HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescriing informtion for. (fliercept) Injection For Intrvitrel Injection Initil U.S. Approvl: 211 RECENT MAJOR CHANGES Dosge nd Administrtion, Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) (2.2) /216 Dosge nd Administrtion, Dietic Mculr Edem (DME) (2.4) /216 Dosge nd Administrtion, Dietic Retinopthy (DR) in Ptients with DME (2.) /216 Contrindictions, Hypersensitivity (4.3) /216 INDICATIONS AND USAGE is vsculr endothelil growth fctor (VEGF) inhiitor indicted for the tretment of ptients with: Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) (1.1) Mculr Edem Following Retinl Vein Occlusion (RVO) (1.2) Dietic Mculr Edem (DME) (1.3) Dietic Retinopthy (DR) in Ptients with DME (1.4) DOSAGE AND ADMINISTRATION Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) The recommended dose for is 2 mg (. ml) dministered y intrvitrel injection every 4 (monthly) for the first 3 months, followed y 2 mg (. ml) vi intrvitrel injection once every 8 (2 months). (2.2) Although my e dosed s frequently s 2 mg every 4 (monthly), dditionl efficcy ws not demonstrted in most ptients when ws dosed every 4 compred to every 8. Some ptients my need every 4 week (monthly) dosing fter the first 12 (3 months). (2.2) Mculr Edem Following Retinl Vein Occlusion (RVO) The recommended dose for is 2 mg (. ml) dministered y intrvitrel injection once every 4 (monthly). (2.3) Dietic Mculr Edem (DME) nd Dietic Retinopthy (DR) in Ptients with Dietic Mculr Edem The recommended dose for is 2 mg (. ml) dministered y intrvitrel injection every 4 (monthly) for the first injections followed y 2 mg (. ml) vi intrvitrel injection once every 8 (2 months). (2.4, 2.) Although my e dosed s frequently s 2 mg every 4 (monthly), dditionl efficcy ws not demonstrted in most ptients when ws dosed every 4 compred to every 8. Some ptients my need every 4 week (monthly) dosing fter the first 2 ( months). (2.4, 2.) DOSAGE FORMS AND STRENGTHS 4 mg/ml solution for intrvitrel injection in single-use vil (3) CONTRAINDICATIONS Oculr or perioculr infection (4.1) Active introculr inflmmtion (4.2) Hypersensitivity (4.3) WARNINGS AND PRECAUTIONS Endophthlmitis nd retinl detchments my occur following intrvitrel injections. Ptients should e instructed to report ny symptoms suggestive of endophthlmitis or retinl detchment without dely nd should e mnged ppropritely. (.1) Increses in introculr pressure hve een seen within 6 minutes of n intrvitrel injection. (.2) There is potentil risk of rteril thromoemolic events following intrvitrel use of VEGF inhiitors. (.3) ADVERSE REACTIONS The most common dverse rections ( %) reported in ptients receiving were conjunctivl hemorrhge, eye pin, ctrct, vitreous floters, introculr pressure incresed, nd vitreous detchment. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Regeneron t 1-8-39-3248 or FDA t 1-8-FDA-88 or www.fd.gov/medwtch. See 17 for PATIENT COUNSELING INFORMATION. Revised: /217 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) 1.2 Mculr Edem Following Retinl Vein Occlusion (RVO) 1.3 Dietic Mculr Edem (DME) 1.4 Dietic Retinopthy (DR) in Ptients with DME 2 DOSAGE AND ADMINISTRATION 2.1 Importnt Injection Instructions 2.2 Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) 2.3 Mculr Edem Following Retinl Vein Occlusion (RVO) 2.4 Dietic Mculr Edem (DME) 2. Dietic Retinopthy (DR) in Ptients with DME 2.6 Preprtion for Administrtion 2.7 Injection Procedure 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Oculr or Perioculr Infections 4.2 Active Introculr Inflmmtion 4.3 Hypersensitivity WARNINGS AND PRECAUTIONS.1 Endophthlmitis nd Retinl Detchments.2 Increse in Introculr Pressure.3 Thromoemolic Events 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8.4 Peditric Use 8. Geritric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) 14.2 Mculr Edem Following Centrl Retinl Vein Occlusion (CRVO) 14.3 Mculr Edem Following Brnch Retinl Vein Occlusion (BRVO) 14.4 Dietic Mculr Edem (DME) 14. Dietic Retinopthy (DR) in Ptients with DME 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or susections omitted from the full prescriing informtion re not listed
.1 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE is indicted for the tretment of: 1.1 Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) 1.2 Mculr Edem Following Retinl Vein Occlusion (RVO) 1.3 Dietic Mculr Edem (DME) 1.4 Dietic Retinopthy (DR) in Ptients with DME 2 DOSAGE AND ADMINISTRATION 2.1 Importnt Injection Instructions For ophthlmic intrvitrel injection. must only e dministered y qulified physicin. 2.2 Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) The recommended dose for is 2 mg (. ml or microliters) dministered y intrvitrel injection every 4 (monthly) for the first 12 (3 months), followed y 2 mg (. ml) vi intrvitrel injection once every 8 (2 months). Although my e dosed s frequently s 2 mg every 4 (monthly), dditionl efficcy ws not demonstrted in most ptients when ws dosed every 4 compred to every 8 [see Clinicl Studies (14.1)]. Some ptients my need every 4 week (monthly) dosing fter the first 12 (3 months). 