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R$ l}/(xz 0AA ff333ff3@8?O ʚ;R3ʚ;g4KdKd0xppp@ <4!d!d 0L(<4dddd 0L( <4BdBd. 0Lg47d7d0p@ pp0___PPT10 pp___PPT9+3n)/ypf}I[ePNG  IHDR asRGB`PLTEkjjjUU@@@??@??+++**+**#g cmPPJCmp07128I tRNS@fAIDAT 0 ~{[8([Pz2S82(\dXP< zIENDB`0n&WvlHMU+vnPNG  IHDR asRGB`PLTEkjjkjjUUTU@@@??@++*+**M#A cmPPJCmp07128I tRNS@f>IDAT1W}{{J %s4!u61QJuRW&x&vxIENDB` ne!(mPɈPNG  IHDRysRGBPLTEffffffff̙̙O) cmPPJCmp0712 jtRNS ADIDATcP, SVA%6AC!P.iuD!".l`)SbPbL@]KIENDB`0nZ'h?E8SAPNG  IHDR lΤPLTEItRNS0J cmPPJCmp0712Om)IDATc1  >|@v| Uc;IENDB`b(7#$(+88? %)E$3PHARMACOVIGILANCE des MEDICAMENTS HORS REFERENTIELS44$4 Centre Midi-Pyrnes de Pharmacovigilance, de Pharmacopidmiologie et d Information sur le mdicament Service de Pharmacologie Clinique CHU de Toulouse (/W-  >(mergence des biothrapiesAnti-TNF Anti-CD20 Anti-IL1 Anti-VEGF Anti-EGF Avances thrapeutiques remarquables, mais& .0/-\6oLes Anticorps monoclonaux Les Anticorps monoclonaux mdicaments: Des anticorps de souris aux anticorps humainsBp(($.?)  Mcanismes gnraux des anticorps: Cytotoxicit cellulaire mdie par les anticorps Activation du complment Mcanismes spcifiques aux anticorps utiliss en tant que mdicaments: Modification du signal de transduction Libration de principes actifs immunomodulation ^# 3K 3G 3X 3#KGX    7 OLes Anticorps monoclonaux Les Anticorps monoclonaux mdicaments: terminologie(P(7$n-mab: anticorps monoclonaux Cellules utilises pour la production: u (homme), o (souris), a (rat), e (hamster), i (primate) mo (souris), xi (chimrique), zu (humanis),mu (humain) Classe thrapeutique: ba(c) pour antibactrien, li(m) pour immunomodulateur, vi(r) pour antiviraux& En cancrologie, organe cible: co(l) pour colon, me(l) pour mlanome& tu(m) pour diverses autres tumeurs Exemples: INF-LI-XI-MAB PA-LI-VI-ZU-MAB CE-TU-XI-MAB< 3P,!3P,t|.#4N7Les anticorps monoclonaux $^Mthode trs rapide de transformation des cibles drives de la gnomique en mdicament. venir: tositumomab- 131I BEXXAR, gentuzumab-calicheamicin MYLOTARG, inolimomab LEUCOTAC, LM609, DC101, SGN30& Evolution des indications Arrt prcoce de l essai du CD28 SuperMab : 6 patients hospitaliss/8  Y3Pt3Pb3P3P[BBB BJB BB B B Bb)Bjb~d      ! 8!@Les Anticorps monoclonaux Les Anticorps monoclonaux mdicaments(A(($9"ALes Anticorps monoclonaux Les Anticorps monoclonaux mdicaments:(B()$:#JLes anticorps monoclonaux en oncologie Trastuzumab en traitement adjuvantKK$( jASCO 2005: rsultats prliminaires de 3 essais cliniques portant sur le trastuzumab en situation adjuvante. NSABP-B31 et NCCTG-N9831: 5491 femmes; taux de survie sans vnement pathologique li au cancer aprs 4 ans de suivi: 85,3 vs 67,1% (p<0,001). Gain de survie 4 ans= 4%. HERA: 5090 femmes; taux de survie sans vnement pathologique li au cancer aprs 1 an de suivi: 85,8 vs 77,4% (p<0,001). 