TAKE CONTROL TO A HIGH Clyton, 34 yers old, is pilot who hikes nd cmps in his spre time. Clyton lives with hemophili B. LEVEL Reinyn Rech for high fctor levels in hemophili B 1 Json, 8 yers old, spends his time plying outdoors. Json lives with hemophili B. All imges of hemophili B ptients shown re for illustrtive purposes only. INDICATIONS AND USAGE Reinyn, Cogultion Fctor IX (Recominnt), GlycoPEGylted, is recominnt DNA derived cogultion Fctor IX concentrte indicted for use in dults nd children with hemophili B for on demnd tretment nd control of leeding episodes nd periopertive mngement of leeding. Limittions of Use: Reinyn is not indicted for routine prophylxis or for immune tolernce induction in ptients with hemophili B. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13.
2 TAKE CONTROL WITH HIGH FACTOR ACTIVITY In phse 3 study of dults with 2% fctor levels, single dose of Reinyn 40 IU/kg ws shown to Elevte fctor levels ove seline levels 1, +94 % 17 % ACHIEVE HIGHER FACTOR ACTIVITY FOR LONGER In phse 1 study, compred to stndrd hlf-life (SHL) FIX, Reinyn ws shown to 2,c Increse FIX ctivity Prolong time in the ody Keep FIX ctivity higher 2x 5x 10x Recovery rte 2,c Hlf-life 2,c Are under the curve 2,c 3 Phrmcokinetics Reinyn : 1.31% d SHL rfix: 0.68% d Reinyn : 93 hours SHL rfix: 19 hours Reinyn : 72 e SHL rfix: 7 e d Per IU/kg. e (U x h/ml). chieved fter n infusion 1, sustined fter 7 dys 1, Bsed on phrmcokinetic ssessment of single dose of Reinyn 40 IU/kg in 6 dults (men FIX ctivity 16.8%), 3 dolescents (men FIX ctivity 14.6%), 13 children ges 7 to 12 (men FIX ctivity 10.9%), nd 12 children ges 0-6 (men FIX ctivity 8.4%) upon enrollment in the phse 3 trils using one-stge ssy nd product-specific stndrd. All vlues re geometric men. Bsed upon 2.34% increse in fctor levels per IU/kg infused in dults. Reinyn chieved n 83-hour men hlf-life in dults 1, 2x THE RECOVERY RATE Reinyn chieved nd mintined higher fctor ctivity 2,c FIX Activity (%) 80 60 40 20 0 5x THE HALF-LIFE Time (hours) 10x THE AREA UNDER THE CURVE Reinyn SHL rfix 0 20 40 60 80 100 120 140 160 180 IMPORTANT SAFETY INFORMATION Contrindictions Reinyn is contrindicted in ptients with known hypersensitivity to Reinyn or its components, including hmster proteins. Wrnings nd Precutions Hypersensitivity rections, including nphylxis, my occur. Signs my include ngioedem, chest tightness, difficulty rething, wheezing, urticri, nd itching. Discontinue Reinyn if llergic or nphylctic-type rections occur nd initite pproprite tretment. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13. In this study, the estimted time to 1% with Reinyn ws 22.5 dys 2,c c Bsed upon phse 1 study of ptients dministered one of three doses of Reinyn (25, 50 or 100 IU/kg) compred with one 50 IU/kg dose of their prior SHL rfix (n=7) or pdfix (n=8) using one-stge ssy nd product-specific stndrd. For Reinyn, estimted men ctivity is djusted to dose of 50 IU/kg. Differences were similr in comprison of Reinyn to pdfix (recovery 1.3 vs 1.1 IU/dL per IU/kg, 1.2x; hlf-life 93 vs 18 hours, 5.2x; AUC 70 vs 9 U x h/ml, 8x). Reinyn is not pproved for routine prophylxis. Animls given repet doses of Reinyn showed ccumultion of PEG in the choroid plexus. The potentil clinicl implictions of these niml findings re unknown.