2.3 Mculr Edem Following Retinl Vein Occlusion (RVO) The recommended dose for is 2 mg (. ml or microliters) dministered y intrvitrel injection once every 4 (monthly) [see Clinicl Studies (14.2), (14.3)]. 2.4 Dietic Mculr Edem (DME) The recommended dose for is 2 mg (. ml or microliters) dministered y intrvitrel injection every 4 (monthly) for the first injections, followed y 2 mg (. ml) vi intrvitrel injection once every 8 (2 months). Although my e dosed s frequently s 2 mg every 4 (monthly), dditionl efficcy ws not demonstrted in most ptients when ws dosed every 4 compred to every 8 [see Clinicl Studies (14.4)]. Some ptients my need every 4 week (monthly) dosing fter the first 2 ( months). 2. Dietic Retinopthy (DR) in Ptients with DME The recommended dose for is 2 mg (. ml or microliters) dministered y intrvitrel injection every 4 (monthly) for the first injections, followed y 2 mg (. ml) vi intrvitrel injection once every 8 (2 months). Although my e dosed s frequently s 2 mg every 4 (monthly), dditionl efficcy ws not demonstrted in most ptients when ws dosed every 4 compred to every 8 [see Clinicl Studies (14.)]. Some ptients my need every 4 week (monthly) dosing fter the first 2 ( months). 2.6 Preprtion for Administrtion should e inspected visully prior to dministrtion. If prticultes, cloudiness, or discolortion re visile, the vil must not e used. Using septic technique, the intrvitrel injection should e performed with 3-guge x ½-inch injection needle. Vil The glss vil is for single use only. 1. Remove the protective plstic cp from the vil (see Figure 1). Figure 1: Figure 2: 3. Remove the 19-guge x 1½-inch, -micron, filter needle from its pouch nd remove the 1-mL syringe supplied in the crton from its pouch. Attch the filter needle to the syringe y twisting it onto the Luer lock syringe tip (see Figure 3). Figure 3:.1.3.4..7.8.9 4. Push the filter needle into the center of the vil stopper until the needle is completely inserted into the vil nd the tip touches the ottom or ottom edge of the vil.. Using septic technique withdrw ll of the vil contents into the syringe, keeping the vil in n upright position, slightly inclined to ese complete withdrwl. To deter the introduction of ir, ensure the evel of the filter needle is sumerged into the liquid. Continue to tilt the vil during withdrwl keeping the evel of the filter needle sumerged in the liquid (see Figures 4 nd 4). Figure 4: Figure 4:.3.4..7.8.9 Solution.1.3.4..7.8.9 Needle Bevel Pointing Down 6. Ensure tht the plunger rod is drwn sufficiently ck when emptying the vil in order to completely empty the filter needle. 7. Remove the filter needle from the syringe nd properly dispose of the filter needle. Note: Filter needle is not to e used for intrvitrel injection. 8. Remove the 3-guge x ½-inch injection needle from the plstic pouch nd ttch the injection needle to the syringe y firmly twisting the injection needle onto the Luer lock syringe tip (see Figure ). Figure :..7.8.9 2. Clen the top of the vil with n lcohol wipe (see Figure 2). 9. When redy to dminister, remove the plstic needle shield from the needle.. Holding the syringe with the needle pointing up, check the syringe for ules. If there re ules, gently tp the syringe with your finger until the ules rise to the top (see Figure 6).
Figure 6:.1.3.4..7.8.9 11. To eliminte ll of the ules nd to expel excess drug, SLOWLY depress the plunger so tht the plunger tip ligns with the line tht mrks. ml on the syringe (see Figures 7 nd 7). Figure 7: Figure 7:.1.3 Dosing Line for. ml.1.3.4.1 Solution fter expelling ir ules nd excess drug Flt Plunger Edge 2.7 Injection Procedure The intrvitrel injection procedure should e crried out under controlled septic conditions, which include surgicl hnd disinfection nd the use of sterile gloves, sterile drpe, nd sterile eyelid speculum (or equivlent). Adequte nesthesi nd topicl rod spectrum microicide should e given prior to the injection. Immeditely following the intrvitrel injection, ptients should e monitored for elevtion in introculr pressure. Approprite monitoring my consist of check for perfusion of the optic nerve hed or tonometry. If required, sterile prcentesis needle should e ville. Following intrvitrel injection, ptients should e instructed to report ny symptoms suggestive of endophthlmitis or retinl detchment (e.g., eye pin, redness of the eye, photophoi, lurring of vision) without dely [see Ptient Counseling Informtion (17)]. Ech vil should only e used for the tretment of single eye. If the contrlterl eye requires tretment, new vil should e used nd the sterile field, syringe, gloves, drpes, eyelid speculum, filter, nd injection needles should e chnged efore is dministered to the other eye. After injection, ny unused product must e discrded. 3 DOSAGE FORMS AND STRENGTHS Single-use, glss vil designed to provide. ml of 4 mg/ml of cler, colorless to ple yellow solution (2 mg) for intrvitrel injection. 