CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-756
`
`APPROVED LABELING
`
`Regeneron Exhibit 1062.001
`
`

`

`NDA21-756
`Page4
`
`MACUGE~
`(pegaptanib sodium injection)
`
`DESCRIPTION
`
`MACUGEN® (pegaptanib sodium injection) is a sterile, aqueous solution containing pegaptanib
`sodium for intravitreous injection. Macugen is supplied in a single-dose, pre-filled syringe and is
`formulated as a 3.47 mg/mL solution, measured as the free acid form of the oligonucleotide. The
`active ingredient is 0.3 mg of the free acid form of the oligonucleotide without polyethylene glycol, in
`a nominal volume of90 µL. This dose is equivalent to 1.6 mg ofpegaptanib sodium (pegylated
`oligonucleotide) or 0.32 mg when expressed as the sodium salt form of the oligonucleotide moiety.
`The product is a sterile, clear, preservative-free solution containing sodium chloride, monobasic
`sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, hydrochloric acid, and/or
`sodium hydroxide to adjust the pH and water for injection.
`
`Pegaptanib sodium is a covalent conjugate of an oligonucleotide of twenty-eight nucleotides in length
`that terminates in a pentylamino linker, to which two 20-kilodalton monomethoxy polyethylene glycol
`(PEG) units are covalently ~ttached via the two amino groups on a lysine residue.
`
`Pegaptanib sodium is represented by the following structural formula:
`
`Regeneron Exhibit 1062.002
`
`

`

`NDA21-756
`Page 5
`
`Where Ris
`
`H
`
`0
`
`,0'1.~~~
`,o'tn°
`
`n O
`
`~N-1
`
`and n is approximately 450.
`
`The chemical name for pegaptanib sodium is as follows: RNA, ((2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'(cid:173)
`deoxy-2 '-fluoro) U-(2'-deoxy-2'-fluoro )C-Am-Gm-(2'-deoxy-2' -fluoro) U-Gm-Am-Am-(2 '-deoxy-2 '(cid:173)
`fluoro) U-Gm-(2'-deoxy-2'-fluoro )C-(2'-deoxy-2'-fluoro) U-(2'-deoxy-2'-fluoro) U-An,-(2 '-deoxy-2 '(cid:173)
`fluoro )U-Am-(2'-deoxy-2'-fluoro )C-Am-(2'-deoxy-2'-fluoro) U-(2'-deoxy-2'-fluoro )C-(2'-deoxy-2 '(cid:173)
`fluoro )C-Gm-(3 '➔3 ')-dT), 5'-ester with a,cl.t-[4,12-dioxo-6-[[[5-
`(phosphoonoxy)pentyl]amino ]carbonyl]-3, 13-dioxa-5, 11-diaza-1, 15-pentadecanediyl]bis[ {O(cid:173)
`methoxypoly(oxy-1,2-ethanediyl)], sodium salt.
`
`The molecular formula for pegaptanib sodium is C294H342f 13N 101Na2sO188P2s[C2H4O]n (where n is
`approximately 900) and the molecular weight is approximately 50 kilodaltons.
`
`Macugen is formulated to have an osmolality of280-360 mOsm/Kg, and a _pH of 6-7.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted
`protein that selectively binds and activates its receptors located primarily on the surface of vascular
`endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation,
`all of which are thought to contribute to the progression of the neovascular (wet) form of age-related
`macular degeneration (AMD), a leading cause of blindness. VEGF has been implicated in blood
`retinal barrier breakdown and pathological ocular neovascularization.
`
`Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional
`conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions,
`pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF165, thereby inhibiting
`VEGF165 binding to its VEGF receptors. The inhibition ofVEGF1 64. the rodent counterpart of human
`VEGF165, was effective at suppressing pathological neovascularization.
`
`Pharmacokinetics
`Absotption
`
`In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous
`administration. The rate of absorption from the eye is the rate limiting step in the disposition of
`pegaptanib in animals and is likely to be the rate limiting step in humans.
`
`In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within 1 to 4 days after
`a 3 mg monocular dose (10 times the recommended dose). The mean area under the plasma
`concentration-time curve (AUC) is about 25 µg·hr/mL at this dose.
`
`Regeneron Exhibit 1062.003
`
`

