`Page 5
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`LUCENTIS safely and effectively. See full prescribing information for
`LUCENTIS.
`
`LUCENTIS® (ranibizumab injection)
`Intravitreal Injection
`Initial U.S. Approval: 2006
`
`-----------------RECENT MAJOR CHANG ES------------------------------------
`• Indications and Usage, Macular Edema Following Retinal Vein Occlusion
`(RVO) ( 1.2), 6/20 l 0
`• Dosage and Administration, Macular Edema Following Retinal Vein
`Occlusion (RVO) (2.3), 6/2010
`• Warnings and Precautions, Thromboembolic Events (5.3), 6/2010
`--------------------------INDICATIONS AND USAGE-------------------------(cid:173)
`LUCENTIS is indicated for the treatment of patients with:
`• Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
`• Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
`-----------------------DOSAGE AND ADMINISTRATION--------------------(cid:173)
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY (2.1)
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMO)
`• LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days) (2.2).
`• Although less effective, treatment may be reduced to one injection every
`three months after the first four injections if monthly injections are not
`feasible. Compared to continued monthly dosing, dosing every 3 months
`will lead to an approximate 5-letter (I-line) loss of visual acuity benefit, on
`average, over the following 9 months. Patients should be treated
`regularly (2.2).
`
`2
`
`I•ULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`I
`\.I Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`1.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`DOSAGE AND ADMINISTRATION
`General Dosing Information
`2.1
`2.2 Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`Preparation for Administration
`2.4
`2.5 Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`Ocular or Periocular Infections
`4. l
`4.2 Hypersensitivity
`S WARNINGS AND PRECAUTIONS
`Endophthalmitis and Retinal Detachments
`5.1
`Increases in Intraocular Pressure
`5 .2
`Thromboembolic Events
`5.3
`6 ADVERSE REACTIONS
`Injection Procedure
`6. L
`Clinical Studies Experience
`6.2
`Immunogenicity
`6.3
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`• l,UCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitrcal injection once a month (approximately 28 days). In the RVO
`clinical studies, patients received monthly injections ofLUCENTIS for six
`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 (2.3).
`---------------------DOSAGE FORMS AND STRENGTHS--------------------(cid:173)
`• 10 mg/mL solution in a single-use vial for intravitreal injection (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 during the week following the
`injection (5.1).
`• Increases in intraocular pressure have been noted within 60 minutes of
`intravitreal injection (5.2).
`------------------------------ADVERSE REACTIONS--------------------------
`• The most wmmon adverse reactions (reported more frequently in
`LUCENTIS-treatcd subjects than control subjects) are conjunctiva!
`hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and
`intraocular inflammation (6.2).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentcch at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 6/2010
`
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.3 Nursing Mothers
`Pediatric Use
`·s.4
`8.5 Geriatric Use
`Patients with Renal Impairment
`8.6
`Patients with Hepatic Dysfunction
`8. 7
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLLL'HCAL PHARMACOLOGY
`12. I Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Neovascular (Wet) Age-Related Macular Degeneration
`(AMD)
`14.2 Macular Edema Following Retinal Vein Occlusion
`(RVO)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the Full Prescribing Information are
`·
`not listed.
`
`Regeneron Exhibit 1027 .001
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`Page 6
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`LUCENT!S is indicated for the treatment of patients with:
`
`1.1
`
`1.2
`
`2
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMO)
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`
`DOSAGE AND ADMINISTRATION
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRA VITREAL INJECTION ONLY.
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`2.2
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`Although less effective, treatment may be reduced to one injection every
`three months after the first four injections if monthly injections are not
`feasible. Compared to continued monthly dosing, dosing every 3 months
`will lead to an approximate 5-letter (I-line) loss of visual aCL1ity benefit, on
`average, over the following 9 months. Patients should be treated regularly
`[see Clinical Studies (14.2)).
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`2.3
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
`intravitreal injection once a month (approximately 28 days).
`
`In Studies RV0-1 and RV0-2, patients received monthly injections of
`LUCENTIS for six 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)].