4 CONTRAINDICATIONS 4.1 Oculr or Perioculr Infections is contrindicted in ptients with oculr or perioculr infections. 4.2 Active Introculr Inflmmtion is contrindicted in ptients with ctive introculr inflmmtion. 4.3 Hypersensitivity is contrindicted in ptients with known hypersensitivity to fliercept or ny of the excipients in. Hypersensitivity rections my mnifest s rsh, pruritus, urticri, severe nphylctic/nphylctoid rections, or severe introculr inflmmtion. WARNINGS AND PRECAUTIONS.1 Endophthlmitis nd Retinl Detchments Intrvitrel injections, including those with, hve een ssocited with endophthlmitis nd retinl detchments [see Adverse Rections (6.1)]. Proper septic injection technique must lwys e used when dministering. Ptients should e instructed to report ny symptoms suggestive of endophthlmitis or retinl detchment without dely nd should e mnged ppropritely [see Dosge nd Administrtion (2.7) nd Ptient Counseling Informtion (17)]..2 Increse in Introculr Pressure Acute increses in introculr pressure hve een seen within 6 minutes of intrvitrel injection, including with [see Adverse Rections (6.1)]. Sustined increses in introculr pressure hve lso een reported fter repeted intrvitrel dosing with vsculr endothelil growth fctor (VEGF) inhiitors. Introculr pressure nd the perfusion of the optic nerve hed should e monitored nd mnged ppropritely [see Dosge nd Administrtion (2.7)]..3 Thromoemolic Events There is potentil risk of rteril thromoemolic events (ATEs) following intrvitrel use of VEGF inhiitors, including. ATEs re defined s nonftl stroke, nonftl myocrdil infrction, or vsculr deth (including deths of unknown cuse). The incidence of reported thromoemolic events in wet AMD studies during the first yer ws 1.8% (32 out of 1824) in the comined group of ptients treted with. The incidence in the DME studies from seline to week 2 ws 3.3% (19 out of 78) in the comined group of ptients treted with compred with 2.8% (8 out of 287) in the control group; from seline to week, the incidence ws 6.4% (37 out of 78) in the comined group of ptients treted with compred with 4.2% (12 out of 287) in the control group. There were no reported thromoemolic events in the ptients treted with in the first six months of the RVO studies. 6 ADVERSE REACTIONS The following potentilly serious dverse rections re descried elsewhere in the leling: Hypersensitivity [see Contrindictions (4.3)] Endophthlmitis nd retinl detchments [see Wrnings nd Precutions (.1)] Increse in introculr pressure [see Wrnings nd Precutions (.2)] Thromoemolic events [see Wrnings nd Precutions (.3)] 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in other clinicl trils of the sme or nother drug nd my not reflect the rtes oserved in prctice. A totl of 2711 ptients treted with constituted the sfety popultion in seven phse 3 studies. Among those, 21 ptients were treted with the recommended dose of 2 mg. Serious dverse rections relted to the injection procedure hve occurred in <.1% of intrvitrel injections with including endophthlmitis nd retinl detchment. The most common dverse rections ( %) reported in ptients receiving were conjunctivl hemorrhge, eye pin, ctrct, vitreous floters, introculr pressure incresed, nd vitreous detchment. Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) The dt descried elow reflect exposure to in 1824 ptients with wet AMD, including 1223 ptients treted with the 2-mg dose, in 2 doule-msked, ctive-controlled clinicl studies (VIEW1 nd VIEW2) for 12 months [see Clinicl Studies (14.1)]. Tle 1: Adverse Rections Most Common Adverse Rections ( 1%) in Wet AMD Studies (N=1824) Active (rniizum) (N=9) Conjunctivl hemorrhge 2% 28% Eye pin 9% 9% Ctrct 7% 7% Vitreous detchment 6% 6% Vitreous floters 6% 7% Introculr pressure incresed % 7% Oculr hyperemi 4% 8% Cornel epithelium defect 4% % Detchment of the retinl pigment 3% 3% epithelium Injection site pin 3% 3% Foreign ody senstion in eyes 3% 4% Lcrimtion incresed 3% 1% Vision lurred 2% 2% Introculr inflmmtion 2% 3% Retinl pigment epithelium ter 2% 1% Injection site hemorrhge 1% 2% Eyelid edem 1% 2% Cornel edem 1% 1% Less common serious dverse rections reported in <1% of the ptients treted with were hypersensitivity, retinl detchment, retinl ter, nd endophthlmitis.