17 Octobre 2005: Protocole temporaire de traitement mis conjointement par l INCA et l AFSSAPS. Dcembre 2005 San Antonio Breast Cancer conference: essai BCIRG006fl3P&" 3P3Pl&>H  ;$Les anticorps monoclonaux en oncologie Profil d effets indsirables du trastuzumab6U&$(-$I VHER2 est normalement prsent sur la membrane cytoplasmique de toutes les cellules y compris sur les cellules myocardiques. Hypothses: Neuregulin 1 active HER2 et HER4 permettant la croissance cellulaire, l organisation des myofilaments et la survie des myocytes. Le trastuzumab provoquerait des dysfonctionnement mitochondriaux. Bilan rtrospectif portant sur 1219 femmes1: frquence des vnements cardiaques + leve en cas d utilisation du trastuzumab (27% AC+ trastu vs 8%AC, 13%P+trastu vs 1%P, 3 7% trastu seul). des cas symptomatiques; 79% ont t amliores par des mdicaments de l insuffisance cardiaque. 1 dcs dans l essai en monothrapie (arythmie), 2 dcs dans l essai avec docetaxel (insuffisance cardiaque) Autres effets indsirables: ractions lies la perfusion, diarrhes, neutropnies et infections 1Seidman A et coll cardiac dysfunction in the trastuzumab clinical trials experience J Clin Oncol 2002 $3Z$3Z$3Zk%3Z$3ZB Bb*bjbnjffB: P         @+"Anticorps monoclonal: Anti-TNFa X#" ((0Indication maladie auto-immunes: Rhumatologie, Crohn et psoriasis Infliximab (Remicade), Etanercept (Enbrel), Adalimumab (Humira) et Anakinra (Kineret) Effets indsirables: Infections opportunistes Lymphome- cancers Affection Dmylinisante Plusieurs registres dans les pays pour suivre ces produits DZDZ;ZZ/    M<A*(Observatoire Ratio- Bilan Septembre 2006))$ 50 infections bactriennes dont 28 arthrites (14 sur matriel), 20 septicmies et 2 fasciites 76 infections opportunistes : 32 tuberculoses 15 lgionelloses 14 viroses (13 zonas/ varicelles, 1 herpes) 18 lymphomes dont 13 lymphomes non hodgkiniens"~N1"""""C"""""""M" " " "$",V  M6P9B,)PV: Infliximab-Lymphome T hpatosplnique**,  Juillet 2006-USA: Survenue de 6 cas de lymphome T chez des patients 12-19 ans traits pour Crohn dont 5 dcs- Association avec azathioprine AMM pdiatrique aux USA depuis mai 2006- Pas d AMM en Europe 1998-2006: 27000 de 18-30 ans et 10000 <18 ans exposs au Remicade pour Crohn Rle de l ge, terrain (maladie), association mdicamenteuse?VZVP[ x >K3D.E/F0L4CExemple mdicament utilis hors rfrentiel: bvacizumab (Avastin)"D-$$,- Anticorps monovlonal dirig contre VEGF (facteur de croissance endothlial vasculaire) impliqu dans l angiogense- Cancer colorectal mtastas en association 5FU+acide folinique +/- irinotcan EI graves: HTA, Thrombose artrielle, hmorragie, perforation digestive et retard la cicatrisation, leucopnie svre Utilisation hors AMM dans dgnrescence maculaire! (novascularization choroidale) 6 publications chez l homme: soit essai non comparatif soit tudes rtrospectives sur de petites sries