after withdrawal of
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`the vial contents and should not be used for intravitreal injection. Thefilter
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`needle should be replaced with a sterile 30-gauge x 1/2-inch needle for the
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`intravitreal injection. The contents should be expelled until the plungertip is
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`aligned with the line that marks 0.05 mL on the syringe.
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`4
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`CONTRAINDICATIONS
`
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`4.1
`Ocular or Periocular Infections
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`LUCENTISis contraindicated in patients with ocular or periocular
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`infections.
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`4.2
`Hypersensitivity
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`LUCENTISis contraindicated in patients with known hypersensitivity. to
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`ranibizumabor any ofthe excipients in LUCENTIS. Hypersensitivity
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`reactions may manifest as.severe intraocular inflammation.
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`WARNINGS AND PRECAUTIONS
`5
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`5.1
`Endophthalmitis and Retinal Detachments
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`Intravitreal injections, including those with LUCENTIS, have been
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`associated with endophthalmitis and retinal detachments. Proper aseptic
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`injection technique should always be used when administering LUCENTIS.
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`In addition, patients should be monitored during the week following the
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`injection to permit early treatment should an infection occur [see Dosage
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`and Administration (2.4, 2.5) and Patient Counseling Information (17)].
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`5.2
`Increases in Intraocular Pressure
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`Increasesin intraocular pressure have been noted within 60 minutes of
`
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`intravitreal injection with LUCENTIS. Therefore, intraocular pressure as
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`well as the perfusion ofthe optic nerve head should be monitored and
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`managed appropriately [see Dosage and Administration (2.5)].
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`5.3
`Thromboembolic Events
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`Althoughthere was a lowrate of arterial thromboembolic events (ATEs)
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`observed in the LUCENTISclinicaltrials, there is ‘a potential risk of ATEs
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`followingintravitreal use of VEGFinhibitors. ATEsare defined as nonfatal
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`stroke, nonfatal myocardial infarction, or vascular death (including deaths of
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`unknown cause).
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`Neovascular (Wet) Age-Related Macular Degeneration
`
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`The ATErate in the three controlled neovascular AMDstudies during the
`
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`first year was 1.9% (17 out of 874) in the combined groupofpatients treated
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`with 0,3 mg or 0.5 mg LUCENTIS compared with 1.1% (5 out of 441) in
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`patients from the control arms[see Clinical Studies (14. 1)]. In the second
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`year of studies AMD-1 and AMD-2,the ATE rate was 2.6% (19 out of 721)
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`in the combined group of LUCENTIS-treated patients compared with 2.9%
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`(10 out of 344) in patients from the control arms.
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`In a pooledanalysis of 2-year controlled studies (AMD-1, AMD-2 and a
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`study of LUCENTISused adjunctively with verteporfin photodynamic
`
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`2.5
`Administration
`therapy), the stroke rate (including both ischemic and hemorrhagic stroke)
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`was 2.7% (13 out of 484) in patients treated with 0.5 mg LUCENTIS
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`The intravitreal injection procedure should be carried out under controlled
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`compared to 1.1% (5 out of 435)in patients in the control arms (oddsratio
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`aseptic conditions, which include the useofsterile gloves, a sterile drape,
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`2.2 (95% confidenceinterval (0.8-7.1))).
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`andasterile eyelid speculum (or equivalent). Adequate anesthesia and a
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`broad-spectrum microbicide should be givenpriorto the injection.
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`Following the intravitreal injection, patients should be monitored for
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`elevation in intraocular pressure and for endophthalmitis. Monitoring may
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`consist of a check for perfusion of the optic nerve head immediately after the
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`injection and tonometry within 30 minutes following the injection. Patients
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`should be instructed to report any symptoms suggestive of endophthalmitis
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`without delay.
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`Each vial should only be used for the treatment of a single eye. Ifthe
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`contralateral eye requires treatment, a new vial should be used and thesterile
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`field, syringe, gloves, drapes, eyelid speculum,filter, and injection needles
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`should be changed before LUCENTIS is administered to the othereye.
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`Nospecial dosage modification is required for any of the populations that
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`have been studied (e.g., gender, elderly).