`
`Preparation for Administration
`2.4
`Using aseptic technique, all (0.2 mL) of the LUCENTIS vial contents are
`withdrawn through a 5-micron, l 9-gauge filter needle attached to a I-cc
`tuberculin syringe. The filter needle should be discarded after withdrawal of
`the vial contents and should not be used for intravitreal injection. The filter
`needle should be replaced with a sterile 30-gauge x 1/2-inch needle for the
`intravitreal injection. The contents should be expelled until the plunger tip is
`aligned with the line that marks 0.05 mL on the syringe.
`
`Administration
`2.5
`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.
`
`Following the intravitreal injection, patients should be monitored for
`elevation in intraocular pressure and for endophthalmitis. Monitoring may
`consist of a check for perfusion of the optic nerve head immediately after the
`injection and tonometry within 30 minutes following the injection. Patients
`should be instructed to report any symptoms suggestive of endophlhalmitis
`without delay.
`
`Each vial should only be used for the treatment of a single eye. lfthe
`contralateral eye requires treatment, a new vial should be used and the sterile
`field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles
`should be changed before LUCENT[S is administered to the other eye.
`
`No special dosage modification is required for any of the populations that
`have been studied (e.g., gender, elderly).
`
`DOSAGE FORMS AND STRENGTHS
`3
`Single-use glass vial designed to provide 0.05 mL of l O mg/mL solution for
`intravitreal injection.
`
`4
`
`CONTRAINDICATIONS
`
`Ocular or Periocular Infections
`4.1
`LUCENTIS is contraindicated in patients with ocular or periocular
`infections.
`
`Hypersensitivity
`4.2
`LUCENTIS is contraindicated in patients with known hypersensitivity to
`ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity
`reactions may manifest as severe intraocular inflammation.
`
`5
`
`WAIU-IINGS AND PRECAUTIONS
`
`Endophthalmitis and Retinal Detachments
`5.1
`Intravitreal injections, including those with LUCENTIS, have been
`associated with endophthalmitis and retinal detachments. Proper aseptic
`injection technique should always be used when administering LUCENTIS.
`In addition, patients should be monitored during the week following the
`injection to permit early treatment should an infection occur [see Dosage
`and Administralion (2.4, 2.5) and Patient Counseling Information (17)].
`
`Increases in Intraocular Pressure
`5.2
`Increases in intraocular pressure have been noted within 60 minutes of
`intravitreal injection with LUCENTIS. Therefore, intraocular pressure as
`well as the perfusion of the optic nerve head should be monitored and
`managed appropriately [see Dosage and Administration (2.5)].
`
`Thromboembolic Events
`5.3
`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 ofVEGF inhibitors. ATEs are defined as nonfatal
`stroke, nonfatal myocardial infarction, or vascular death (including deaths of
`unknown cause).
`
`Neovascular (Wet) Age-Related Macular Degeneration
`The ATE rate in the three controlled neovascular AMO studies during the
`first year was 1.9% (l 7 out of874) in the combined group of patients treated
`with 0.3 mg or 0.5 mg LUCENTIS compared with l.l% (5 out of 441) in
`patients from the control arms [see Clinical Studies (14. l)]. In the second
`year of studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 oul of721)
`in the combined group of LUCENTIS-treated patients compared with 2.9%
`(10 out of344) in patients from the control arms.
`
`In a pooled analysis of2-year controlled studies (AMD-l, AMD-2 and a
`study of LUCENT IS used adjunctively with verteporfin photodynamic
`therapy), the stroke rate (including both ischemic and hemorrhagic stroke)
`was 2. 7% (13 out of 484) in patients treated with 0.5 mg LUCENTIS
`compared to 1.1 % (5 m1t of 435) in patients in the control arms (odds ratio
`2.2 (95% confidence interval (0.8-7.1))).
`
`,'vfacular Edema Following Retinal Vein Occlusion
`The ATE rate in the two controlled RVO studies during the first six months
`was 0.8% in both the LUCENTIS and control arms of the studies (4 out of
`525 in the combined group of patients treated with 0.3 mg or 0.5 mg
`LUCENTIS and 2 out of260 in the control arms) [see Clinical Studies
`(14.2)1. The stroke rate was 0.2% (I out of 525) in the combined group of
`LUCENTIS-treated patients compared to 0.4% ( l out of 260) in the control
`arms.