4 5 ACHIEVE CONTROL WHEN BLEEDS OCCUR PROTECTION FROM A SINGLE DOSE DURING SURGERY 98 % leeds treted with 1-2 infusions 1 n=143 leeding episodes Single In ll mjor surgeries studied 1,c 80 IU/kg 100 % Efficcy: On-demnd & Surgery preopertive dose 1 intropertive success rte 1 95 % rted their leed control s successful (defined s excellent or good) 1, n=142 leeding episodes c Results shown re from the surgery tril, which included 13 previously treted dolescent nd dult sujects. On the dy of their respective surgeries, ptients received 1 infusion of Reinyn 80 IU/kg. Postopertively, sujects received infusions of Reinyn 40 IU/kg t the investigtor s discretion for up to 3 weeks fter surgery. Across 13 surgicl procedures (9 mjor) which included 9 orthopedic, 1 gstrointestinl, nd 3 orl cvity procedures the hemosttic effect during surgery ws evluted on 4-point scle of excellent, good, moderte, or poor. Tretment success ws defined s excellent or good hemostsis. FIX ctivity sustined up to 48 hours postsurgery 1,3,d Results shown re from the on-demnd rm of the dolescent/ dult tril, in which 15 previously treted dolescent/dult sujects were treted for on-demnd leeds. In 14 sujects, there were totl of 143 leeding episodes. In 1 suject, no leeding episode dt were recorded. Results shown re sed on leed ssessment y either the ptient (for home tretment) or the study investigtor (for tretment under medicl supervision). Bleeds were ssessed using 4-point scle of excellent, good, moderte, or poor. FIX Activity, % 150 120 90 60 30 Norml FIX ctivity rnge (50% to 150%) 4,e Json, 8 yers old, spends his time plying outdoors. Json lives with hemophili B. 0-4 0 4 8 12 16 20 24 48 Time (h) Wrnings nd Precutions (cont d) Development of neutrlizing ntiodies (inhiitors) to Fctor IX my occur. Monitor ptients for development of fctor IX inhiitors if leeding is not controlled with the recommended dose of Reinyn or if expected Fctor IX ctivity plsm levels re not ttined. Fctor IX ctivity ssy results my vry with the type of ctivted prtil thromoplstin time regent used. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13. d In the surgery study, men FIX ctivity following n initil preopertive Reinyn 80 IU/kg in 13 procedures ws ssessed y one-stge ssy with product-specific stndrd. At 8 nd 24 hours, one suject who hd no FIX ctivity mesurement otined ws excluded. At 48 hours, 2 sujects who hd no FIX ctivity mesurement otined were excluded nd 4 sujects re-dosed prior to the second dy fter surgery for whom FIX ctivity t 24 hours were 84%, 112%, 131%, nd 134%. The FIX ctivity t 48 hours reflects mesurement on the second dy fter surgery (rnge 47-57 hours). e Rnge shded represents the norml popultion FIX ctivity rnge of 50% to 150%.
6 7 TAKE CONTROL WITH SIMPLIFIED DOSING FAST INFUSIONS AND FLEXIBLE STORAGE Unlike other FIX products, there is no need to clculte desired FIX ctivity levels when determining the pproprite dose 1,5-9 The recommended dose for ll ptients is Reinyn cn e infused in 1-4 MINUTES 1 With MixPro, prepring dose of Reinyn is s quick s A single dose should e sufficient for minor nd moderte leeds. Additionl doses of 40 IU/kg cn e given. 40 IU/kg for minor or moderte leeds 1, 80 IU/kg for mjor leeds FPO ATTACH 1, Prefilled diluent syringe contins 4 ml of diluent works with ny dose strength TWIST 1, Adpter connects the syringe nd vil, with 25 μm inline prticle filter Dosing nd Administrtion MIX 1, After mixing, the reconstituted solution cn e dministered 2000 1000 Mrkus, 33 yers old, spends his time with his fmily nd plying pool. Mrkus lives with hemophili B. For complete instructions on reconstitution nd dministrtion, plese refer to the Instructions for Use. 500 No refrigertion required (up to 86 F) 1,c Wrnings nd Precutions (cont d) The use of Fctor IX-contining products hs een ssocited with thromotic complictions. Monitor for thromotic nd consumptive cogulopthy when dministering Reinyn to ptients with liver disese, post-opertively, to neworn infnts, or to ptients t risk of thromosis or disseminted intrvsculr cogultion (DIC). Nephrotic syndrome hs een reported following immune tolernce induction therpy with Fctor IX products in hemophili B ptients with Fctor IX inhiitors, often with history of llergic rections to Fctor IX. The sfety nd efficcy of using Reinyn for immune tolernce induction hve not een estlished. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13. Room temperture stle for up to 6 months c If you choose to store Reinyn t room temperture, do not return it to the refrigertor. Reinyn vils cn lso e stored in the refrigertor t 36ºF-46ºF for up to 24 months or until the expirtion dte stted on the lel. Plese see Prescriing Informtion for complete storge instructions. Postreconstitution storge for up to 4 hours