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`DOSAGE FORMS AND STRENGTHS
`3
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`Single-use glass vial designed to provide 0.05 mL of-10 mg/mLsolution for
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`intravitreal injection.
`
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`
`Exhibit 2213
`
`Page 02 of 07
`
`Macular Edema Following Retinal Vein Occlusion
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`The ATErate in the two controlled RVO studies during the first six months
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`was 0.8% in both the LUCENTIS and control armsofthe studies (4 out of
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`525 in the combined group ofpatients treated with 0.3 mg or 0.5 mg
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`LUCENTISand2.out of 260 in the control arms) [see Clinical Studies
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`(14.2)]. The stroke rate was 0.2% (1 out of 525) in the combined group of
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`LUCENTIS-treated patients compared to 0.4% (1 out of 260) in the control
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`arms.
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`6
`ADVERSE REACTIONS
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`Becauseclinical trials are conducted under widely varying conditions,
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`adverse reaction rates observed in one clinicaltrial of a drug cannot be
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`directly compared with rates in the clinicaltrials of the same or another drug
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`and may notreflect the rates observed in practice.
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`6.1
`Injection Procedure
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`Serious adverse reactionsrelated to the injection procedure have occurred in
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`<0.1% ofintravitreal injections, including endophthalmitis [see Warnings
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`Exhibit 2213
`Page 02 of 07
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`

`

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`The data belowreflect exposure to 0.5 mg LUCENTISin 440 patients with
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`neovascular AMDin three double-masked, controlled studies (AMD-1,
`RVO 6-month
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`AMD-2, and AMD-3)[see Clinical Studies (14.1)] as well as exposure to 0.5
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`mg LUCENTISin 259patients with macular edema following RVO.in two
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`double-masked, controlled studies (RVO-1 and RVO-2)[see Clinical Studies
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`a
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`=
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`Adverse Reaction
`Z
`q
`G
`&
`(14.2)].
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`o
`2
`Y
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`.
`Ocular Reactions
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`=
`~
`a
`=
`a
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`Table 1 shows frequently reported ocular adverse reactions in LUCENTIS
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`treated patients compared with the control group.
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`Nasopharyngitis
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`9%
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`Headache
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`Arthralgia
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`Bronchitis
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`Urinary tract infection
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`Cough
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`Nausea
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`Upperrespiratory
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`tract infection
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`Sinusitis
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`Anemia
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`Influenza
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`Chronic obstructive
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`pulmonary disease
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`Hypercholesterotemia
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`Pain in extremity
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`Atrial fibrillation
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`Anxiety
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`Dyspnea
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`Gastroenteritis viral
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`Table |
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`Ocular Reactions in AMD and RVOStudies
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`AMD2-year
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`13%
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`Immunogenicity
`6.3
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`As with all therapeutic proteins, there is the potential for an immune
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`responsein patients treated with LUCENTIS. The immunogenicity data
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`reflect the percentage of patients whosetest results were considered positive
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`for antibodies to LUCENTIS in immunoassays and are highly dependent on
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`the sensitivity and specificity of the assays.
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`The pre-treatment incidence of immunoreactivity to LUCENTIS was
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`0%-5% across treatment groups. After monthly dosing with LUCENTISfor
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`6 to 24 months, antibodies to LUCENTIS weredetected in approximately
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`1%-8% ofpatients.
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`The clinical significance of immunoreactivity to LUCENTISis unclearat
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`this time. Among neovascular AMDpatients with the highest levels of
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`immunoreactivity, some were notedto haveiritis or vitritis. Intraocular
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`inflammation was not observed in the RVO patients with the highestlevels
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`of immunoreactivity.
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`STN BL 125156/053
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`Page 7
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`and Precautions (5.1)], thegmatogenousretinal detachments, and iatrogenic
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`traumatic cataracts.
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`Non-Ocular Reactions
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`Table 2 shows frequently reported non-ocular adverse reactionsin
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`LUCENTIStreated patients compared with the control group.
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`6.2
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`Clinical Studies Experience
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`Table 2
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`Non-Ocular Reactions in AMD and RVOStudies
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`.