Mculr Edem Following Retinl Vein Occlusion (RVO) The dt descried elow reflect 6 months exposure to with monthly 2 mg dose in 218 ptients following CRVO in 2 clinicl studies (COPERNICUS nd GALILEO) nd 91 ptients following BRVO in one clinicl study (VIBRANT) [see Clinicl Studies (14.2), (14.3)]. Tle 2: Most Common Adverse Rections ( 1%) in RVO Studies Adverse Rections CRVO BRVO (N=218) (N=142) (N=91) (N=92) Eye pin 13% % 4% % Conjunctivl 12% 11% 2% 4% hemorrhge Introculr pressure 8% 6% 2% % incresed Cornel epithelium % 4% 2% % defect Vitreous floters % 1% 1% % Oculr hyperemi % 3% 2% 2% Foreign ody senstion 3% % 3% % in eyes Vitreous detchment 3% 4% 2% % Lcrimtion incresed 3% 4% 3% % Injection site pin 3% 1% 1% % Vision lurred 1% <1% 1% 1% Introculr inflmmtion 1% 1% % % Ctrct <1% 1% % % Eyelid edem <1% 1% 1% % Less common dverse rections reported in <1% of the ptients treted with in the CRVO studies were cornel edem, retinl ter, hypersensitivity, nd endophthlmitis. Dietic Mculr Edem (DME) The dt descried elow reflect exposure to in 78 ptients with DME treted with the 2-mg dose in 2 doule-msked, controlled clinicl studies (VIVID nd VISTA) from seline to week 2 nd from seline to week [see Clinicl Studies (14.4)]. Tle 3: Adverse Rections Most Common Adverse Rections ( 1%) in DME Studies Bseline to Week 2 Bseline to Week (N=78) (N=287) (N=78) (N=287) 28% 17% 31% 21% Conjunctivl hemorrhge Eye pin 9% 6% 11% 9% Ctrct 8% 9% 19% 17% Vitreous floters 6% 3% 8% 6% Cornel % 3% 7% % epithelium defect Introculr % 3% 9% % pressure incresed Oculr hyperemi % 6% % 6% Vitreous 3% 3% 8% 6% detchment Foreign ody 3% 3% 3% 3% senstion in eyes Lcrimtion 3% 2% 4% 2% incresed Vision lurred 2% 2% 3% 4% Introculr 2% <1% 3% 1% inflmmtion Injection site pin 2% <1% 2% <1% Eyelid edem <1% 1% 2% 1% Less common dverse rections reported in <1% of the ptients treted with were hypersensitivity, retinl detchment, retinl ter, cornel edem, nd injection site hemorrhge. 6.2 Immunogenicity As with ll therpeutic proteins, there is potentil for n immune response in ptients treted with. The immunogenicity of ws evluted in serum smples. The immunogenicity dt reflect the percentge of ptients whose test results were considered positive for ntiodies to in immunossys. The detection of n immune response is highly dependent on the sensitivity nd specificity of the ssys used, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, comprison of the incidence of ntiodies to with the incidence of ntiodies to other products my e misleding. In the wet AMD, RVO, nd DME studies, the pre-tretment incidence of immunorectivity to ws pproximtely 1% to 3% cross tretment groups. After dosing with for 24-, ntiodies to were detected in similr percentge rnge of ptients. There were no differences in efficcy or sfety etween ptients with or without immunorectivity. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Risk Summry Adequte nd well-controlled studies with hve not een conducted in pregnnt women. Afliercept produced dverse emryofetl effects in rits, including externl, viscerl, nd skeletl mlformtions. A fetl No Oserved Adverse Effect Level (NOAEL) ws not identified. At the lowest dose shown to produce dverse emryofetl effects, systemic exposures (sed on AUC for free fliercept) were pproximtely 6 times higher thn AUC vlues oserved in humns fter single intrvitrel tretment t the recommended clinicl dose [see Animl Dt]. Animl reproduction studies re not lwys predictive of humn response, nd it is not known whether cn cuse fetl hrm when dministered to pregnnt womn. Bsed on the nti-vegf mechnism of ction for fliercept [see Clinicl Phrmcology (12.1)], tretment with my pose risk to humn emryofetl development. should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus. All pregnncies hve ckground risk of irth defect, loss, or other dverse outcomes. The ckground risk of mjor irth defects nd miscrrige for the indicted popultion is unknown. In the U.S. generl popultion, the estimted ckground risk of mjor irth defects nd miscrrige in cliniclly recognized pregnncies is 2-4% nd 2%, respectively. Dt Animl Dt In two emryofetl development studies, fliercept produced dverse emryofetl effects when dministered every three dys during orgnogenesis to pregnnt rits t intrvenous doses 3 mg per kg, or every six dys during orgnogenesis t sucutneous doses.1 mg per kg. Adverse emryofetl effects included incresed incidences of postimplnttion loss nd fetl mlformtions, including nsrc, umilicl herni, diphrgmtic herni, gstroschisis, cleft plte, ectrodctyly, intestinl tresi, spin ifid, encephlomeningocele, hert nd mjor vessel defects, nd skeletl mlformtions (fused vertere, sternere, nd ris; supernumerry verterl rches nd ris; nd incomplete ossifiction). The mternl No Oserved Adverse Effect Level (NOAEL) in these studies ws 3 mg per kg. Afliercept produced fetl mlformtions t ll doses ssessed in rits nd the fetl NOAEL ws not identified. At the lowest dose shown to produce dverse emryofetl effects in rits (.1 mg per kg), systemic exposure (AUC) of free fliercept ws pproximtely 6 times higher thn systemic exposure (AUC) oserved in humns fter single intrvitrel dose of 2 mg. 8.2 Lcttion Risk Summry There is no informtion regrding the presence of fliercept in humn milk, the effects of the drug on the restfed infnt, or the effects of the drug on milk production/excretion. Becuse mny drugs re excreted in humn milk, nd ecuse the potentil for sorption nd hrm to infnt growth nd development exists, is not recommended during restfeeding. The developmentl nd helth enefits of restfeeding should e considered long with the mother s clinicl need for nd ny potentil dverse effects on the restfed child from.