`

`NDA21-756
`Page6
`
`Distribution/Metabolism/Excretion
`Twenty-four hours after intravitreous administration of a radio labeled dose ofpegaptanib to both eyes
`of rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After
`intravitreous and intravenous administrations ofradiolabeled pegaptanib to rabbits, the highest
`concentrations of radioactivity ( excluding the eye for the intravitreous dose) were obtained in the
`kidney. In rabbits, the component nucleotide, 2.'..ftoorouridine is found in plasma and urine after single
`radio labeled pegaptanib intravenous and intravitreous doses. In rabbits, pegaptanib is eliminated as
`parent drug and metabolites primarily in the urine.
`
`Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.
`
`In humans, after a 3 mg monocular dose (10 times the recommended dose), the average(± standard
`deviation) apparent plasma half-life ofpegaptanib is 10 (±4) days.
`
`Special Populations
`Plasma concentrations do not appear to be affected by age or gender, but have not been studied in
`patients under the age of 50.
`
`Renal Insufficiency
`Dose adjustment for patients with renal impairment is not needed when administering the 0.3 mg dose.
`
`Following a single 3 mg dose (10 times the recommended dose), in patients with severe (N=7),
`moderate (N=l8), and mild (N=lO) renal impairment, the mean (CV%) pegaptanib AUC values were
`37.8 (17%), 26.7 (31%), and 23.6 (21%) µg.hr/mL, respectively. The corresponding Cmax values
`were 96.8 (23%), 81.6 (29.2%), and 66.5 (47%) ng/mL, respectively.
`
`In patients with renal impairment, following administration of 3 mg pegaptanib doses every 6 weeks,
`the last detectable pegaptanib concentrations in plasma after the fourth dose were highly variable
`(ranging from 8 ng/mL to 66 ng/mL) and the variability was more pronounced in patients with severe
`renal impairment.
`
`Hemodialysis
`Macugen has not been studied in patients requiring hemodialysis.
`
`Hepatic Ill11)ainnent
`Macugen has not been studied in patients with hepatic impairment.
`
`Clinical Studies
`Macugen was studied in two controlled, double-masked, and identically designed randomized studies
`in patients with neovascular AMO. Patients were randomized to receive control (sham treatment) or
`0.3 mg, 1 mg or 3 mg Macugen administered as intravitreous injections every 6 weeks for 48 weeks.
`A total of approximately 1200 patients were enrolled with 892 patients receiving Macugen and 298
`receiving a sham injection. The median age of the patients was 77 years. Patients received a mean 8.5
`treatments out of a possible 9 total treatments across all treatment arms. Patients were re-randomized
`between treatment and no treatment during the second year. Patients who continued treatment in year
`2 received a mean of 16 treatments out of a possible total 17 overall.
`
`The two trials enrolled patients with neovascular AMD characteristics including classic, occult, and
`mixed lesions ofup to 12 disc areas and baseline visual acuity in the study eye between 20/40 and
`
`I .
`
`Regeneron Exhibit 1062.004
`
`

`

`NDA21-756
`Page7
`
`20/320. The primary efficacy endpoint was the proportion of patients losing less than 15 letters of
`visual acuity, from baseline up to 54 week assessinent. Verteporfm photodynamic therapy (PDT)
`usage was permitted at the discretion of the investigators in patients with predominantly classic
`lesions.
`
`The groups treated with Macugen 0.3 mg exhibited a statistically significant result in both trials for the
`primary efficacy endpoint at l year: Study EOP1003, Macugen 73% vs. Sham 60%; Study EOPI004,
`Macugen 67% vs. Sham 53%. Concomitant use of PDT overall was low. More sham treated patients
`(75/296) received PDT than Macugen 0.3 mg treated patients (58/294).
`
`On average, Macugen 0.3 mg treated patients and sham treated patients continued to experience vision
`loss. However, the rate of vision decline in the Macugen treated group was slower than the rate in the
`patients who received sham treatment. See Figure l.
`
`Mean Visual Acuity: Year 1
`
`EOPI003
`
`P_T.._(Y .. t11
`+ (0.3..,al
`0, (Sham)
`
`..
`
`50
`
`I ..
`j
`j.u
`~...,
`
`• • .. •
`
`EOP1004
`
`Potlont TrHlment (Yo• 11
`♦ (0.3mg)
`0. [st.am)
`
`121124JOM ."205 .4
`W•k
`
`Figure l
`
`..
`
`n
`
`••
`.. -~-~~-~~-~~-~~
`•
`
`At the end of the first year (week 54), approximately 1050 of the original 1200 patients were re(cid:173)
`randomized to either continue the same treatment or to discontinue treatment through week 102. See
`Figure 2.
`
`Macugen was less effective during the second year than during the first year. The percentage of
`patients losing less thaR 15 letters from baseline to week 102 was: Study EOP1003, Macugen 38/67
`(57%); Sham 30/54 (56%); Study EOP1004, Macugen 40/66 (61 %); Sham 18/53 (34%).
`
`Regeneron Exhibit 1062.005
`
`