sur courte dure! Pertinence des donnes? Bevacizumab: a new way of doing business? Eye, 2006, 20(9):985-7fZZ'07zA P  #     O8Les anticorps monoclonaux $Transfrabilit?: Du modle conceptuel la ralit clinique Du modle in vitro la ralit clinique Entre les diffrents protocoles utiliss Entre les essais cliniques et la ralit clinique & @3ZZ( +@Immunoglobulines IV et Insuffisance rnale: enqute PV 1999-2005AA `Tgline: 84 cas >65 ans: 75% Dlai: 3 jours Epuration extra-rnale: 24 cas Dcs: 5 Associations Mdcte (diurtique, IEC, sartans, pdt contraste,& ): 62 cas Facteurs de risque: diabte, HTA, fontion rnale altre Sandoglobuline: 6 cas Endobuline et Octagam: pas de cas notifi Gammagard: 1 cas douteuxxZ " Z" ZZZ Z  $ -8  ,@Immunoglobulines IV et Insuffisance rnale: enqute PV 1999-2005AA Enqute pralable en 1999: mise en vidence des facteurs de risque: ge, fonction rnale altre, dose totale administre, HTA, IEC, diurtique- Cas dcrits avec Ig contenant la saccharose Mise en garde des RCP en 1999: & chez les patients risque, l utilisation Ig IV ne contenant pas de saccharose doit tre envisage Pas de modification d incidence depuis (estimation 8 cas pour 1000 Kg de Tgline) Bilan 2006: rle de la saccharose et la pertinence des FR. L existence d au moins un FR (diabte, hypovolmie,>65 ans, mdcts nphrotoxiques) se retouvent dans 97% des cas Information prescripteurs, et mise en garde sur les RCP de toutes IghBZFZeEdd   TC-Divers (IBosentan (Tracleer*) dans HAPP (antagoniste de 2 sous-types des rcepteurs l'endothline (ETa et ETb) qui diminuent les rsistances vasculaires la fois systmiques et pulmonaires et augmentent ainsi le dbit cardiaque sans modifier de faon significative la frquence cardiaque)- Rares cas de cirrhoses hpatiques et d'insuffisances hpatiques survenant gnralement au cours des 26 premires semaines d'utilisation, mais parfois plus tardivement, chez des patients prsentant de multiples facteurs associs de co-morbidits et polymdicaments- Ncessit de surveillance hpatiqueZ.Rl :&I1.  7 ` flf3` 3f{FEɄ` OY?HsLp` nk3cR` Td4HV,{nR|:U^` N/qTʉ` ̙Ԝν@f` xfmR׍Ƴ~` [4>?" dd@,?lZd@  d lZ@ d`lZ n?" dd@   @@``PT $   @ ` `0p>> 32+2..1(  B,T   "  c BlC DE F* @ y   l l y y @`" ~   c BC DE F*y @ [    [ [ @`"~   c BCDEF" @ @`"i (  c BCBDEF"@ B<0BB@`" ~:   0e0e     ?BCIDEF"  @ 5% 8c8c     ?1 d0u0@Ty2 NP'p<'p A)BCD|E||IMkII@`S"  BCeDEF" 0e00@`"v~   B]CDEF ]]] @`"#~    c B'C\DEF& @ \7\'*'\\@`"#   B CDEF"  @`"1   c B}CzDEF"d @ }~}z}~}~@`"~   BCDEF  @`"O ~?   