8.3 Femles nd Mles of Reproductive Potentil Contrception Femles of reproductive potentil re dvised to use effective contrception prior to the initil dose, during tretment, nd for t lest 3 months fter the lst intrvitrel injection of. Infertility There re no dt regrding the effects of on humn fertility. Afliercept dversely ffected femle nd mle reproductive systems in cynomolgus monkeys when dministered y intrvenous injection t dose pproximtely times higher thn the systemic level oserved humns with n intrvitrel dose of 2 mg. A No Oserved Adverse Effect Level (NOAEL) ws not identified. These findings were reversile within 2 fter cesstion of tretment [see Nonclinicl Toxicology (13.1)]. 8.4 Peditric Use The sfety nd effectiveness of in peditric ptients hve not een estlished. 8. Geritric Use In the clinicl studies, pproximtely 76% (249/271) of ptients rndomized to tretment with were 6 yers of ge nd pproximtely 46% (12/271) were 7 yers of ge. No significnt differences in efficcy or sfety were seen with incresing ge in these studies. 11 DESCRIPTION (fliercept) is recominnt fusion protein consisting of portions of humn VEGF receptors 1 nd 2 extrcellulr domins fused to the Fc portion of humn IgG1 formulted s n iso-osmotic solution for intrvitrel dministrtion. Afliercept is dimeric glycoprotein with protein moleculr weight of 97 kilodltons (kd) nd contins glycosyltion, constituting n dditionl % of the totl moleculr mss, resulting in totl moleculr weight of 1 kd. Afliercept is produced in recominnt Chinese hmster ovry (CHO) cells. is sterile, cler, nd colorless to ple yellow solution. is supplied s preservtive-free, sterile, queous solution in single-use, glss vil designed to deliver. ml ( microliters) of (4 mg/ml in mm sodium phosphte, 4 mm sodium chloride,.3% polysorte 2, nd % sucrose, ph 6.2). 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action Vsculr endothelil growth fctor-a (VEGF-A) nd plcentl growth fctor (PlGF) re memers of the VEGF fmily of ngiogenic fctors tht cn ct s mitogenic, chemotctic, nd vsculr permeility fctors for endothelil cells. VEGF cts vi two receptor tyrosine kinses, VEGFR-1 nd VEGFR-2, present on the surfce of endothelil cells. PlGF inds only to VEGFR-1, which is lso present on the surfce of leucocytes. Activtion of these receptors y VEGF-A cn result in neovsculriztion nd vsculr permeility. Afliercept cts s solule decoy receptor tht inds VEGF-A nd PlGF, nd therey cn inhiit the inding nd ctivtion of these cognte VEGF receptors. 12.2 Phrmcodynmics Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) In the clinicl studies ntomic mesures of disese ctivity improved similrly in ll tretment groups from seline to week 2. Antomic dt were not used to influence tretment decisions [see Clinicl Studies (14.1)]. Mculr Edem Following Retinl Vein Occlusion (RVO) Reductions in men retinl thickness were oserved in COPERNICUS, GALILEO, nd VIBRANT t week 24 compred to seline. Antomic dt were not used to influence tretment decisions [see Clinicl Studies (14.2), (14.3)]. Dietic Mculr Edem (DME) Reductions in men retinl thickness were oserved in VIVID nd VISTA t 2 nd compred to seline. Antomic dt were not used to influence tretment decisions [see Clinicl Studies (14.4)]. 12.3 Phrmcokinetics is dministered intrvitrelly to exert locl effects in the eye. In ptients with wet AMD, RVO, or DME, following intrvitrel dministrtion of, frction of the dministered dose is expected to ind with endogenous VEGF in the eye to form n inctive fliercept: VEGF complex. Once sored into the systemic circultion, fliercept presents in the plsm s free fliercept (unound to VEGF) nd more predominnt stle inctive form with circulting endogenous VEGF (i.e., fliercept: VEGF complex). Asorption/Distriution Following intrvitrel dministrtion of 2 mg per eye of to ptients with wet AMD, RVO, nd DME, the men C mx of free fliercept in the plsm ws.2 mcg/ml (rnge: to.4 mcg/ml),. mcg/ml (rnge: to.81 mcg/ml), nd.3 mcg/ml (rnge: to.76 mcg/ml), respectively nd ws ttined in 1 to 3 dys. The free fliercept plsm concentrtions were undetectle two post-dosing in ll ptients. Afliercept did not ccumulte in plsm when dministered s repeted doses intrvitrelly every 4. It is estimted tht fter intrvitrel dministrtion of 2 mg to ptients, the men mximum plsm concentrtion of free fliercept is more thn fold lower thn the concentrtion of fliercept required to hlf-mximlly ind systemic VEGF. The volume of distriution of free fliercept following intrvenous (I.V.) dministrtion of fliercept hs een determined to e pproximtely 6L. Metolism/Elimintion Afliercept is therpeutic protein nd no drug metolism studies hve een conducted. Afliercept is expected to undergo elimintion through oth trgetmedited disposition vi inding to free endogenous VEGF nd metolism vi proteolysis. The terminl elimintion hlf-life (t1/2) of free fliercept in plsm ws pproximtely to 6 dys fter I.V. dministrtion of doses of 2 to 4 mg/kg fliercept. Specific Popultions Renl Impirment Phrmcokinetic nlysis of sugroup of ptients (n=492) in one wet AMD study, of which 43% hd renl impirment (mild n=12, moderte n=74, nd severe n=16), reveled no differences with respect to plsm concentrtions of free fliercept fter intrvitrel dministrtion every 4 or 8. Similr results were seen in ptients in RVO study nd in ptients in DME study. No dose djustment sed on renl impirment sttus is needed for either wet AMD, RVO, or DME ptients. Other No specil dosge modifiction is required for ny of the popultions tht hve een studied (e.g., gender, elderly). 