`

`NDA21-756
`Page 8
`
`Figure 2
`
`1G
`
`55
`
`I·
`-; •
`f
`:;;.
`
`35
`
`3G ...
`
`Mean Visual Acuity: Year 2
`
`EOP1003
`
`.,_,T_(Y-t) ➔ (Y-Z)
`•(Un,g) ➔ ID'_,.._)
`+10.3 n,gl ➔ (Ullllll
`<>-i-1 ➔ -0I'-
`
`1G
`
`!15
`
`EOP1004
`
`_ , . T...........t (Y•r 1) .... IY•••ZI
`+ (0.3 mg) .... (0.3 mg)
`it (0.3 mg) ... (Olscondooo)
`o (Sh..,) -+ -.,, o, dl-,tln.,.
`
`Is.
`!
`;~lie.=-•-=---""-----------(cid:173)
`;;
`> ~...----.......
`
`Dose levels above 0.3 mg did not demonstrate any additional benefit.
`
`The safety or efficacy of Macugen beyond 2 years has not been demonstrated.
`
`INDICATIONS AND USAGE
`
`Macugen is indicated for the treatment ofneovascular (wet) age-related macular degeneration.
`
`CONTRAINDICATIONS
`
`Macugen is contraindicated in patients with ocular or periocular infections.
`
`WARNINGS
`
`Intravitreous injections including those with Macugen have been associated with endophthalmitis.
`Proper aseptic injection technique should always be utilized when administering Macugen. In
`addition, patients should be monitored during the week following the injection to permit early
`treatment, should an infection occur (see DOSAGE AND ADMINISTRATION).
`
`Increases in intraocular pressure have been seen within 30 minutes of injection with Macugen.
`Therefore, intraocular pressure as well as the perfusion of the optic nerve head should be monitored
`and managed appropriately.
`
`Regeneron Exhibit 1062.006
`
`

`

`NDA21-756
`Page9
`
`PRECAUTIONS
`
`General
`FOR OPHTHALMIC INTRA VITREAL INJECTION ONLY.
`
`Information for Patients
`In the days following Macugen administration, patients are at risk for the development of
`endophthalmitis. If the eye becomes red, sensitive to light, painful or develops a change in vision, the
`patient should seek the immediate care with their ophthalmologist.
`
`Drug Interactions
`Drug interaction studies have not been conducted with Macugen. Pegaptanib is metabolized by
`nucleases and is generally not affected by the cytochrome P450 system.
`
`Two early clinical studies conducted in patients who received Macugen alone and in combination with
`PDT revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.
`
`Carcinogenesis. Mutagenesis. Impairment of Fertility
`Carcinogenicity studies with pegaptanib have not been conducted.
`
`Pegaptanib and its monomer component nucleotides (2'-MA, 2'-MG, 2'-FU, 2'-FC) were evaluated
`for genotoxicity in a battery of in vitro and in vivo assay systems. Pegaptanib, 2'-O-methyladenosine
`(2'-MA), and 2'-O-methylguanosine (2'-MG) were negative in all assay systems evaluated. 2'(cid:173)
`fluorouridine (2'-FU) and 2'-fluorocytidine (2'-FC) were nonclastogenic and were negative in all S.
`typhimurium tester strains, but produced a non-dose related increase in revertant frequency in a single
`E. coli tester strain. Pegaptanib, 2'-FU, and 2'-FC tested negative in cell transformation assays.
`
`No data are available to evaluate male or female mating or fertility indices.
`
`Pregnancy
`Teratogenic Effects: Pregnancy Category B.
`Pegaptanib produced no maternal toxicity and no evidence ofteratogenicity or fetal mortality in mice
`at intravenous doses ofup to 40 mg/kg/day (about 7,000 times the recommended human monocular
`ophthalmic dose of 0.3 mg/eye). Pegaptanib crosses the placenta in mice.
`
`There are no studies in pregnant women. The potential risk to humans is unknown. Macugen should
`be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the
`· fetus.
`
`Nursing Mothers
`It is not known whether pegaptanib is excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when Macugen is administered to a nursing woman.
`
`Pediatric Use
`Safety and effectiveness ofMacugen in pediatric patients have not been studied.
`
`Regeneron Exhibit 1062.007
`
`