8 9 DESIGNED FOR SAFETY ACHIEVE A LONG HALF-LIFE In clinicl trils, 115 previously treted mle ptients were given Reinyn for 8801 exposure dys 1 PEGyltion is technology used to extend hlf-life 12 0 Inhiitors nd thromotic events 1,10,11, Selective Attchment Prolonged Circultion Activted FIX Relese site-directed glycopegyltion Adverse rections include hypersensitivity (1%), itching (3%), nd injection-site rections (4%) 1, ctive FIX Formtion of inhiitors nd thromotic complictions hve een ssocited with FIX tretment. Monitor ptients for the development of inhiitors nd signs of thromosis 1 Identified in 115 previously treted ptients who were treted with Reinyn in clinicl studies. A previously treted ptient ws defined s suject with history of t lest 150 exposure dys to other FIX products (dolescent/dult sujects) or 50 exposure dys to other FIX products (peditric sujects) nd no history of inhiitors. There were totl of 8801 exposure dys, equivlent to 170 ptient-yers. A totl of 40 ptients (35%) were treted for more thn 2 yers. PEG selectively ttches to the FIX ctivtion peptide y site-directed glycopegyltion 13 PEG=polyethylene glycol. GlycoPEGyltion keeps Reinyn in the loodstrem longer where it needs to e to stop leeding 13 Reinyn releses rfix similr to ntive humn FIX once ctivted 1 Sfety Profile nd PEGyltion Leopoldo, 61 yers old, is n IT engineer who spends time siling. Leopoldo lives with hemophili B. Adverse Rections The most common dverse rections reported in clinicl trils ( 1%) were itching nd injection site rections. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13. Adverse Rections (cont d) Animls dministered repet doses of Reinyn showed ccumultion of PEG in the choroid plexus. The potentil clinicl implictions of these niml findings re unknown.
10 11 INFORMATION FOR YOUR PATIENTS TRIAL PROGRAM Eligile ptients cn receive up to 1-month supply of Reinyn PRODUCT ASSISTANCE PROGRAM Apply for the Product Assistnce Progrm y clling 1-844-NOVOSEC (1-844-668-6732) for more informtion CO-PAY ASSISTANCE PROGRAM Get help with co-py costs for Reinyn c Ptients who hve een prescried Novo Nordisk hemophili nd rre leeding disorder product for n FDA-pproved indiction, nd who hve commercil insurnce, my e eligile to receive limited supply of free product. Ptients who prticipte in ny government, stte, or federlly funded medicl or prescription enefit progrms, including Medicre, Medicid, Medigp, VA, DOD, nd TRICARE, including ptients who prticipte in mnged Medicid progrm or hve Medicid s secondry insurnce, re not eligile to receive product support. Product is provided t no cost to the ptient or the HCP, is not contingent on ny product purchse, nd the ptient nd HCP must not: (1) ill ny third prty for the free product, or (2) resell the free product. The Novo Nordisk Ptient Assistnce Progrm (PAP) is dministered y NovoSecure. To qulify for the PAP, ptients must demonstrte finncil need nd must hve ttempted to find lterntive reimursement. Severl fctors re considered in evluting finncil need, including cost of living, size of household, nd urden of totl medicl expenses. If the pplicnt qulifies under the PAP guidelines, limited supply of the requested mediction(s) will e shipped to the ptient. Ptients who qulify for PAP my e eligile to receive the prescried Novo Nordisk product, for up to 1 yer from the pprovl dte. Product limits vry. c Novo Nordisk Hemophili nd Rre Bleeding Disorders Co-py/Coinsurnce Terms nd Conditions: Enrolled ptients re eligile for up to $12,000 in co-py/coinsurnce ssistnce per clendr yer for ech NNI hemophili or rre leeding disorder product. Assistnce is retroctive to 60 dys. Ptients must e commercilly insured nd my not e prticipting in ny government, stte, or federlly funded medicl or prescription enefit progrms, including Medicre, Medicid, Medigp, VA, DOD, nd TRICARE, including ptients who prticipte in mnged Medicid progrm or hve Medicid s secondry insurnce. Uninsured, csh-pying ptients re not eligile to prticipte. Ptients re eligile to receive co-py/coinsurnce ssistnce on n nnul sis (12 months). Offer good only in the USA, Puerto Rico, Gum, Sipn, nd Virgin Islnds with prticipting phrmcies nd cnnot e redeemed t governmentsusidized clinics. Void where txed, restricted, or prohiited y lw. Asent chnge in Msschusetts lw, effective July 1, 2019, the Svings Crd will no longer e vlid for residents of Msschusetts. Ptient is responsile for complying with ny insurnce crrier co-pyment disclosure requirements, including disclosing ny svings received from this progrm. Re-confirmtion of informtion my e requested periodiclly to ensure ccurcy of dt nd complince with terms. This is not n insurnce progrm. Novo Nordisk reserves the right to rescind, revoke, or mend this offer without notice t ny time. Non-mediction expenses, such s ncillry supplies or dministrtion-relted costs, re not eligile. Must hve current prescription for n FDA-pproved indiction. Visit MyNovoSecure.com or cll 1-844-NOVOSEC (1-844-668-6732) to spek with NovoSecure Specilist Support Plese see Importnt Sfety Informtion throughout nd on pges 12 nd 13.