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility No studies hve een conducted on the mutgenic or crcinogenic potentil of fliercept. Effects on mle nd femle fertility were ssessed s prt of 6- month study in monkeys with intrvenous dministrtion of fliercept t weekly doses rnging from 3 to 3 mg per kg. Asent or irregulr menses ssocited with ltertions in femle reproductive hormone levels nd chnges in sperm morphology nd motility were oserved t ll dose levels. In ddition, femles showed decresed ovrin nd uterine weight ccompnied y compromised lutel development nd reduction of mturing follicles. These chnges correlted with uterine nd vginl trophy. A No Oserved Adverse Effect Level (NOAEL) ws not identified. Intrvenous dministrtion of the lowest dose of fliercept ssessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) for free fliercept tht ws pproximtely times higher thn the systemic exposure oserved in humns fter n intrvitrel dose of 2 mg. All chnges were reversile within 2 fter cesstion of tretment. 13.2 Animl Toxicology nd/or Phrmcology Erosions nd ulcertions of the respirtory epithelium in nsl turintes in monkeys treted with fliercept intrvitrelly were oserved t intrvitrel doses of 2 or 4 mg per eye. At the NOAEL of. mg per eye in monkeys, the systemic exposure (AUC) ws 6 times higher thn the exposure oserved in humns fter n intrvitrel dose of 2 mg. Similr effects were not seen in clinicl studies [see Clinicl Studies (14)]. 14 CLINICAL STUDIES 14.1 Neovsculr (Wet) Age-Relted Mculr Degenertion (AMD) The sfety nd efficcy of were ssessed in two rndomized, multicenter, doule-msked, ctive-controlled studies in ptients with wet AMD. A totl of 2412 ptients were treted nd evlule for efficcy (1817 with ) in the two studies (VIEW1 nd VIEW2). In ech study, ptients were rndomly ssigned in 1:1:1:1 rtio to 1 of 4 dosing regimens: 1) dministered 2 mg every 8 following 3 initil monthly doses ( 2Q8); 2) dministered 2 mg every 4 ( 2Q4); 3). mg dministered every 4 (.Q4); nd 4) rniizum dministered. mg every 4 (rniizum. mg Q4). Ptient ges rnged from 49 to 99 yers with men of 76 yers. In oth studies, the primry efficcy endpoint ws the proportion of ptients who mintined vision, defined s losing fewer thn letters of visul cuity t week 2 compred to seline. Dt re ville through week 2. Both 2Q8 nd 2Q4 groups were shown to hve efficcy tht ws cliniclly equivlent to the rniizum. mg Q4 group. Detiled results from the nlysis of the VIEW1 nd VIEW2 studies re shown in Tle 4 nd Figure 8 elow.
Tle 4: Efficcy Outcomes t Week 2 (Full Anlysis Set with LOCF) in VIEW1 nd VIEW2 Studies VIEW1 rniizum. mg Q4 VIEW2 rniizum. mg Q4 Full Anlysis Set N=31 N=34 N=34 N=36 N=39 N=291 Efficcy Outcomes Proportion of 94% 9% 94% 9% 9% 9% ptients who mintined visul cuity (< letters of BCVA loss) Difference (9.1% CI) (-3.2, 4.4) 1.3 (-2.4,.) (-2.9, 4.) -.3 (-4., 3.3) Men chnge 7.9.9 8.1 8.9 7.6 9.4 in BCVA s mesured y ETDRS letter score from Bseline Difference in LS men (9.1% CI).3 (-2., 2.) 3.2 (.9,.4) -.9 (-3.1, 1.3) -2. (-4.1, ) Numer of ptients who gined t lest letters of vision from Bseline Difference (9.1% CI) 92 (31%) -.4 114 (38%) 6.6 (-7.7, 7.) (-1., 14.1) 94 (31%) 96 (31%) -2.6 91 (29%) -4.6 (-1, 4.9) (-12.1, 2.9) BCVA = Best Corrected Visul Acuity; CI = Confidence Intervl; ETDRS = Erly Tretment Dietic Retinopthy Study; LOCF = Lst Oservtion Crried Forwrd (seline vlues re not crried forwrd); 9.1% confidence intervls were presented to djust for sfety ssessment conducted during the study. After tretment initition with 3 monthly doses group minus the rniizum group Figure 8: from Bseline to Week 2 in VIEW1 nd VIEW2 Studies VIEW 1 4 8 12 16 2 24 28 32 36 4 44 48 2 2mg Q8 VIEW 2 4 8 12 16 2 24 28 32 36 4 44 48 2 2mg Q4 Rniizum.mg Q4 +.9 +8.1 +7.9 +9.4 +8.9 +7.6 99 (34%) 14.2 Mculr Edem Following Centrl Retinl Vein Occlusion (CRVO) The sfety nd efficcy of were ssessed in two rndomized, multicenter, doule-msked, shm-controlled studies in ptients with mculr edem following CRVO. A totl of 38 ptients were treted nd evlule for efficcy (217 with ) in the two studies (COPERNICUS nd GALILEO). In oth studies, ptients were rndomly ssigned in 3:2 rtio to either 2 mg dministered every 4 (2Q4), or shm injections (control group) dministered every 4 for totl of 6 injections. Ptient ges rnged from 22 to 89 yers with men of 64 yers. In oth studies, the primry efficcy endpoint ws the proportion of ptients who gined t lest letters in BCVA compred to seline. At week 24, the group ws superior to the control group for the primry endpoint. Results from the nlysis of the COPERNICUS nd GALILEO studies re shown in Tle nd Figure 9 elow. Tle : Efficcy Outcomes t Week 24 (Full Anlysis Set with LOCF) in COPERNICUS nd GALILEO Studies Efficcy Outcomes Proportion of ptients who gined t lest letters in BCVA from Bseline Weighted Difference, (9.1% CI) Men chnge in BCVA s mesured y ETDRS letter score from Bseline (SD) Difference in LS men,d (9.1% CI) COPERNICUS GALILEO N=73 N=114 N=68 N=3 12% 6% 22% 6% -4. (18.) 