`
`ADVERSE REACTIONS
`6
`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.
`
`Injection Procedure
`6.1
`Serious adverse reactions related to the injection procedure have occurred in
`<0. l % of inlravilreal injections, including endophthalmitis [see Warnings
`
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`Page7
`
`and Precautions (5. !)], rhegmatogenous retinal detachments, and iatrogenic
`traumatic cataracts.
`
`Non-Ocular Reactions
`Table 2 shows frequently reported non-ocular adverse reactions in
`LUCENTIS treated patients compared with the control group.
`
`Table 2
`Non-Ocular Reactions in AMO and RVO Studies
`
`AMD2-year
`
`AMO I-year
`
`RVO 6-month
`
`6.2
`
`Clinical Studies Experience
`
`The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with
`neovascular AMO in three double-masked, controlled studies (AMD-1,
`AM0-2, and AM0-3) [see Clinical Studies (14.1)] as well as exposure to 0.5
`mg LUCENTIS in 259 patients with macular edema following RVO in two
`double-masked, controlled studies (RV0-1 and RV0-2) [see Clinical Studies
`(14.2)].
`
`Ocular Reactions
`Table l shows frequently reported ocular adverse reactions in LUCENTIS
`treated patients compared with the control group.
`
`Table l
`Ocular Reactions in AMD and RVO Studies
`
`AMD2-year
`
`AMO !-year
`
`RVO 6-month
`
`Adverse Reaction
`
`U'J
`i::
`~
`
`i
`8
`
`g
`!
`u
`
`U'J
`i::
`a:i
`u
`::i
`.-l
`
`Cl'l
`~
`z
`"'
`8
`.-l
`n=440
`
`8%
`
`6%
`
`,.
`
`Adverse Reaction
`
`Nasopharyngitis
`Headache
`
`Arthralgia
`
`Bronchitis
`Urinary tract infection
`Cough
`
`Cl'l
`
`! .-l
`
`]
`
`n=379
`16%
`
`12%
`ii%
`ii%
`9%
`..... 9%
`
`9%
`
`n=379
`13%
`
`9%
`9%
`.9%
`
`9%
`8%
`.... 6o/~
`
`1
`!
`u
`
`n=44\
`9%
`
`s·1~
`
`3%
`2%
`5%
`.•... . 0%
`
`U'J
`i::
`~
`g
`
`.-l
`n=259
`5%
`
`0
`
`!
`
`u
`
`n=260
`4%
`
`3%
`
`1%
`
`2%
`
`5%
`5%
`so/~
`
`1%
`
`2%
`i%
`
`2%
`2%
`.: ..................
`2%
`
`....
`
`4%
`so/~
`
`Conjunctiva!
`hemorrhage
`Eye pain
`Vitreous floaters
`Intraocular pressure
`increased
`Vitreous detachment
`Intraocular
`inflammation
`Cataract
`Foreign body sensation
`in eyes
`Eye irritation
`Lacrimation increased
`Blepharitis
`
`Dry eye
`Visual disturbance
`or vision blurred
`Eye pruritis
`Ocular hyperemia
`Retinal disorder
`Maculopathy
`Retinal degeneration
`
`OcLtlar discomfort
`Conjunctiva! hyperemia
`Posterior capsule
`opacification
`Injection site
`hemorrhage
`
`U'J
`i::
`z
`"'
`§5
`.-l
`
`::i
`.-l
`
`n=379
`
`n=379
`
`n=440
`
`N=44 I
`
`n=259
`
`n=26
`0
`
`Nausea
`Upper respiratory
`tract infection
`Sinusitis
`
`Anemia
`
`Influenza
`Chronic obstructive
`pulmonary disease
`Hypercholesterolemia
`
`Insomnia
`Pain in extremity
`Atrial fibrillation
`
`Anxiety
`Dyspnea
`Gastroenteritis viral
`
`9%
`
`8%
`8%
`7%
`
`6%
`
`5%
`.. So/~ .