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`AMD2-year
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`a
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`3
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`oO
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`AMDl-year
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`a
`e
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`n=379|n=379|n=440 n=259
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`RVO 6-month
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`AMD1-year
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`LUCENTIS
`LUCENTIS
`LUCENTIS
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`Adverse Reaction
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`Intraocular pressure
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`increased
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`Vitreous detachment
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`Intraocular
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`inflammation
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`Cataract
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`Foreign body sensation
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`in eyes
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`Eye irritation
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`Lacrimation increased
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`Blepharitis
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`Visual disturbance
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`or vision blurred
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`Eye pruritis
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`Ocular hyperemia
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`Retinal disorder
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` Maculopathy
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`Retinal degeneration
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`Ocular discomfort
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` Conjunctival hyperemia
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`Posterior capsule
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`opacification
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`Injection site
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`hemorrhage
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`Conjunctival
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`hemorrhage
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`Exhibit 2213
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`Page 03 of 07
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`Exhibit 2213
`Page 03 of 07
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`

`

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`STN BL 125156/053
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`Page 8
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`7
`DRUG INTERACTIONS
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`Drug interaction studies have not been conducted with LUCENTIS.
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`LUCENTISintravitreal injection has been used adjunctively with verteporfin
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`photodynamic therapy (PDT). Twelve of 105 (11%) patients with
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`neovascular AMD developedserious intraocular inflammation; in 10 of the
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`12 patients, this occurred when LUCENTIS was administered 7 days
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`(+2 days) after verteporfin PDT.
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`USE IN SPECIFIC POPULATIONS
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`8
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`8.1
`Pregnancy
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`Pregnancy Category C. Animal reproductionstudies have not been
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`conducted with ranibizumab.
`It is also not known whether ranibizumab can
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`causefetal harm when administered to a pregnant woman orcan affect
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`reproduction capacity. LUCENTIS shouldbe given to a pregnant woman
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`only if clearly needed.
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`8.3
`Nursing Mothers
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`It is not known whether ranibizumab is excreted in human milk. Because
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`many drugs are excreted in human milk, and because the potential for
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`absorption and harm to infant growth and developmentexists, caution should
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`be exercised when LUCENTISis administered to a nursing woman.
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`8.4
`Pediatric Use
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`Thesafety and effectiveness of LUCENTISin pediatric patients has not been
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`established,
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`8.5
`Geriatric Use
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`In the clinical studies, approximately 82% (1146/1406) of the patients
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`randomized to treatment with LUCENTIS were 265 years of age and
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`approximately 55% (772/1406) were 275 years of age. No notable
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`differencesin efficacy or safety were seen with increasing age in these
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`studies. Age did not havea significant effect on systemic exposure in
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`population pharmacokinetic analyses after correcting for creatinine
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`clearance.
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`8.6
`Patients with Renal Impairment
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`Noformal studies have been conducted to examine the pharmacokinetics of
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`ranibizumab in patients with renal impairment.
`In population
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`pharmacokinetic analyses of patients, 54% (389/725) had renal impairment
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`(39% mild, 12% moderate, and 2% severe). The reduction in ranibizumab
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`- clearance in patients with renal impairmentis considered clinically
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`insignificant. Dose adjustmentis not expected to be needed for patients with
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`renal impairment.
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`8.7
`Patients with Hepatic Dysfunction
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`Noformal studies have been conducted to examine the pharmacokinetics of
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`ranibizumab in patients with hepatic impairment. Dose adjustmentis not
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`expected to be neededfor patients with hepatic dysfunction.
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`OVERDOSAGE
`10
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`Plannedinitial single doses of ranibizumabinjection 1 mg were associated
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`with clinically significant intraocular inflammation in 2 of 2 neovascular
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`AMDpatients injected. With an escalating regimen of doses beginning with
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`initial doses of ranibizumabinjection 0.3 mg, doses as high as 2 mg were
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`tolerated in 15 of 20 neovascular AMDpatients.
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`DESCRIPTION
`il
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`LUCENTIS®(ranibizumabinjection) is a recombinant humanized IgG1
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`kappa isotype monoclonal antibody fragment designed for intraocular use.