4 12 13 ACHIEVE CONTROL WHEN BLEEDS OCCUR IMPORTANT SAFETY INFORMATION INDICATIONS AND USAGE Adverse Rections Reinyn, Cogultion Fctor IX (Recominnt), GlycoPEGylted, is recominnt DNA derived cogultion Fctor IX concentrte indicted for use in dults nd children with hemophili B for on demnd tretment nd control of leeding % mngement leeds treted with 1-2 infusions1 episodes nd periopertive of leeding. leeding episodesprophylxis indicted for routine or for immune Limittions of Use: Reinyn is notn=143 tolernce induction in ptients with hemophili B. The most common dverse rections reported in clinicl trils ( 1%) were itching nd injection site rections. Animls dministered repet doses of Reinyn showed ccumultion of PEG in the choroid plexus. The potentil clinicl implictions of these niml findings re unknown. 98 IMPORTANT SAFETY INFORMATION Contrindictions Reinyn is contrindicted in ptients with known hypersensitivity to Reinyn or its components, including hmster proteins. Wrnings nd Precutions 95 rted their leed control successful Hypersensitivity rections, nphylxis, my occur.s Signs my include % including 1, (defined s excellent or good) ngioedem, chest tightness, difficulty rething, wheezing, urticri, nd itching. nphylctic-type rections occur nd initite Discontinue Reinyn if llergic orn=142 leeding episodes pproprite tretment. Development of neutrlizing ntiodies (inhiitors) to Fctor IX my occur. Monitor ptients for development of fctor IX inhiitors if leeding is not controlled with the recommended dose of Reinyn or if expected Fctor IX ctivity plsm levels re not ttined. Fctor IX ctivity ssy results my vry with the type of ctivted Results shownthromoplstin re from the on-demnd rm regent of the dolescent/ prtil time used. dult tril, in which 15 previously treted dolescent/dult The were use treted of Fctor IX-contining sujects for on-demnd leeds. In 14products sujects, hs een ssocited with thromotic complictions. for thromotic there were totl of 143Monitor leeding episodes. In 1 suject, no nd consumptive cogulopthy when leeding episode dt were recorded. to ptients with liver disese, post-opertively, to neworn dministering Reinyn Results shown or re to sed on leedt ssessment either the infnts, ptients risk ofythromosis or disseminted intrvsculr ptient (for home tretment) cogultion (DIC). or the study investigtor (for tretment under medicl supervision). Bleeds were ssessed Nephrotic syndrome hs een reported using 4-point scle of excellent, good, moderte, or poor. following immune tolernce induction therpy with Fctor IX products in hemophili B ptients with Fctor IX inhiitors, often with history of llergic rections to Fctor IX. The sfety nd efficcy of using Reinyn for immune tolernce induction hve not een estlished. References 1. Reinyn [pckge insert]. Plinsoro, NJ: Novo Nordisk Inc; My 2017. 2. Negrier C, Knoe K, Tiede A, Gingrnde P, Møss J. Enhnced phrmcokinetic properties of glycopegylted recominnt fctor IX: first humn dose tril in ptients with hemophili B. Blood. 2011;118(10):2695-2701. 3. Escor MA, Tehrnchi R, Krim FA, et l. Low-fctor consumption for mjor surgery in hemophili B with long-cting recominnt glycopegylted fctor IX. Hemophili. 2017;23(1):67-76. 4. 1-Stge APTT-Bsed Fctor Assys. Prcticl-Hemostsis We site. http://prcticl-hemostsis.com/fctor%20assys/1_stge_ptt_ssys.html. Accessed August 3, 2017. 5. Alprolix [pckge insert]. Cmridge, MA: Biogen Inc; 2017. 6. Rixuis [pckge insert]. Westlke Villge, CA: Bxlt Helthcre Corportion; 2016. 