`5%
`4o/o
`
`4%
`
`8%
`
`7%
`
`5%
`
`3%
`So/~
`
`5%
`6%
`4o/~
`4o/o ···
`
`3%
`
`1%
`
`5%
`
`5%
`
`5%
`
`5%
`··30;.;
`
`··········.
`
`1% I 0%
`. jii)~ ··,'········2····%·········· .,
`
`2%
`
`3%
`3%
`2% ......... iii);
`-- ·· "i% .. ·
`
`3o/o ··
`
`2%
`
`3%
`
`1%
`
`3%
`
`0%
`
`1%
`
`1%
`1%
`
`1%
`1%
`
`2%
`
`2%
`1%
`2%
`
`0%
`
`\%
`
`1%
`1%
`
`0%
`2%
`0%
`
`0%
`
`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 resulis 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 immunoreaetivity 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
`I %-8% of patients.
`
`The clinical significance of immunorcactivity 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. lntraocular
`inflammation was not observed in the RVO patients with the highest levels
`of immunoreactivity.
`
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`DRUG INTERACTIONS
`7
`Drug interaction studies have not been conducted with LUCENTIS.
`
`LUCENTIS intravitreal injection has been used adjunctively with verteporfin
`photodynamic therapy (PDT). Twelve of 105 (11%) patients with
`neovascular AMO developed serious intraocular inflammation; in LO of the
`12 patients, this occurred when LUCENTIS was administered 7 days
`(±2 days) after verteporfin PDT.
`USE IN SPECIFIC POPULATIONS
`
`8
`
`8.1
`Pregnancy
`Pregnancy Category C. Animal reproduction studies have not been
`conducted with ranibizumab. It is also not known whether ranibizumab can
`cause fetal harm when administered to a pregnant woman or can affect
`reproduction capacity. LUCENTIS should be given to a pregnant woman
`only if clearly needed.
`
`Nursing Mothers
`8.3
`It is not known whether ranibizumab is ex~reted in human milk. Because
`many drugs are excreted in human milk, and because the potential for
`absorption and harm to infant growth and development exists, caution should
`be exercised when LUCENTIS is administered to a nursing woman.
`
`Pediatric Use
`8.4
`The safety and effectiveness of LUCENTIS in pediatric patients has not been
`established.
`
`Geriatric Use
`8.5
`In the clinical studies, approximately 82% (1146/1406) of the patients
`randomized to treatment with LUCENTIS were~ 65 years of age and
`approximately 55% (772/1406) were :! 75 years of age. No notable
`differences in efficacy or safety were seen with increasing age in these
`studies. Age did not have a significant effect on systemic expo,ure in
`population pharmacokinetic analyses after correcting for creatinine
`clearance.
`
`Patients with Renal Impairment
`8.6
`No formal studies have been conducted to examine the pharmacokinetics of
`ranibizumab in patients with renal impairment. In population
`pharmacokinetic analyses of patients, 54% (389/725) had renal impairment
`(39% mild, 12% moderate, and 2% severe). The reduction in ranibizumab
`clearance in patients with renal impaimtent is considered clinically
`insignificant. Dose adjustment is not expected to be needed for patients with
`renal impairment.
`
`Patients with Hepatic Dysfunction
`8.7
`No formal studies have been conducted to examine the pharm~okinetics of
`ranibizumab in patients with hepatic impainnent. Dose adjustment is not
`expected to be needed for patients with hepatic dysfunction.
`
`OVERDOSAGE
`10
`Planned initial single doses of ranibizumab injection l mg were associated
`with clinically significant intraocular inflammation in 2 of2 neovascular
`AMD patients injected. With an escalating regimen of doses beginning with
`initial doses ofranibizumab injection 0.3 mg, doses as high as 2 mg were
`tolerated in 15 of20 neovascular AMO patients.
`
`DESCRIPTION
`11
`LUCENTIS® (ranibizumab injection) is a recombinant humanized IgGl
`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 has a molecular
`weight of approximately 48 kilodaltons and is produced by an £. coli
`expression system in a nutrient medium containing the antibiotic
`tetracycline. Tetracycline is not detectable in the final product.