44.8% c (32.9, 6.6) 17.3 (12.8) 21.7 c (17.3, 26.1) 3.3 (14.1) 38.3% c (24.4, 2.1) 18. (12.2) 14.7 c (.7, 18.7) Difference is minus Difference nd CI re clculted using Cochrn-Mntel-Henszel (CMH) test djusted for seline fctors; 9.1% confidence intervls were presented to djust for the multiple ssessments conducted during the study. c p<.1 compred with d LS men nd CI sed on n ANCOVA model Figure 9: Men Chnge in BCVA s Mesured y ETDRS Letter Score from Bseline to Week 24 in COPERNICUS nd GALILEO Studies COPERNICUS 2-2 - 4 8 12 16 2 24 GALILEO 4 8 12 16 2 24 Group +17.3 Tretment effects in evlule sugroups (e.g., ge, gender, rce, seline visul cuity, retinl perfusion sttus, nd CRVO durtion) in ech study nd in the comined nlysis were in generl consistent with the results in the overll popultions. -4. +18. +3.3
14.3 Mculr Edem Following Brnch Retinl Vein Occlusion (BRVO) The sfety nd efficcy of were ssessed in 24-week, rndomized, multi-center, doule-msked, controlled study in ptients with mculr edem following BRVO. A totl of 181 ptients were treted nd evlule for efficcy (91 with ) in the VIBRANT study. In the study, ptients were rndomly ssigned in 1:1 rtio to either 2 mg dministered every 4 (2Q4) or lser photocogultion dministered t seline nd susequently s needed (control group). Ptient ges rnged from 42 to 94 yers with men of 6 yers. In the VIBRANT study, the primry efficcy endpoint ws the proportion of ptients who gined t lest letters in BCVA t week 24 compred to seline. At week 24, the group ws superior to the control group for the primry endpoint. Detiled results from the nlysis of the VIBRANT study re shown in Tle 6 nd Figure elow. Tle 6: Efficcy Outcomes t Week 24 (Full Anlysis Set with LOCF) in VIBRANT Study VIBRANT N=9 N=91 Efficcy Outcomes Proportion of ptients who 26.7% 2.7% gined t lest letters in BCVA from Bseline Weighted Difference, (9% CI) Men chnge in BCVA s mesured y ETDRS letter score from Bseline (SD) Difference in LS men,d (9% CI) 6.9 (12.9) 26.6% c (13., 4.1) 17. (11.9). c (7.1, 14.) Difference is minus Difference nd CI re clculted using Mntel-Henszel weighting scheme djusted for region (North Americ vs. Jpn) nd seline BCVA ctegory (> 2/2 nd 2/2) c p<.1 compred with d LS men nd CI sed on n ANCOVA model Figure : Men Chnge in BCVA s Mesured y ETDRS Letter Score from Bseline to Week 24 in VIBRANT Study 2 VIBRANT 4 8 12 16 2 24 Group +17. Tretment effects in evlule sugroups (e.g., ge, gender, nd seline retinl perfusion sttus) in the study were in generl consistent with the results in the overll popultions. 14.4 Dietic Mculr Edem (DME) The sfety nd efficcy of were ssessed in two rndomized, multicenter, doule-msked, controlled studies in ptients with DME. A totl of 862 rndomized nd treted ptients were evlule for efficcy. Ptient ges rnged from 23 to 87 yers with men of 63 yers. Of those, 76 were rndomized to groups in the two studies (VIVID nd VISTA). In ech study, ptients were rndomly ssigned in 1:1:1 rtio to 1 of 3 dosing regimens: 1) dministered 2 mg every 8 following initil monthly injections ( 2Q8); 2) dministered 2 mg every 4 ( 2Q4); nd 3) mculr lser photocogultion (t seline nd then s needed). Beginning t week 24, ptients meeting pre-specified threshold of vision loss were eligile to receive dditionl tretment: ptients in the groups could receive lser nd ptients in the lser group could receive. +6.9 In oth studies, the primry efficcy endpoint ws the men chnge from seline in BCVA t week 2 s mesured y ETDRS letter score. Efficcy of oth 2Q8 nd 2Q4 groups ws sttisticlly superior to the control group. This sttisticlly superior improvement in BCVA ws mintined t week in oth studies. Results from the nlysis of the VIVID nd VISTA studies re shown in Tle 7 nd Figure 11 elow. Tle 7: Efficcy Outcomes t 2 nd (Full Anlysis Set with LOCF) in VIVID nd VISTA Studies VIVID VISTA Full Anlysis Set N=13 N=136 N=132 N=1 N=4 N=4 Efficcy Outcomes t Week 2 Men chnge in BCVA s mesured y ETDRS letter score from Bseline (SD) Difference,c in LS men (97.% CI) Proportion of ptients who gined t lest letters in BCVA from Bseline Adjusted Difference c,e (97.% CI).7 (9.3) 9.1 d. (9.6) 9.3 d 1.2 (1).7 (8.2). d 12. (9.) 12.2 d (12.) (6.3, 11.8) (6., 12.) (7.7, 13.2) (9.4,.) 33.3% 32.4% 9.1% 31.1% 41.6% 7.8% 24.2% d 23.3% d (13., 34.9) (12.6, 33.9) Efficcy Outcomes t Week Men chnge in BCVA s mesured y ETDRS letter score from Bseline (SD) Difference,c in LS men (97.% CI) Proportion of ptients who gined t lest letters in BCVA from Bseline Adjusted Difference c,e (97.% CI) 9.4 (.) 8.2 d 11.4 (11.2).7 d.7 (11.8) 23.3% d 34.2% d (13., 33.1) (24.1, 44.4) 11.1 (.7).1 d 11. (13.8) 1 d.9 (13.9) (.2, 11.3) (7.6, 13.8) (7., 13.3) (7.1, 14.2) 31.1% 38.2% 12.1% 33.1% 38.3% 13.% 19.% d 26.1% d (8., 29.9) (14.8, 37.) 2.1% d 2.8% d (9.6, 3) (.1, 36.6) After tretment initition with monthly injections LS men nd CI sed on n ANCOVA model with seline BCVA mesurement s covrite nd fctor for tretment group. Additionlly, protocol specified strtifiction fctors were included in the model. c Difference is group minus group d p<.1 compred with e Difference with confidence intervl (CI) nd sttisticl test is clculted using Mntel- Henszel weighting scheme djusted y protocol specified strtifiction fctors.