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`Ranibizumabbindsto and inhibits the biologic activity of human vascular
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`endothelial growth factor A (VEGF-A). Ranibizumab has-a molecular
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`weightof approximately 48 kilodaltons and is produced byan E.coli
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`expression system in a nutrient medium containing the antibiotic
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`tetracycline. Tetracycline is not detectable in the final product.
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`LUCENTISisa sterile, colortess to pale yellow solution in a single-use glass
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`vial. LUCENTISis supplied as a preservative-free, sterile solution in a
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`single-use glass. vial designedto deliver 0.05 mL of 10 mg/mL LUCENTIS
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`Exhibit 2213
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`Page 04 of 07
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`aqueoussolution with 10 mM histidine HCI, 10% o,a-trehalose dihydrate,
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`0.01% polysorbate 20, pH 5.5.
`;
`:
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`CLINICAL PHARMACOLOGY
`2
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`12.1 Mechanism of Action
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`Ranibizumabbinds to the receptor bindingsite of active forms of VEGF-A,
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`including the biologically active, cleaved form of this molecule, VEGF 110.
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`VEGE-A has been shown to cause neovascularization and leakage in models
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`of ocular angiogenesis and vascular occlusion, and is thought to contribute to
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`the progression of neovascular AMDand macular edemafollowing RVO.
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`The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A
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`with its receptors (VEGFR1 and VEGFR2) onthe surface of endothelial
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`cells, reducing endothelial cell proliferation, vascular leakage, and new
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`blood vessel formation.
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`12.2.
`Pharmacodynamics
`
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`Increased center point thickness (CPT)as assessed by optical coherence
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`tomography (OCT)is associated with neovascular AMD and macular edema
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`following RVO. Leakage from choroidal neovascularization (CNV)as
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`assessed by fluorescein angiographyis associated with neovascular AMD.
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`Neovascular (Wet) Age-Related Macular Degeneration
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`In Study AMD-3, CPT. was assessed by OCTin 118/184 patients. OCT
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`In
`measurements were collected at baseline, Months |, 2, 3, 5, 8, and 12.
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`patients treated with LUCENTIS, CPT decreased, on average, more than the
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`sham group from baseline through Month 12, CPT decreased by Month 1
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`and decreased further at Month 3, on average. CPT data did not provide
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`information useful in influencing treatment decisions [see Clinical
`
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`Studies (14.1)].
`
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`In patients treated with LUCENTIS,the area of vascular leakage, on
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`average, decreased by Month 3 as assessed by fluorescein angiography. The
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`area of vascular leakage for an individual patient was not correlated with
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`visual acuity.
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`Macular Edema Following Retinal Vein Occlusion
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`On average, CPT reductions were observed in Studies RVO-1 and RVO-2
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`beginning at Day 7 followingthe first LUCENTIS injection through Month
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`6. CPT was not evaluated as.a meansto guide treatment decisions[see
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`Clinical Studies (14.2)].
`
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`:
`.
`12.3.
`Pharmacokinetics
`
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`In animal studies, following intravitreal injection, ranibizumab was cleared
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`from the vitreous with a half-life of approximately 3 days. After reaching a
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`maximum at approximately | day, the serum concentration of ranibizumab
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`declined in parallel with the vitreous concentration.
`In these animalstudies,
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`systemic exposure of ranibizumab is more than 2000-fold lowerthan in the
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`vitreous.
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`In patients with neovascular AMD,following monthly intravitreal
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`
`administration, maximum ranibizumab serum concentrations were low
`
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`(0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of
`
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`ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the
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`biological activity of VEGF-A by 50%, as measuredin anin vitro cellular
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`proliferation assay. The maximum observed serum concentration was dose
`
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`proportional over the dose range of 0.05 to | mg/eye. Serum ranibizumab
`
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`concentrations in RVO patients were similar to those observed in
`
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`neovascular AMDpatients.
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`Basedon a neovascular AMDpopulation pharmacokinetic analysis,
`
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`maximum serum concentrations of 1.5 ng/mL are predicted to be reached at
`
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`approximately | day after monthly intravitreal administration of LUCENTIS
`
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`0.5 mg/eye. Based on the disappearance of ranibizumab from serum,the
`
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`estimated average vitreous elimination half-life was approximately 9 days.