`
`LUCENT IS is a sterile, colorless to pale yellow solution in a single-use glass
`vial. LUCENTIS is supplied as a preservative-free, sterile solution in a
`single-use glass vial designed to deliver 0.05 mL of 10 mg/mL LUCENTIS
`
`aqueous solution with 10 mM histidine I-ICI, 10% a,a-trehalose dihydrate,
`0.01% polysorbate 20, pH 5.5.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Ranibizumab binds to the receptor binding site of active forms ofVEGF-A,
`including the biologically active, cleaved form of this molecule, VEGF uo.
`VEGF-A has been shown to cause neovascularization and leakage in models
`of ocular angiogenesis and vascular occlusion, and is thought to contribute to
`the progression of neovascular AMO and macular edema following RVO.
`The binding ofranibizumab to VEGF-A prevents the interaction ofVEGF·A
`with its receptors (VEGFRJ and VEGFR2) on the surface of endothelial
`cells, reducing endothelial cell proliferation, vascular leakage, and new
`blood vessel formation.
`
`Pharmacodynamics
`12.2
`Increased center point thickness (CPT) as assessed by optical coherence
`tomography (OCT) is associated with neovascular AMD and macular edema
`following RVO. Leakage from choroidal neovascularization (CNV) as
`assessed by fluorescein angiography is associated with neovascular AMD.
`
`Neovascular (Wet) Age-Related Macular Degeneration
`In Study AMD-3, CPT was assessed by OCT in 118/184 patients. OCT
`measurements were collected at baseline, Months I, 2, 3, 5, 8, and 12. In
`patients treated with LUCENTIS, CPT decreased, on average, more than the
`sham group from baseline through Month 12. CPT decreased by Month I
`and decreased further at Month 3, on average. CPT data did not provide
`information useful in influencing treatment decisions [see Clinical
`Studies (14./)]
`
`In patients treated with LUCENTIS, the area of vascular leakage, on
`average, decreased by Month 3 as assessed by lluorescein angiography. The
`area of vascular leakage for an individual patient was not correlated with
`visual acuity.
`
`Macular Edema Following Retinal Vein Occlusion
`On average, CPT reductions were observed in Studies RV0-1 and RV0-2
`beginning at Day 7 following the first LUCENTIS injection through Month
`6. CPT was not evaluated as a means to guide treatment decisions [see
`Clinical Studies (I 4.2)].
`
`Pharmacokinetics
`12.3
`In animal studies, following intravitreal injection, ranibizumab was cleared
`from the vitreous with a hall:Jife of approximately 3 days. After reaching a
`mm<imum at approximately l day, the serum concentration ofranibizumab
`declined in parallel with the vitreous concentration. In these animal studies,
`systemic exposure ofranibizumab is more than 2000-fold lower than in the
`vitreous.
`
`In patients with neovascular AMD, following monthly intravitreal
`administration, maximum ranibizumab serum concentrations were low
`(0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of
`ranibizumab (11 nglmL to 27 ng/mL) thought to be necessary to inhibit the
`biological activity ofVEGF-A by 50%, as measured in an in vitro cellular
`proliferation assay. The maximum observed serum concentration was dose
`proportional over the dose range of 0.05 to 1 mg/eye. Serum ranibizumab
`concentrations in RVO patients were similar to those observed in
`neovascular AMO patients.
`
`Based on a neovascular AMO population pharmacokinetic analysis,
`maximum serum concentrations of 1.5 ng/mL are predicted to be reached at
`approximately I day after monthly intravitreal administration ofLUCENTIS
`0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the
`estimated average vitreous elimination half-life was approximately 9 days.
`Steady-state minimum concentration is predicted to be 0.22 nglmL with a
`monthly dosing regimen. [n humans, serum ranibizumab concentrations arc
`predicted to he approximately 90,000-fold lower than vitreal concentrations.
`
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`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.l
`No carcinogenicity or mutagenicity data are available for ranibizumab
`injection in animals or humans.
