NN&I - June 2010

Nephrology News & IssuesBrief Summary FOSRENOL®(foss-wren-all) ( Lant hanum C arna 7 and1000 m gC h ewa b l e Ta b l . INDIC A TIONS ANDUSAGE FOSRL®i indica ted reducrumphpha te inpa tienith end a ge renaldia. CONTRAINDIC A TIONS ne kn n. PREC AUTIONS General: Pa t i e n i t hacute p e p t iculce r ulce ra t i ve c lit i r hn di a r l ruct i n we r e n include dinF OSR L®clinical udi . C aut i n h uld be u dinpa t i e n w i t h t h c ndit i n . DiagnosticTests: Abdminalx-ray fpa tienaking lanthanumcarna te mayha ve aradi-paque appearancet ypical fanima ging a gent. Long-term Effects: The r ewe r e n diffe r e nc in t h e ra ffract ur rm r t alit yinpa t i e n r e a ted w i t h F OSR L®c mpare d alterna t i veth e rapyf rup 3y e ar .The dura t i n f t r e a t -m e n te xp ure and t im f r v a t i nin t h e clinicalprramar h r c nclude t ha t F OSR L®d n affe c tt h e ri k ffract ur rm r t alit y bey nd3ye ar . Information for theP atient: FOSRL®tablhuld betaken with rimmedia telyafterm eal.Ta bl huld be chewedc mpletely befr all ing.T aidinchewinabl may be cruhed.Intactt ablhuldnalld. ifyy urphy ician t ha t y uaret aking F OSR L®pri r anab d minalx-ray PREC A UTI O N S,D iagnosti cTests ) . DrugInteractions: Lanthanumi n metalized. The a rpt i nandpharmac kinetic fF OSR L®are unaffe c ted b y c -adminira t i n w i t hcit ra te-c n t aining c mp und CLINIC A L PHARMACOLOGY: InV itro/InV ivoDrugInteractions ). An udy h dn ide ncet ha t F OSR L®f rm inlub l e c mple x w i t h w arfarin dixin furmid phe ny in m pr l land e nalaprilin imula ted g a ricfluid.In udi inhe alt hy lunteer F OSR L® h e nadminir e d3 0 minu inadv anc didn alter t h e pharmac kinetic f ral w arfarin dixin r m pr l l.Hr i t i r e c mme nde d t ha t c mp und u bjec r e duce da rp-t i n w h e nc -adminir e d w i t hant acid. g .aluminum-ma g n ium-rcalcium-b a d h uldnake n w i t hin 2 h ur fd ingw i t hF OSR L®. xamplf r e l evant cla fc mp und h e r e ant acid ha vebeend e m n ra ted r e duce b i a v ailab ilit yinclude ant i b i icucha uin l n ampicillinand tetracyclin t hyr idh rm n A -inhib i r a t inlipidregula r andant i-malarial . Theb i a v ailab ilit y f ralcipr fl xacin w a d e cre a d b yappr xima tely h e n t ake n h e r w i t hF OSR L®ina ing l e -dudyinhe alt hy lunteer .I t i r e c mme nd-e d t ha ral q uin l n e ant i b i ic are n ake n imult anu ly w i t hF OSR L®. Theb ia vailability fl hyrxinew a decr ead byapprxima tely4hen taken her withF OSRL®. nuently hyridhrmne replacement therapy huldnaken imultanuly withF OSRL®andmnirin f TSHl evel i recmmendedinpa tien receivinhm edicinala gen. Carcinogenesis,Mutagenesis, Impairmentof Fe rtility: Oraladminira tin flanthanumcarna ra frup 104 week a t d up 1 m f th alt perk g/day [2. imhe maximumrecmmendeddaily humandMRHf 7 mnam g/m2bai auming a 60-kg pa tient] revealedn idenc fcarcinnicpntial.In the muraladminira tin f lanthanumcarna te frup k a t ad f1 mg/kg/day (1.3 tim the MRHD)wa acia ted withanincreadincidenc f glandular mach adenma inmale mice. Lant hanumcarna dn egat i ve f rmut agenicact i v i t yinan Am a ay u ing and rain and H G PRT gen e mut at i nandchr m malaberra t i na ay in C hin hamr aryce ll . Lant hanumcarna te aldn egat i ve inan ralm u micr nucle u a aya t d up m g /kg( 1.7 t imh e MRH andinmicr nucle u andun che dule d DNA ynt h i a ay inra i venI V lant hanumchl ride at d up .1mg /k a d ha t pr duce dpla malant hanumc nce n t ra t i n imh e p e akhuman pla mac nce n t ra t i n. Lanthanumcarna a t d up mg/kg/day (3.4 timhe MRH did n affect fertility rma ting perfrmanc fmal rf emale ra . Pregnanc y: Pregnancy Ca ry C. adequa te and well-cntrlled udi ha vebeen cnductedinpregnanmen.Thee ffec fF OSRL®n the arptin f vitamin and hernutrien ha nn udiedinpregnanmen.FOSRL®i n recmmendedf ru during pregnancy. Inpregnant ra raladminira tin flanthanumcarna te a t d a higha 2000 mg/kg /day (3.4 timhe MRHD) rultedinnidenc fharm he fetu. Inpregnant rabbiraladminira tin flanthanumcarna te a t 1 mg/kg/day imhe MRHD)wa acia ted withar eductininma ternal dy weightg ain andfdc numptin increadp -implanta tinl reducedf etal weigh and d e