`

`NDA21-756
`Page 10
`
`Geriatric Use
`Approximately 94% (834/892) of the patients treated with Macugen were~ 65 years of age and
`approximately 62% (553/892) were~ 75 years of age. No difference in treatment effect or systemic
`exposure was seen with increasing age.
`
`ADVERSE EVENTS
`
`Serious adverse events related to the injection procedure occurring in< l % of intravitreous injections
`included endophthalmitis (see WARNINGS), retinal detachment, and iatrogenic traumatic cataract.
`
`The most frequently reported adverse events in patients treated with Macugen 0.3 mg for up to two
`years were anterior chamber inflammation, blurred vision, cataract, conjunctiva! hemorrhage, corneal
`edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP),
`ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and
`vitreous opacities. These events occurred in approximately 10-40% of patients.
`
`The following events were reported in 6-10% of patients receiving Macugen 0.3 mg therapy:
`
`Ocular: blepharitis, conjunctivitis, photopsia, vitreous disorder.
`
`Non-Ocular: bronchitis, diarrhea, dizziness, headache, nausea, urinary tract infection.
`
`The following events were reported in 1-5% of patients receiving Macugen 0.3 mg therapy:
`
`Ocular: allergic conjunctivitis, conjunctiva! edema, corneal abrasion, corneal deposits, corneal
`epithelium disorder, endophthalrnitis, eye inflammation, eye swelling, eyelid irritation, meibomianitis,
`mydriasis, periorbital hematoma, retinal edema, vitreous hemorrhage.
`
`Non-Ocular: arthritis, bone spur, carotid artery occlusion, cerebrovascular accident, chest pain, contact
`dermatitis, contusion, diabetes mellitus, dyspepsia, hearing loss, pleural effusion, transient ischemic
`attack, urinary retention, vertigo, vomiting.
`
`OVERDOSAGE
`
`Doses of Macugen up to IO times the recommended dosage of0.3 mg have been studied. No
`additional adverse events have been noted but there is decreased efficacy with doses above 1 mg.
`
`DOSAGE AND ADMINISTRATION
`
`Macugen 0.3 mg should be administered once every six weeks by intra vitreous injection into the eye to
`be treated.
`
`Macugen should be inspected visually for particulate matter and discoloration prior to administration.
`Administration of the syringe contents involves attaching the threaded plastic plunger rod to the rubber
`stopper inside the barrel of the syringe. Do not pull back on the plunger. The syringe needle cap is
`then removed to allow administration of the product.
`
`Regeneron Exhibit 1062.008
`
`

`

`NDA 21-756
`Page 11
`
`The injection procedure should be carried out under controlled aseptic conditions, which includes 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 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, tonometry within 30 minutes following the injection, and biomicroscopy between
`two and seven days following the injection. Patients should be instructed to report any symptoms
`suggestive of endophthalmitis without delay.
`
`No special dosage modification is required for any of the populations that have been studied (i.e.
`gender, elderly).
`
`The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been
`studied.
`
`HOW SUPPLIED
`
`Macugen (pegaptanib sodium injection) is supplied in a single use 1 mL glass syringe with a gray
`rubber plunger containing 0.3 mg in a 90 uL deliverable volume. Each syringe is fitted with a fixed 27
`gauge needle covered with a gray rubber needle shield and a rigid plastic outside sheath. All are
`contained in a foil pouch. The accompanying polystyrene plunger rod and white flange are in a
`separate foil pouch. The two foil pouches are packaged in a carton.
`
`Storage
`Store in the refrigerator at 2° to 8°C (36° to 46°F). Do not freeze or shake vigorously.
`Rx only.
`
`NDC 68782-001-01
`
`Manufactured by:
`
`Gilead Sciences, Inc
`650 Cliffside Drive
`San Dimas, CA 91773
`
`For:
`
`clD)tech
`
`Eyetech Pharmaceuticals, Inc.
`Three Times Square
`New York, NY 10036
`
`Pfizer Inc.
`235 E.42nd St.
`New York, NY 10017
`
`Regeneron Exhibit 1062.009
`
`

`

`---------------~--------.. ____ ,..,.. __________________________ _
`
`This is a representation of an electronic record that was signed electronically and
`this page Is the manifestation of the electronic signature.
`
`/s/
`
`Jonca Bull
`12/17/04 06:57:56 PM
`
`Regeneron Exhibit 1062.010
`
`