`
`No studies on the effects of ranibizumab on fertility have been conducted.
`
`14
`
`CLINICAL STUDIES
`
`Neovascular (Wet) Age-Related Macular Degeneration (AMD)
`14.1
`The safety and efficacy of LUCENTIS were assessed in three randomized,
`double-masked, sham- or active-controlled studies in patients with
`neovascular AMO. A total of 1323 patients (LUCENTIS 879, Control 444)
`were enrolled in the three studies.
`
`Studies AMD-1 and AMD-2
`In Study AMD-1, patients with minimally classic or occult (without classic)
`CNV lesions received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal
`injections or monthly sham injections. Data are available through Month 24.
`Patients treated with LUCENTIS in Study AMO-I received a mean of
`22 total treatments out of a possible 24 from Day O to Month 24.
`
`In Study AMD-2, patients with predominantly classic CNV lesions received
`one of the following: 1) monthly LUCENTIS 0.3 mg intravitreal injections
`and sham PDT; 2) monthly LUCENTIS 0.5 mg intravitreal injections and
`sham PDT; or 3) sham intravitreal injections and active verteporfin PDT.
`Sham PDT (or active verteporfin PDT) was given with the initial
`LUCENT IS (or sham) intravitreal injection and every 3 months thereafter if
`fluorescein angiography showed persistence or recurrence of leakage. Data
`are available through Month 24. Patients treated with LUCENTIS in
`Study AMD-2 received a mean of2 I total treatments out ofa possible
`24 from Day O through Month 24.
`
`Table 4
`
`Outcomes at Month 12 and Month 24 in Study AMD-2
`
`Outcome Measure Month
`12
`Loss of
`< IS letters in
`visual acuity (%)"
`
`24
`
`Gain of
`<:: 15 letters in
`visual acuity (%t
`
`Mean change in
`visual acuity
`(letters) (SD)"
`
`12
`
`24
`
`12
`
`24
`
`Verteporfin
`PDT
`n=143
`64%
`
`LUCENTIS
`0.5 mg
`n= 139
`96%
`
`66%
`
`6%
`
`6%
`
`90%
`
`40%
`
`41%
`
`-9.5 (16.4)
`
`+ 11.3 (14.6)
`
`-9.8 (17.6)
`
`+ 10.7 (!6.5)
`
`Estimated
`Difference
`(95%CI)'
`33%
`(25%,41%)
`25%
`(16%,34%)
`35%
`(26%,44%)
`35%
`(26%,44%)
`21.l
`(17.5, 24.6)
`20.7
`(16.8 24 7)
`
`7
`
`' Adjusted estimate based on the stratified model.
`b p<0.01.
`
`Figure l
`Mean Change in Vimal Acuity from Baseline
`to Month 24 in Study AMD-1 and Study AMD-2
`
`AMD-1
`
`..
`
`.......
`
`~ ..
`__.. ""o-e......
`
`+ 6.6
`
`..-.. ... _ -14.9
`
`6
`
`8
`
`16 18
`
`20 22 24
`
`15
`
`10
`
`5
`
`a,
`·:1
`if
`ni
`::,
`Ill
`5-
`C: I!!
`·-"' 0
`a, Ji
`I
`
`,- -5
`
`u
`
`-10
`
`-15
`
`In both studies, the primary efficacy endpoint was the proportion of patients
`who maintained vision, defined as losing fewer than 15 letters of visual
`acuity at 12 months compared with baseline. Almost all LUCENTIS-treated
`patients (approximately 95%) maintained their visual acuity. 34%-40% of
`LUCENT!S-treated patients experienced a clinically significant
`improvement in vision, de tined as gaining 15 or more letters at 12 months.
`The size of the lesion did not significantly affect the results. Detailed results
`are shown in the Table 3, Table 4, and Figure I below.