c BCDEF"y @ HHH@`"U   c BC>DEF"d@ >86>>@`" ~'   c BCDEF" @ V@`"   c B[ C DEF"y @ I [ f@`"M   c BCC+DEF"yd @ C+CC+C+@`"; ~   BCODEF" O`ZOO@`"e ~k   c B2 Cx DEF"vy @  x 2  @`" v   BCDEF  @`" ~j   c B C DEF"y @  B@`"(     0e0e     ?BC DEF"  @ 5% 8c8c     ?1 d0u0@Ty2 NP'p<'p A)BCD|E||  =@`S" 6   c BTC`DEF"yd @ T`TZ T`T`@`"* ~   BCDEF" M@`"R~V  c B>CDEF" @ >S@`"0  c BUCDEF" @ U@`"#x  B<C8DEF" <8<6@`"B~  c BlCHDEF"y @ slHl*ss@`"Az   BCDEF  @`"z    c BlC9DEF"y @ nl9l3nn@`"hz    c BlCDEF" @ 0ll00@`"i z ! c B`Ci DEF"|y @ `i `Q }@`"zi  " c B| C6 DEF"y @ | 6 | 0 B@`" z6   # c BC DEF& @  @`"nz  $ c BCDEF"y @ *@`"z % c B"CDEF"y @ ""6@`"Vz & c BCDEF"y @ *@`"uz\ `~  ' "`~   ( c BKC!DEF& @ n3!?K@`"`V   ) c B9CDEF&d @ 9 H999@`"> ~  * 6 " `  ['Cliquez pour modifier le style du titre( (H + 0< " `  vCliquez pour modifier les styles du texte du masque Deuxime niveau Troisime niveau Quatrime niveau Cinquime niveau4 w , 6\< #" `] `} < b*0  - 6 < #" ``  < d* 0  . 64< #" `] `} < d* 0 Z  By޽h @ ? 3f{FEɄ<0___PPT10. ,/___PPT9BpBB  Rayonm2  11@..[1(  B,T   "  c BlC DE F* @ y   l l y y @`" ~   c BC DE F*y @ [    [ [ @`"~   c BCDEF" @ @`"i (  c BCBDEF"@ B<0BB@`" ~:   0e0e     ?BCIDEF"  @ 5% 8c8c     ?1 d0u0@Ty2 NP'p<'p A)BCD|E||IMkII@`S"  BCeDEF" 0e00@`"v~   B]CDEF ]]] @`"#~    c B'C\DEF& @ \7\'*'\\@`"#   B CDEF"  @`"1   c B}CzDEF"d @ }~}z}~}~@`"~   BCDEF  @`"O ~?   c BCDEF"y @ HHH@`"U   c BC>DEF"d@ >86>>@`" ~'   c BCDEF" @ V@`"   c B[ C DEF"y @ I [ f@`"M   c BCC+DEF"yd @ C+CC+C+@`"; ~   BCODEF" O`ZOO@`"e ~k   c B2 Cx DEF"vy @  x 2  @`" v   BCDEF  @`" ~j   c B C DEF"y @  B@`"(     0e0e     ?BC DEF"  @ 5% 8c8c     ?1 d0u0@Ty2 NP'p<'p A)BCD|E||  =@`S" 6   c BTC`DEF"yd @ T`TZ T`T`@`"* ~   BCDEF" M@`"R~V  c B>CDEF" @ >S@`"0  c BUCDEF" @ U@`"#x  B<C8DEF" <8<6@`"B~  c BlCHDEF"y @ slHl*ss@`"Az   BCDEF  @`"z    c BlC9DEF"y @ nl9l3nn@`"hz    c BlCDEF" @ 0ll00@`"i z ! c B`Ci DEF"|y @ `i `Q }@`"zi  " c B| C6 DEF"y @ | 6 | 0 B@`" z6   # c BC DEF& @  @`"nz  $ c BCDEF"y @ *@`"z % c B"CDEF"y @ ""6@`"Vz & c BCDEF"y @ *@`"uz\ `~  ' "`~   ( c BKC!DEF& @ n3!?K@`"`V   ) c B9CDEF&d @ 9 H999@`"> ~  * 6k> " `p > ['Cliquez pour modifier le style du titre( ( + 0^> " `   > l8Cliquez pour modifier le style des sous-titres du masque9 9 , 6> #" `] `} > b*0  - 6> #" ``  > d* 0  . 6> #" `] `} > d* 0 Z  By޽h @ ? 3f{FEɄ80___PPT10. ,/ 0 F>D(  D D 0F P   F X*  D 0F    F Z* d D c $ ?  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Qx; bZ0(     <<>Ԕ *S" p > x  c $>+` p > 4  # A@@  C AP `fH  0޽h ? ̙33y___PPT10Y+D=' = @B +  ((  ( ( B G q7Donnes physiopathologiques aux indications mdicaments8 28 ( 64P` Mdicament caractris par ses proprits pharmacodynamiques mais les effets exprims peuvent diffrer selon le terrain du patient (facteurs de risque, schma d administration,& )- Exemples nombreux: Etude CAST: excs de mortalit anti-arythmique/placebo Aggravation IC sous anti-TNFa PREMET: mtronidazole et accouchement prmatur CLARICOR: excs de dcs cardiovasculaire dans le groupe clarithromycine aprs 3 ans Donnes biologiques fragmentaires et rductionnistesVrification humaine !8 f27!8 f2!8 fn2J 8 f2!8 fn274>WSYH ( 0޽h ? 3f{FEɄ___PPT10i.6+D=' = @B +  X<(  X~ X s *\!