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`Steady-state minimumi concentration is predicted to be 0.22 ng/mL with a
`
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`monthly dosing regimen. {n humans, serum ranibizumab concentrations are
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`predicted to be approximately 90,000-fold lower than vitreal concentrations.
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`
`Exhibit 2213
`Page 04 of 07
`
`
`
`

`

`
` 2
`
`MeanChangeinVisualAcuity
`
`
`o
`
`
`2
`
`
`4
`
`
`6
`
`
`8
`
`
`14
`12
`
`Month
`
`
`
`AMD-2
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`0
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`2
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`
`4 6 8
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`10
`
`
`14
`12
`
`Month
`
`
`16
`
`18
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`20
`
`22
`
`24
`
`
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`
`
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`
`
`
`
`
`
`
`LUCENTIS_Estimated
`
`
`
`Difference
`Outcome
`0.5 mg
`
`
`
`
`
`
`95% CI*
`n=240
`Measure
`
`
`
`
`32%
`Loss of < 15
`
`
`
`
`26%, 39%
`letters in visual
`
`
`acuity (%)°
`37%
`
`
`
`29%, 44%)
`29%
`
`(22%, 35%
`
`
`In both studies, the primary efficacy endpoint was the proportion ofpatients
`
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`who maintained vision, defined as losing fewer than 15 letters of visual
`
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`
`
`
`acuity at 12 months compared with baseline. Almost all LUCENTIS-treated
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`patients (approximately 95%) maintained their visual acuity. 34%-40% of
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`LUCENTIS-treated patients experienced a clinically significant
`
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`
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`improvement in vision, defined as gaining 15 or moreletters at 12 months.
`
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`Thesize ofthe lesion did notsignificantly affect the results. Detailed results
`
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`
`
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`are shownin the Table 3, Table 4, and Figure 1 below.
`
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`Table 3
`
`
`
`Outcomes at Month 12 and Month 24 in Study AMD-1
`
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`
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`Gain of 215
`
`
`letters in visual
`
`
`acuity (%)°
`
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`
`
`
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`
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`
`:
`
`:
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`Mean change in
`
`
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`‘| visual acuity
`
`
`(letters) (SD)?
`
`
`
`
`
`
`
`~10.5 (16.6)
`
`
`
`
` +7.2 (14.4)
`
`
`
`
`=14.9 (18.7)
`
`
`
`
`+6.6 (16.5)
`
`
`
`
`’ Adjusted estimate based on the stratified model.
`
`
`
`
`
`
`
`> p<0.01.
`
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`
`Exhibit 2213
`
`Page 05 of 07
`
`AMD-1:
`
`—™ LUCENTIS 0.5 mg (n=240)
`
`
`
`
`—@ Sham (n=238)
`
`
`
`
`
`
`AMD-2:
`
`—@® LUCENTIS 0.5 mg (n=139)
`
`
`
`
`—® Verteporfin PDT (n=143)
`
`
`
`
`
`
`
`
`
`Patients in the group treated with LUCENTIS had minimal observable CNV
`
`
`
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`
`
`
`
`
`
`
`lesion growth, on average. At Month 12, the mean changein the total area
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the CNVlesion was 0.1-0.3 DA for LUCENTISversus 2.3-2.6 DA for
`
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`
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`the control arms. At Month 24, the mean change in the total area of the
`
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`CNVlesion was 0.3-0.4 DA for LUCENTIS versus 2.9-3.1 DA forthe
`
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`control arms.
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`3 <8 3>&o 5o
`
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`O
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`
`STN BL 125156/053
`
`
`
`Page 9
`,
`
`
`
`13
`
`
`NONCLINICAL TOXICOLOGY
`
`
`
`
`
`
`13.1.
`Carcinogenesis, Mutagenesis, Impairmentof Fertitity
`
`
`
`
`
`
`No carcinogenicity or mutagenicity data are available for ranibizumab
`
`
`
`
`
`
`
`
`
`injection in animals or humans.
`:
`
`
`
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`
`
`Nostudies on the effects of ranibizumabonfertility have been conducted.
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`
`
`
`
`
`CLINICAL STUDIES
`
`
`
`
`14
`
`
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`14.1.
