From: Reese Gorman Sent: Tuesday, October 03, 2017 9:53 AM To: Chris Truitt Subject: Test - Don’t Leave HER2 Exposed In HER 2+ mBC, don't leave HER 2 expo sed Don't Leav e HER 2 Expo sed TYKE RB(R ) (lapat inib) is the only HER 2- target ed agent that can pass throu gh the cell mem brane to intrac ellula rly block HER 2 and EGF R recep tor signal ing.(1 ) Patie nt Reso urce: TYKE RB and HER 2+: https: //ww w.hcp .nova rtis.c om/pr oduct s/tyke rb/her 2- abc- mbc/ patie nt- resou rces/ ?site =D2Z T7&s ource =010 25 Dosin g and MOA Infor matio n: https: //ww w.hcp .nova rtis.c om/pr oduct s/tyke rb/her 2- abc- mbc/ ?site =27A 5J&s ource =010 25 Addr essin g HER 2+ meta static breas t canc er disea se progr essio n In HER 2+ mBC, clinic al trials have demo nstrat ed the benef it of conti nuing HER 2- direct ed treat ment s after progr essio n on a prior HER 2- direct ed thera py(1, 2) HER 2 signal ing is the main driver of cell prolif eratio n and disea se progr essio n in HER 2+ mBC and shoul d be addre ssed( 3,4) Resis tance to HER 2 direct ed thera pies remai ns a clinic al challe nge(3 ) Extra cellul ar chan ges to the HER 2 recep tor preve nt drug bindi ng but allow for conti nued signal ing throu gh intrac ellula r kinas e activit y(3) Thes e chan ges includ e recon figura tion of the bindi ng site or cleav age of the extra cellul ar doma in altog ether( 3) Targe t HER 2 differ ently with TYKE RB TYKE RB is a small mole cule that pass es throu gh the cell mem brane and binds to the part of HER 2 found inside the cell(1 ) TYKE RB is the only HER 2- direct ed agent that inhibit s the intrac ellula r tyrosi ne kinas e doma ins of both HER 2 and EGF R recep tors(1 ) TYKE RB retain s activit y again st HER 2 and EGF R activit y in trastu zuma b- resist ant breas t canc er cell lines, sugg estin g no cross - resist ance betw een TYKE RB and trastu zuma b(1) For more infor matio n about TYKE RB, click here: https: //ww w.hcp .nova rtis.c om/pr oduct s/tyke rb/her 2- abc- mbc/ ?site =MN G Direct &sour ce=0 1025 INDI CATI ON TYKE RB is indica ted in comb inatio n with cape citabi ne for the treat ment of patie nts with adva nced or meta static breas t canc er whos e tumor s overe xpres s huma n epide rmal growt h factor recep tor 2 (HER 2) and who have recei ved prior thera py includ ing an anthr acycli ne, a taxan e, and trastu zuma b. Limit ation of use: Patie nts shoul d have disea se progr essio n on trastu zuma b prior to initiati on of treat ment with TYKE RB in comb inatio n with cape citabi ne. IMPO RTA NT SAFE TY INFO RMA TION -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- WAR NING : Hepa totoxi city has been obser ved in clinic al trials and post mark eting exper ience . The hepat otoxic ity may be sever e and death s have been report ed. Caus ality of the death s is uncer tain. -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- Contr aindic ation: TYKE RB is contr aindic ated in patie nts with know n sever e hyper sensit ivity (eg, anap hylaxi s) to this produ ct or any of its comp onent s. Decr ease d Left Ventri cular Ejecti on Fracti on (LVE F): TYKE RB has been report ed to decre ase LVEF . In clinic al trials, >57% of LVEF decre ases occur red within the first 12 week s of treat ment. Use cauti on if admi nister ing to patie nts with condi tions that could impai r LVEF . Confi rm norm al LVEF befor e starti ng TYKE RB, and conti nue evalu ation s durin g treat ment. Hepa totoxi city: Hepa totoxi city (alani ne trans amin ase [ALT] or aspar tate trans amin ase [AST] >3 times the upper limit of norm al and total biliru bin >2 times the upper limit of norm al) has been obser ved in clinic al trials (<1% of patie nts) and post mark eting exper ience . The hepat otoxic ity may be sever e and death s have been report ed. Caus ality of the death s is uncer tain. The hepat otoxic ity may occur days to sever al mont hs after initiati on of treat ment. Liver functi on tests (trans amin ases, biliru bin, and alkali ne phos phata se) shoul d be monit ored befor e initiati on of treat ment, every 4 to 6 week s durin g treat ment, and as clinic ally indica ted. If chan ges in liver functi on are sever e, thera py with TYKE RB shoul d be disco ntinu ed and patie nts shoul d not be retrea ted with TYKE RB. Patie nts With Sever e Hepa tic Impai rment : If TYKE RB is to be admi nister ed to patie nts with sever e preex isting hepat ic impai rment , dose reduc tion