* `   ~ X s *"+ `  H X 0޽h ? ̙33G8  ^7V7``46(  4 4 s p'0e0e *3"0e`   L L 6  4# j N @  4 6 T  X 4# O 0 f2 4 6 3? H@ f2 4 6 3?  H f2 4 6 3?( @Xf2  4 6 3?( XT  X  4# ? of2  4 6 3? H@ f2  4 6 3?  H f2  4 6 3?( @Xf2 4 6 3?( XT  X 4C# h@  f2 4 6 3? H@ f2 4 6 3?  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H Z2 F4 s * ?( @XZ2 G4 s * ?( XN  X H4 h Z2 I4 s * ? H@ Z2 J4 s * ?  H Z2 K4 s * ?( @XZ2 L4 s * ?( XT  X M4C#  0 Z2 N4 s * ? H@ Z2 O4 s * ?  H Z2 P4 s * ?( @XZ2 Q4 s * ?( X R4      BHCDE(F Ԕ 8c8c     ?A)BCD|E|| -'88CI=M@hCGH @      S4B      BHCDE(F Ԕ 8c8c     ?A)BCD|E|| -'88CI=M@hCGH @   X  l2 T4 <u 3?Yl2 U4 <u 3?0=wl2 V4B <u 3?" l2 W4B <u 3?]~B X4 N D?088 Y4 04=?n YQ  , de souris 1975 & momab2 33 Z4 s *dB? pB d  0 chimriques 1984 & ximab< 3  [4 s * H?0 p t  6 humaniss 1988-1991 & zumab< 3 \4 s *M?   2 humains 1994 1999 & mumab< 3 ]4 s *LS? `Immunogniques  ^4 NX GcLH?"` @ 3  _4 6Z? = @ B Humanisation    `4 s *^? nMoins immunogniques H 4 0޽h ? fff___PPT10i.CHs؂+D=' = @B +  ,$\(  \~ \ s *d+ `   \  pegֳgֳ ?*#" 0e `    \ Zfgֳgֳ ?@`` zFLes Anticorps Mcanismes d action$$(B \ s *޽h ? ̙3̙80___PPT10.Yp  80(  8x 8 c $Xm*q   x 8 c $n+ c  H 8 0޽h ? fff___PPT10i.G0B+D=' = @B +.   E =  (  2  N31?"`Fi2  N31?"`~ ix  c $ }*q   ~  s *}+m     N1?"`] "  TP1?C  [cible$0 23 2  N1?"`}C   T1?"Ft s#Gnomique AND recombinant Hybridome$0 2$$    S 0e0eA3Ԕ +Site Ac"`=      T01? w  dAnticorps monoclonal0 2 2   N31?"`V pf    T(1? t ] indications 0(2     T31?"`   T1?vP B -Selon les donnes fondamentales et cliniques?4.0 2,33.   T1?v)B w!Selon les besoins de la socit? $"0 2"3"   T j31?"`&B  s *޽h ? ̙3̙___PPT10i.X0Q+D=' = @B +   <@(  < <0 <A ?+/q  x < c $*   B < s *޽h ? ___3fy___PPT10Y+D=' = @B +  0@@(  @ @0 <A ?+xp  x @ c $*q   B @ s *޽h ? ̙3̙y___PPT10Y+D=' = @B +   @D(  D~ D s *<+<   D s 0e0e *q   H D 0޽h ? ffPy___PPT10Y+D=' = @B +    PH(  H~ H s *+]h   H c T0e0e *3"0e`   H H 0޽h ? fff___PPT10i.AH`u+D=' = @B +V  `d(  dr d S +P   d  0e0e *@`   H d 0޽h ? 3f{FEɄ  p`O(  `x ` c $@*` `0   x ` c $+&   ` 0XP < yLgionellose: en 2004, estimation incidence de 42/100000 soit un RR de 21 par rapport la population gnrale (2/100000)"z0zH ` 0޽h ? 3f{FEɄ c[P(  X  C 0Asans titre1`  <>V  @ f   B|>pM Anti TNFa et lymphomes>      0d> . C  fH  0޽h ? ^WNff3l `(  R  s *^H  3 A?img670  0h>0 jRegistre sudois (Geborek et al. Ann Rheum dis, 2005, 64:699-703): 757 patients exposs infliximab ou etanercept, 1/2/99 au 31/12/02 compar 800 patients RA sans anti TNF802jb -  4H  0޽h ? 3f{FEɄ  h$(  hr h S `* `   r h S + `  H h 0޽h ? 