`
`
`
`
`
`
`
`The safety and efficacy of LUCENTISwereassessed in three randomized,
`
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`
`
`
`
`double-masked, sham- or active-controlled studies in patients with
`
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`
`
`
`
`
`neovascular AMD.A total of 1323 patients (LUCENTIS 879, Control 444)
`
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`
`
`
`
`
`
`were enrolled in the three studies.
`.
`
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`
`
`
`Studies AMD-1 and AMD-2
`
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`
`
`
`In Study AMD-I, patients with minimally classic or occult (withoutclassic)
`
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`CNVlesions received monthly LUCENTIS 0.3 mgor 0.5 mg intravitreal
`
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`
`
`
`
`injections or monthly sham injections. Data are available through Month 24.
`
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`
`
`Patients treated with LUCENTISin Study AMD-1 received a mean of
`
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`22 total treatments out of a possible 24 from Day 0 to Month 24.
`
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`
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`In Study AMD-2, patients with predominantly classic CNV lesions received
`
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`
`
`one ofthe following: 1) monthly LUCENTIS 0.3 mg intravitreal injections
`
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`
`and sham PDT; 2) monthly LUCENTIS0.5 mgintravitreal injections and
`
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`
`
`sham PDT; or 3) sham intravitreal injections and active verteporfin PDT.
`
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`
`
`Sham PDT(oractive verteporfin PDT) was given with the initial
`
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`
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`LUCENTIS(or sham) intravitreal injection and every 3 months thereafter if
`
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`
`
`fluorescein angiography showedpersistence or recurrence of leakage. Data
`
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`
`
`
`
`
`
`are available through Month 24. Patients treated with LUCENTIS in
`
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`
`
`Study AMD-2 received a mean of 21 total treatments out ofa possible
`
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`24 from Day 0 through Month 24.
`
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`
`
`Table 4
`
`
`
`
`Outcomes at Month 12 and Month 24 in Study AMD-2
`
`
`
`
`
`
`
`
`
`
`
`
`Outcome Measure Month
`
`
`Loss of
`,
`
`
`<15 letters in
`
`
`
`
`visual acuity (%)°
`
`
`
`
`24
`
`
`
`
`Gain of
`
`215 letters in
`
`
`
`
`visual acuity (%)°
`
`
`
`
`Mean changein
`
`
`
`visual acuity
`
`
`(letters) (SD)
`
`
`
`
`
`
`24
`
`
`
`
`
`
`
`
`Verteporfin
`PDT
`
`n=143
`
`
`
`
`
`. LUCENTIS
`0.5-mg
`
`
`n= 139
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-9.5 (16.4)
`
`
`
`
`+11.3 (14.6)
`
`
`
`
`-9,8 (17.6)
`
`
`
`
`+10.7 (16.5)
`
`
`
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`
`
`
`
`
`
`
`
`
`74 Adjusted estimate based on thestratified model.
`
`
`
`> p<0.01.
`
`
`Estimated
`Difference
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`Figure 1
`
`
`Mean Change in Visual Acuity from Baseline
`
`
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`
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`
`
`
`to Month 24 in Study AMD-1 and Study AMD-2
`
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`AMD-1
`
`
`
`
`
`
`
`10
`
`
`
`18
`
`
`20
`
`22
`
`16
`
`
`
`24
`
`
`Exhibit 2213
`Page 05 of 07
`
`
`
`

`

`
`
`2
`
`414.9
`
`oe - @ - —9 +08
`
`
`
`
`
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`
`
`
`
`!