Figure 11: Men Chnge in BCVA s Mesured y ETDRS Letter Score from Bseline to Week in VIVID nd VISTA Studies 4 12 2 28 36 44 2 6 68 76 84 92 Tretment effects in the sugroup of ptients who hd previously een treted with VEGF inhiitor prior to study prticiption were similr to those seen in ptients who were VEGF inhiitor nïve prior to study prticiption. Tretment effects in evlule sugroups (e.g., ge, gender, rce, seline HA1c, seline visul cuity, prior nti-vegf therpy) in ech study were in generl consistent with the results in the overll popultions. 14. Dietic Retinopthy (DR) in Ptients with DME In the VIVID nd VISTA studies, n efficcy outcome ws the chnge in the Erly Tretment Dietic Retinopthy Study (ETDRS) Dietic Retinopthy Severity Scle (ETDRS-DRSS). The ETDRS-DRSS score ws ssessed t seline nd pproximtely every 6 months therefter for the durtion of the studies [see Clinicl Studies (14.4)]. All enrolled ptients hd DR nd DME t seline. The mjority of ptients enrolled in these studies (77%) hd moderte-to-severe nonprolifertive dietic retinopthy (NPDR) sed on the ETDRS-DRSS. At week, the proportion of ptients improving y t lest 2 steps on the ETDRS-DRSS ws significntly greter in oth tretment groups (2Q4 nd 2Q8) when compred to the control group. Results from the nlysis of ETDRS-DRSS t week in the VIVID nd VISTA studies re shown in Tle 8 elow. Tle 8: Proportion of Ptients who Achieved 2-Step Improvement from Bseline in the ETDRS-DRSS Score t Week (LOCF ) in VIVID nd VISTA Studies VIVID VISTA Evlule Ptients c N=1 N=97 N=99 N=148 N=3 N= Numer of ptients with 2-step improvement on ETDRS-DRSS from Bseline Difference d,e (97.% CI) 32 (32%) 24% f (12, 36) 27 (28%) 21% f (9, 33) VIVID +.7 +. +.7 7 (7%) 6 (38%) 22% f (11, 33) 8 (38%) 22% f (11, 33) +11.4 24 (16%) Non-grdle post-seline ETDRS-DRSS vlues were treted s missing nd were imputed using the lst grdle ETDRS-DRSS vlues (including seline vlues if ll postseline vlues were missing or non-grdle) After tretment initition with monthly injections +1.2 VISTA +12. + 4 12 2 28 36 44 2 6 68 76 84 92 Group +9.4 +.7 +11. +11.1 +.9 c The numer of evlule ptients included ll ptients who hd vlid ETDRS-DRSS dt t seline d Difference with confidence intervl (CI) ws clculted using Mntel-Henszel weighting scheme djusted y protocol specified strtifiction fctors e Difference is minus group f p<.1 compred with Results of the evlule sugroups (e.g., ge, gender, rce, seline HA1c, seline visul cuity) on the proportion of ptients who chieved 2-step improvement on the ETDRS-DRSS from seline to week were, in generl, consistent with those in the overll popultion. 16 HOW SUPPLIED/STORAGE AND HANDLING Ech Vil is for single eye use only. is supplied in the following presenttion [see Dosge nd Administrtion (2.6) nd (2.7)]. NDC NUMBER CARTON TYPE CARTON CONTENTS 617--2 Vil one single-use, sterile, 3-mL, glss vil designed to deliver. ml of 4 mg/ml one 19-guge x 1½-inch, - micron, filter needle for withdrwl of the vil contents one 3-guge x ½-inch injection needle for intrvitrel injection one 1-mL syringe for dministrtion one pckge insert Storge should e refrigerted t 2 C to 8 C (36 F to 46 F). Do Not Freeze. Do not use eyond the dte stmped on the crton nd continer lel. Protect from light. Store in the originl crton until time of use. 17 PATIENT COUNSELING INFORMATION In the dys following dministrtion, ptients re t risk of developing endophthlmitis or retinl detchment. If the eye ecomes red, sensitive to light, pinful, or develops chnge in vision, dvise ptients to seek immedite cre from n ophthlmologist [see Wrnings nd Precutions (.1)]. Ptients my experience temporry visul disturnces fter n intrvitrel injection with nd the ssocited eye exmintions [see Adverse Rections (6)]. Advise ptients not to drive or use mchinery until visul function hs recovered sufficiently. Mnufctured y: Regeneron Phrmceuticls, Inc. 777 Old Sw Mill River Rod Trrytown, NY 91-677 U.S. License Numer 176 is registered trdemrk of Regeneron Phrmceuticls, Inc. 217, Regeneron Phrmceuticls, Inc. All rights reserved. Issue Dte: My 217 US-LEA-(6)