7. Idelvion [pckge insert]. Knkkee, IL: CSL Behring LLC; 2017. 8. Ixinity [pckge insert]. Berwyn, PA: Aptevo BioTherpeutics LLC; 2016. 9. Benefix [pckge insert]. Phildelphi, PA: Wyeth Phrmceuticls, Inc.; 2017. 10. Crco M, Zk M, Krim FA, et l. Noncog et pegol in previously treted children with hemophili B: results from n interntionl open-lel phse 3 tril. J Throm Hemost. 2016;14(8):1521-1529. 11. Collins PW, Young G, Knoe K, et l; prdigm 2 Investigtors. Recominnt long-cting glycopegylted fctor IX in hemophili B: multintionl rndomized phse 3 tril. Blood. 2014;124(26):3880-3886. 12. Swierczewsk M, Lee KC, Lee S. Wht is the future of PEGylted therpies? Expert Opin Emerg Drugs. 2015;20(4):531-536. 13. Østergrd H, Bjelke JR, Hnsen L, et l. Prolonged hlf-life nd preserved enzymtic properties of fctor IX selectively PEGylted on ntive N-glycns in the ctivtion peptide. Blood. 2011;118(8):2333-2341. rs. Json lives with hemophili B. Json, 8 yers old, spends his time plying outdoo Development of neutrlizing ntiodies (inhiitors) to Fctor IX my occur. Monitor ptients for development of fctor IX inhiitors if leeding is not controlled with the recommended dose of Reinyn or if expected Fctor IX ctivity plsm levels re not ttined. Fctor IX ctivity ssy results my vry with the type of ctivted prtil thromoplstin time regent used. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13. old, is pilot wh o hikes nd cm ps in his spre tim e. Clyton lives with hemophili B. Importnt Sfety Informtion Wrnings nd Precutions (cont d) Clyton, 34 yers
TAKE CONTROL TO A HIGH LEVEL High Fctor Activity 17 % Sustined fter 7 dys with single 40 IU/kg dose in dults with 2% fctor levels 1, Higher Fctor Activity For Longer 2x 5x 10x Recovery rte 2, Hlf-life 2, AUC 2, compred to SHL rfix 2, Bsed upon single initil dose of Reinyn 40 IU/kg in suset of 6 dults upon enrollment in the phse 3 trils. Men FIX ctivity ws 16.8% (one-stge ssy with product-specific stndrd), incrementl recovery ws 2.34 IU/dL per IU/kg nd hlf-life ws 83 hours. Phse 1 study of 15 dults dministered single doses of Reinyn (25, 50 nd 100 IU/kg) nd prior product (50 IU/kg). Comprison of recovery (Reinyn vs SHL rfix: 1.31 vs 0.68 IU/dL per IU/kg), hlf-life (Reinyn vs SHL rfix: 93 vs 19 hours), nd AUC (Reinyn vs SHL rfix: 72 vs 7 [U x h/ml]) re for 7 ptients dministered oth their prior SHL rfix nd Reinyn using one-stge ssy nd product-specific stndrd. Estimted men ctivity for Reinyn ws djusted to dose of 50 IU/kg. Reinyn is not pproved for routine prophylxis. Animls given repet doses of Reinyn showed ccumultion of PEG in the choroid plexus. The potentil clinicl implictions of these niml findings re unknown. INDICATIONS AND USAGE Reinyn, Cogultion Fctor IX (Recominnt), GlycoPEGylted, is recominnt DNA derived cogultion Fctor IX concentrte indicted for use in dults nd children with hemophili B for on demnd tretment nd control of leeding episodes nd periopertive mngement of leeding. Limittions of Use: Reinyn is not indicted for routine prophylxis or for immune tolernce induction in ptients with hemophili B. Plese see dditionl Importnt Sfety Informtion throughout nd on pges 12 nd 13. Novo Nordisk Inc., 800 Scudders Mill Rod, Plinsoro, New Jersey 08536 U.S.A. MixPro nd Reinyn re registered trdemrks nd NovoSecure is trdemrk of Novo Nordisk Helth Cre AG. Novo Nordisk is registered trdemrk of Novo Nordisk A/S. 2018 Novo Nordisk Printed in the U.S.A. USA17BIO02170 Jnury 2018