shoul d be consi dered . Diarr hea: Diarr hea has been report ed durin g treat ment with TYKE RB. The diarrh ea may be sever e, and death s have been report ed. Diarr hea gener ally occur s early durin g treat ment with TYKE RB, with almo st half of those patie nts with diarrh ea first exper iencin g it within 6 days. This usuall y lasts 4 to 5 days. Lapat inib- induc ed diarrh ea is usuall y low- grade , with grade 3 and 4 diarrh ea occur ring in <10% and <1% of patie nts, respe ctivel y. Prom pt treat ment of diarrh ea with antidi arrhe al agent s (such as loper amid e) after the first unfor med stool is reco mme nded. Sever e cases of diarrh ea may requir e admi nistra tion of oral or intrav enou s electr olytes and fluids, use of antibi otics such as fluoro quino lones (espe cially if diarrh ea is persi stent beyo nd 24 hours , there is fever, or grade 3 or 4 neutr openi a), and interr uptio n or disco ntinu ation of thera py with TYKE RB. Inters titial Lung Disea se/Pn eumo nitis: TYKE RB has been assoc iated with inters titial lung disea se and pneu monit is. Patie nts shoul d be monit ored for pulm onary symp toms indica tive of inters titial lung disea se or pneu monit is. Disco ntinu e TYKE RB in patie nts who exper ience pulm onary symp toms indica tive of great er than or equal to grade 3 inters titial lung disea se/pn eumo nitis. QT Prolo ngati on: TYKE RB prolo ngs the QT interv al in some patie nts and shoul d be admi nister ed with cauti on in patie nts who have or may devel op QT prolo ngati on, includ ing patie nts with hypo kale mia or hypo magn esem ia, cong enital long QT syndr ome, patie nts takin g cumu lative high- dose anthr acycli ne, antiar rhyth mics, or other produ cts that lead to QT prolo ngati on. Hypo kale mia and hypo magn esem ia shoul d be corre cted prior to admi nistra tion, and electr ocard iogra m and electr olyte monit oring shoul d be consi dered . Sever e Cuta neou s React ions have been report ed. Disco ntinu e TYKE RB if life- threat ening reacti ons (eg, eryth ema multif orme, Steve ns- John son syndr ome, or toxic epide rmal necro lysis) are susp ected . Preg nanc y: TYKE RB can caus e fetal harm when admi nister ed to a pregn ant wom an. Wom en shoul d be advis ed not to beco me pregn ant when takin g TYKE RB. If this drug is used durin g pregn ancy, or if the patie nt beco mes pregn ant while takin g this drug, the patie nt shoul d be appri sed of the poten tial hazar d to the fetus. Adver se React ions: The most com mon adver se reacti ons (?10 %) durin g thera py with TYKE RB plus cape citabi ne vs cape citabi ne were diarrh ea (65%, 40%), palm ar- plant ar erythr odys esthe sia (53%, 51%), naus ea (44%, 43%), rash (28%, 14%), vomiti ng (26%, 21%), fatigu e (23%, 25%), muco sal infla mmat ion (15%, 12%), stom atitis (14%, 11%), pain in extre mity (12%, 7%), dysp nea (12%, 8%), back pain (11%, 6%), dysp epsia (11%, 3%), dry skin (10%, 6%), and inso mnia (10%, 6%). The most com mon grade 3 and 4 adver se reacti ons with TYKE RB plus cape citabi ne comp ared to cape citabi ne were diarrh ea (14%, 10%) and palm ar- plant ar erythr odys esthe sia (12%, 14%). Labor atory Abno rmaliti es: Labor atory abnor maliti es durin g thera py with TYKE RB plus cape citabi ne vs cape citabi ne includ ed incre ased AST (49%, 43%), incre ased ALT (37%, 33%), and incre ased total biliru bin (45%, 30%). Pleas e see full Presc ribing Infor matio n, includ ing Boxe d WAR NING : https: //ww w.ph arma. us.no vartis .com/ sites/ www. phar ma.u s.nov artis. com/f iles/ty kerb. pdf EGF R, epide rmal growt h factor recep tor; HER 2, huma n epide rmal growt h factor recep tor 2; mBC, meta static breas t canc er. Refer ence s: 1. Tyker b [pres cribin g infor matio n]. East Hano ver, NJ: Nova rtis Phar mace utical s Corp; 2017. 2. Kadc yla [pres cribin g infor matio n]. South San Franc isco, CA: Gene ntech , Inc; 2016. 3. Rexe r BN, Artea ga CL. Intrin sic and acqui red resist ance to HER 2- target ed thera pies in HER 2 gene- ampli fied breas t canc er: mech anis ms and clinic al implic ation s. Crit Rev Oncol . 2012; 17(1): 1-16. 4. Card oso F, Costa A, Norto n L, et al. ESO- ESM O 2nd intern ation al cons ensu s guide lines for adva nced breas t canc er (ABC 2). Ann Oncol . 2014; 25(10 ):187 1- 1888. This mess age was inten ded for Robe rtCha rles@ test.c om. News Chan nel is a progr am from MNG Direct . 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