`
`Table 3
`
`Outcomes at Month 12 and Month 24 in Study AMO-I
`
`Outcome
`Measure
`Loss of< 15
`letter, in visual
`acuity(%)"
`
`Gain of<:: 15
`letters in visual
`acuity(%)"
`
`Mean change in
`visual acuity
`(letters) (SD)"
`
`-
`
`Month
`12
`
`24
`
`12
`
`24
`
`12
`
`24
`
`Sham
`n=238
`62%
`
`53%
`
`5%
`
`4%
`
`LUCENTIS
`0.5 mg
`n=240
`95%
`
`90%
`
`34%
`
`33%
`
`-10.5 (16.6) + 7.2 (14.4)
`
`-14.9 (18.7) + 6.6 ( 16.5)
`
`Estimated
`Difference
`(95% Cl)'
`32%
`(26%, 39%)
`37%
`(29%, 44%)
`29%
`(22%, 35%)
`29%
`(23%, 35%)
`17.5
`([4.8, 20.2)
`21.l
`(18.l, 24.2)
`
`' Adjusted estnnate based on the stratified model.
`b p<0.01.
`
`0
`
`2
`
`4
`
`10
`
`14
`12
`Month
`
`AMD-2
`
`15
`
`"'..9,l
`
`f
`1
`5~ 5
`.s;j 0
`J- -5
`I -15
`
`u
`
`-10
`
`0
`
`-.
`
`...._ ..........
`
`+10.7
`
`. ..-..... ___ .......... -9.8
`
`2
`
`4
`
`6
`
`8
`
`10
`
`14 16 18
`12
`Month
`
`20 22
`
`24
`
`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
`lesion growth, on average. At Month 12, the mean change in the total area
`of the CNV lesion was O.l-0.3 DA for LUCENTIS versus 2.3-2.6 DA for
`the control arms. At Month 24, the mean change in the total area of the
`CNV lesion was 0.3-0.4 DA for LUCENTIS versus 2.9-3.1 DA for the
`control arms.
`
`Regeneron Exhibit 1027 .005
`
`
`
`STN BL 125156/053
`Page 10
`
`StudyAMD-3
`Study AMD-3 was a randomized, double-masked, sham-controlled, two-year
`study designed to assess the safety and efficacy of LUCENTIS in patients
`with neovascular AMO (with or without a classic CNV component). Data
`are available through Month 12. Patients received LUCENTIS 0.3 mg or
`0.5 mg intravitreal injections or sham injections once a month for
`3 consecutive doses, followed by a dose administered once every 3 months
`for 9 months. A total of 184 patients were enrolled in this study
`(LUCENTIS 0.3 mg, 60; LUCENTIS 0.5 mg, 61; sham, 63); 171 (93%)
`completed 12 months of this study. Patients treated with LUCENTIS in
`Study AMD-3 received a mean of 6 total treatments out of a possible 6 from
`Day O through Month 12.
`In Study AMD-3, the primary efficacy endpoint was mean change in visual
`acuity at 12 months compared with baseline (see Figure 2). After an initial
`increase in visual acuity (following monthly dosing), on average, patients
`dosed once every three months with LUCENTIS lost visual acuity, returning
`to baseline at Month 12. In Study AMD-3, almost all LUCENTIS-treated
`patients (90%) maintained their visual acuity at Month 12.
`
`Tables
`Percentage of Pati(;)lts with Gain of::15 lettel's in Visual Acuity
`from Baseline to Month 6 in Study RV0-1 and Study RV0-2
`
`Study
`
`Sham
`
`LUCENTIS
`0.5 mg
`
`RV0-1
`
`29%
`
`61%
`
`17%
`RV0-2
`'p < 0.0 l, adjusted estimate based on stratified model
`
`48%
`
`Estimated
`Difference
`(95% Cl)
`31%'
`(20%,43%)
`30%'
`(20%,41%)
`
`Figure 3
`Mean Change in Visual Acuity from Baseline
`to Month 6 in Study RV0-1 and Study RV0-2
`
`Figure 2
`Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3
`
`20
`
`RV0-1
`
`+18.3
`
`0
`
`2
`
`8
`6
`Month
`LUCENTIS 0.5 mg (n=61)
`-e-
`-+ Sham (n=63)
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`14.2
`The safety and efficacy of LUCENTIS were assessed in two randomized,
`double-masked, one-year studies in patients with macular edema following
`RVO. Sham controlled data are available through Month 6. Patient age ranged
`from 20 to 91 years, with a mean age of 67 years. A total of789 patients
`(LUCENTIS 0.3 mg. 266 patients; LUCENTIS 0.5 mg, 261 patients; sham, 262
`patients) were enrolled, with 739 (94%) patients completing through Month 6.