`
`BZ
`
`
`
`2.2¢
`
`
`2g
`5
`
`
`
`¢9
`
`2
`
`3g
`
`ODay7
`
`1
`
`
`
`
`2
`
`
`
`3
`
`
`Month
`
`4
`
`
`
`5
`
`6
`
`
`
`RVO-1:
`
`—® LUCENTIS 0.5 mg (n=131)
`
`
`
`
`-® Sham (n=132)
`:
`
`
`
`
`
`
`
`RVO-2:
`—@- LUCENTIS 0.5 mg (n=130)
`
`
`
`
`-® Sham (n=130)
`
`
`
`p< 0.01 forall time points
`
`
`
`
`
`
`
`
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
`
`Each LUCENTIS carton, NDC $0242-080-01, contains a 0.2 mL fill of
`
`
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`
`
`
`
`
`
`10 mg/mLranibizumabin a 2-ce glass vial; one 5-micron,
`
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`19-gauge x 1-1/2-inch filter needle for withdrawalofthe vial contents; one
`
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`
`. 30-gauge x 1/2-inch injection needle for the intravitreal injection; and one
`
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`
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`package insert [see Dosage and Administration (2.5)|. VIALS ARE FOR
`
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`
`
`SINGLE EYE USE ONLY.
`
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`
`
`LUCENTIS should berefrigerated at 2°-8°C (36°-46°F). DO NOT
`
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`
`
`
`
`
`
`FREEZE. Do notuse beyondthe date stamped on the label. LUCENTIS
`
`
`
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`
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`
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`
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`
`0
`
`
`8
`6
`
`Month
`
`~# LUCENTIS 0.5 mg (n=61)
`
`
`
`-@ Sham (n=63)
`
`
`
` AMD-3 -MeanChangeinVisualAcuity
`
`2
`
`
`
`4
`
`10
`
`12
`
`
`
`
`
`
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`14.2
`
`
`
`
`
`
`
`
`
`The safety and efficacy of LUCENTIS were assessed in two randomized,
`
`
`
`
`
`
`
`
`
`
`
`double-masked, one-yearstudies in patients with macular edemafollowing
`
`
`
`
`
`
`
`
`
`RVO. Sham controlled data are available through Month 6. Patient age ranged
`
`
`
`
`
`
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`
`
`
`
`
`from 20 to 91 years, with a mean age of 67 years. A total of 789 patients
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(LUCENTIS0.3 mg, 266 patients; LUCENTIS0.5 mg, 261 patients; sham, 262
`
`
`
`
`
`
`
`
`
`
`
`
`patients) were enrolled, with 739 (94%) patients completing through Month 6.
`
`
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`
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`
`
`All patients completing Month 6 were eligible to receive LUCENTISinjections
`
`
`
`
`
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`
`
`
`guided by pre-specified re-treatment criteria until the end ofthe studies at
`
`
`
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`
`
`
`
`
`
`
`Month 12.
`
`
`In Study RVO-L, patients with macular edema following branch or hemi-
`
`
`
`
`
`
`
`
`
`
`RVO,received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections
`
`
`
`
`
`
`
`
`
`
`
`or monthly sham injections for 6 months. All patients were eligible for
`
`
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`
`
`
`
`
`
`
`
`rescue laser treatment beginning at Month 3 of the 6 month treatment period.
`
`
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`
`
`
`
`
`
`
`Rescue laser treatment was givento 26 of 131 (20%) patients treated with
`
`
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`
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`
`
`
`
`
`0.5 mg LUCENTISand 72 of 132 (5 5%) patients treated with sham.
`
`
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`
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`
`
`
`
`
`
`In Study RVO-2,patients with macular edema following central RVO
`
`
`
`
`
`
`
`
`
`
`
`received monthly LUCENTIS 0.3 mgor 0.5 mg intravitreal injections or
`
`
`
`
`
`
`
`
`
`
`monthly sham injections for 6 months.
`
`
`
`
`
`
`At Month6,after montlily treatment with 0.5 mg LUCENTIS,the following
`
`
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`
`
`
`
`
`clinical results were observed:
`
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`
`
`
`
`
`Exhibit 2213
`
`Page 06 of 07
`
`Study AMD-3
`
`Study AMD-3 was a randomized, double-masked, sham-controlled, two-year
`
`
`
`
`
`
`study designed to assess the safety and efficacy of LUCENTISin patients
`
`
`
`
`
`
`
`
`
`
`
`
`with neovascular AMD(with or without a classic CNV component). Data
`
`
`
`
`
`
`
`
`
`
`are available through Month 12. Patients received LUCENTIS 0.3 mg or
`
`
`
`
`
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`
`
`
`
`
`0.5 mgintravitreal injections or sham injections once a month for
`
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`
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`
`
`3 consecut