laye df etal ifica t i n.Lant hanumcarna te adminir e d ra fr m implanta tin thrughlacta tina t2000 mg/kg/day (3.4 timhe MRHD) caud d e laye d e y p e nin r e duct i nin dy wei g h tg ain andde laye d xual develpment( preputial para tinand va ginal peninf th ffpring. lant hanumcarna tetr e a t m e n t -re la ted e ffe c nlarandde livery wer nin animal udi.Thee ffe c flant hanumcarna nlarandde liveryinhuman i unkn n. It i n kn n whetherlanthanumcarna te i xcretedinhumanmilk. cau manydru aree xcretedinhumanmilk cautin huld beexercid when FOSRL®i adminired anurinman. GeriatricUse: Of thalnumber fpa tien inclinical udifF OSRL® 33re hil .3 1re 7. ralldifferenc in afety r effectiven werr ved betweenpa tien year fa ge andyungerpa tien. Pe diatricUse: W hileg r ha b n rmalit i r e n ide n t ifie dinl n g -termanimal udi lanthanum wa depitedin develpinne includingg rhpla te.The c n u e ncf uchde p i t i nind evel pinn e inpe dia t ricpa t i e n are unkn n.The r e f r h e u fF OSR L®in t hi p pula t i ni n r e c mme nde d. ADVERSEREACTIONS The m c mm nadver n f rF OSR L®wer eg a r ininal even uch a nauaand mit ing and t h e y gen e rallyab ated r t imew i t hc n t inue dd ing . Induble-blind plac-cntrlled udihere a al f1 and RD pa tienre rand mized FOSRL®andplac rpectively fr4-6week f trea tmenhe m cmmn evenha twere mre frequent( difference) in the FOSRL®grup were nauamitin dialyi raf ccluin and abdminalpain (Ta ble 1). T a b l e1. Adver seEventsT hatWe r eMor eCo mmononFOSREN OL®i nP lacebo-Cont r o lle d ,Dou b l e-B lin d St udieswi t h T r e a t m entPeri o d so f 4-6Weeks. FOSRL®Plac 1 Naua 11 mitin 4 Dialyi raf ccluin 1 Abdminalpain Th afety fF OSRL®waudiedin lng-termclinical trialhich included1 21 pa tienrea ted withF OSRL®and 43 withalterna tivetherapy. F urteenp ercent( 14fpa tien in th cmpara tipen-label udi di c n t inue din t h e F OSR L®-t r e a ted g r updu adver n . Garininaladvernucha naua diarrheaand mitingweret he m cmmn typ f event leadin dicntinua tin. The m cmmnadvern in either trea tmentg rup) in h the lng-term (2 yearpen-label active cntrlledudy fF OSRL®.alterna tive therapy (StudyA) and the6 -mnth cmpara tiudy fF OSRL®.calcium carna te(Study ar h ninTable2 .InTabludyA even ha vebeen adjudf rm ean expure differencn trea tmentg rupitham ean expur f 0. year nlanthanumand1.3year nalterna tivetherapy).The adjument frm ean expurew a achieved bymultiplyingt hr vedadver event ra in the alterna tivetherapy grup by 0.71. OVERDOSAGE There i n xperiencew ithF OSRL®rda ge.Lanthanumcarna tewa n acutely xicinanimal y th ralrute. dea th andn adverffec ccurredinmic ra rd after ingl raldf 2000 m g/kg.Inclinical trial dailyd up 471 mg/day flanthanum werewell lera tedinhealthy adulhenadminired withf d ith thee xceptin f GI ympm. Given the picalactivity flanthanumin theg u and thee xcretininfecf the marity f the dupprtivetherapyi recmmendedf r rda ge. DOSAGE AND ADMINISTRA TION ThaldailydfF OSRL®huld be dividedand taken withm eal.The recmmendedinitial aldailydfF OSRL®i 1 mg.The dhuld betitra ted every 2-3 week untilanacceptablrumphpha te leveli reached. Serumphpha te level huld be mnireda neededduring ditra tinand nar egular bai hereafter. Inclinical udif RD pa tien FOSRL®d up 37 mgwere evalua ted.M pa tien requiredaaldailydn1 mg and3000 mg reduce plamaphpha te level lhan 6.0 mg /dL. regenerally titra tedinincremenf7 mg/day. T abletsshould bechewed completely beforeswallowing.To aidinc hewing, tablets may becrushed. Intacttabletsshould notbeswallowed. re a 77F): excurin permitted 1-3-F) [See USPc ntrlledr m tempera ture] Prct frmm iure Rxonly Manufact ure df r S hire U S Inc. ayn PA1 7 U S A1--- Rev:1 0/1 0107 004AFOS-0073 T able2. Incidenceof T reatment-E me rgent Adver seEventsthatOccurre di n 5% of P atients(inE ither T rea tmentGroup) andi nBot h ComparativeStudies Aa nd B StudyA udy Alterna tive C alcium FOSRL®TherapyFOSR L®Carna te AdjudRa 7337) Naua3 16 13 mit ing 26211 11 Dialy i raft cmplica tin 3 Diarrhea 23 22 1310 Headache2 1 Dialy i raf ccluin 21 20 4 6 Abdminalpain 1717 3 Hypnin1 6 17 n ipa ti n 1413 6 7 rnchit i Rhiniti 77 6 Hypercalcemia 4 Ads_NNI0610.indd 16 5/4/10 10:17:56 AM