`All patients completing Month 6 were eligible to receive LUCENTIS injections
`guided by pre-specified re-treatment criteria until the end of the studies at
`Month 12.
`In Study RV0-1, patients with macular edema following branch or hemi(cid:173)
`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
`rescue laser treatment beginning at Month 3 of the 6 month treatment period.
`Rescue laser treatment was given to 26 of 13 l (20%) patients treated with
`0.5 mg LUCENTIS and 72 of 132 (55%) patients treated with sham.
`In Study RV0-2, patients with macular edema following central RVO
`received monthly LUCENT!S 0.3 mg or 0.5 mg intravitreal injections or
`monthly sham injections for 6 months.
`At Month 6, after monthly treatment with 0.5 mg LUCENTIS, the following
`clinical results were observed:
`
`~
`:,
`<'t
`<ii
`:,
`.!!!
`0
`>en
`.5j -5 0
`(I>.
`'a.
`Cl~
`aj ~-10
`.c
`u
`ai
`I
`
`10
`
`5
`
`-15
`
`-20
`
`AMD-3
`
`-0.2
`
`Q
`
`-
`
`"
`
`- .....
`
`....
`
`0
`
`-16.3
`
`4
`
`10 12
`
`_.. - _. - -a--- -
`
`-e-
`
`~ _. - -o + 7.3
`
`-5 >-r---r------...---...... - - - - ~ -
`6
`5
`4
`3
`0Day7 1
`Month
`
`RV0-2
`
`+14.9
`
`- - - -
`
`-e _ -<>- -
`
`-e--
`
`•
`
`...,..
`
`-
`
`-<> + 0.8
`
`20
`
`15
`
`a
`
`-5 1 - , r - - - r - - - ~ - -..... - -..... - - - - - -
`6
`4
`3
`2
`0Day7 1
`Month
`
`RV0-1:
`- - LUCENTIS 0.5 mg (n;131)
`- . Sham (n;t 32)
`
`p < 0.01 for all time points
`
`RV0-2:
`- - LUCENTIS 0.5 mg (n;130)
`- . Sham (n;130)
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`Each LUCENTIS carton, NOC 50242-080-01, contains a 0.2 mL fill of
`l O mg/mL ranibizumab in a 2-cc glass vial; one 5-micron,
`19-gauge x l-l/2-inch filter needle for withdrawal of the vial contents; one
`30-gauge x 1/2-inch injection needle for the intravitreal injection; and one
`package insert [see Dosage and Administration (2.5)]. VIALS ARE FOR
`SINGLE EYE USE ONLY.
`LUCENT IS should be refrigerated at 2°-8°C (36°-46°F). 110 NOT
`FREEZE. Do not use beyond the date stamped on the label. LUCENT1S
`
`Regeneron Exhibit 1027 .006
`
`
`
`STN BL 125 l 56/053
`Page 11
`
`vials should be protected from light. Store in the original carton until time of
`use.
`
`PATIENT COUNSELING INFORMATION
`17
`In the days following LUCENTlS administration, patients are at risk of
`developing endophthalmitis. If the eye becomes red, sensitive to light,
`painful, or develops a change in vision, the patient should seek immediate
`care from an ophthalmologist [see Warnings and Precautions (5./)].
`
`LUCENTIS" (ranibizumab injectionJ
`Manufactured by:
`Genentech, Inc.
`A Member of the Roche Group
`L DNA Way
`South San Francisco, CA 94080-4990
`
`4851401
`Initial US Approval June 2006
`Revision Date June 20 L 0
`LUCENTIS® is a registered
`trademark of Genentech, Inc.
`®2010 Genentech, Inc.
`
`Regeneron Exhibit 1027 .007
`
`