3f{FEɄ  -(    <0>0] B     0O>d,$D  0 AIntrt thorique dans la maladie de Wegener Essai randomis etanercept versus placebo en association avec corticoides+MTX ou cyclophosphamide: 180 patients pdt 27 mois Pas de diffrence pour la rmission (69,7% Etanercept versus 75,3% placebo) Pas de diffrence sur la priode low-level disease activity Pas de diffrence de RR/100 patient-anne pour flambe maladie (NS) Au moins un EI grave: 56,2% Etanercept et 57,1% placebo (NS) Tumeur solide chez 6 patients sous Etanercept et 0 sous placebo (p<0,01) n( 2( 2( 2 2= $ 3 :h 9 b  BZ>O,$D  0 Etanercept et Maladie de Wegener: B/R Etanercept plus standard therapy for Wegener s granulomatosis, N Engl Med, 2005, 4:351-61. & Zl   H  0޽h ? ^WNff3 pp(  p p BX> URituximab (Mabthera) et PR rfractaires Edwards, N Engl J Med, 2004, 350(25):2572-81VV    -H ! p B<>@` g/Essai Randomis, n=161, 24 semaines, 4 groupes:0 20s p 6F Methotrexate (n=40 dont 26 48 semaines) 1 abcs cornen Rituximab (n=40 dont 32 48 semaines) 1 arthrite septique 1 bronchopneumonie fatale 1 gastroentrite (48 S) Rituximab+cyclophosphamide (n=41 dont 34 48 semaines) 1 arthrite septique associe septicmie staph 1 pneumonie Pseudomonas aeruginosa (2 pisodes) Rituximab+MTX (n=40 dont 38 48 semaines) 1 pyelonephrite (48 S) * f2 2' f2F 28 f2d f2+ f2 2 f2  40         . 4  J $H p 0޽h ? ^WNff3 t-(  tA t 6!F` iRituximab et cryoglobulinmie chez transplants rnaux Basse et al, Transplantation, 2005, 80(11):1560-64*j 7 3$ M t 0%F4`XP___PPT92* 7 patients TR (dont 5 hpatite C) avec cryoglobulinmie III (Ritux, 2 4 semaines 375mg/m2)- Amlioration de la fonction rnale mais infections graves : Femme-60A- Tacrolimus+corticoides - fasciite bactrienne (avant bras) 2 mois aprs la dernire perfusion Ritux - meningoencephalite Cryptococcus neoformans 2 S plus tard - Dcs 2) Homme 56A-HCV- Tacrolimus+corticoides+MMF - Infection Herps simplex 2, 4 mois aprs la dernire perf Ritux - Evolution favorable  " N  \@ N ?'f   <+  B  @`H t 0޽h ? ^WNff3    xG (  x x <0GF. E ( ff x 0PF`   (Ractivation de l hpatite B (Fulminant hepatitis B virus reactivation with concomitant listeriosis after fludarabine and rituximab therapy: case report. Ann Hemato, 2001, 80(9):549-52) Rituximab dans pathologies auto-immunes-Etudes CHU Toulouse (total de 37 dossiers analyss) 2 cas de pneumocystose (dont un suivi de dcs par choc septique) 1 cas d infection respiratoire non prcis  m - -\mft(  4   x 6\F= `Existence d un signal sur la possibilit de survenue plus frquente des infections graves lors d utilisation dans les maladies auto-immunes et donc en association avec d autres immunosuppresseurs Profil d EI du mdicament selon le terrain Ncessit de confirmer (ou infirmer?) le signal par un travail prospectif et exhaustif( f2+( f2W( f2! *2H x 0޽h ? ^WNff3  0(  x  c $,* `   x  c $+ `  H  0޽h ? 3f{FEɄ  (  ~  s *!+ `    s "gֳgֳ ?*#" 0eq   B  s *޽h ? ̙3̙80___PPT10.Y-  $(  r  S 4(* `   r  S (+  H  0޽h ? 3f{FEɄ  $(  r  S ,* `   r  S -+0   H  0޽h ? 3f{FEɄ  JBl(  lr l S ;*` `0   r l S XS+ `@   l <Ug: N B0 H l 0޽h ? 3f{FEɄh    (    0FP` \: Docetaxel (Taxotere) et Pneumopathie interstitielle: 38 cas bien documents dans la banque nationale de PV dont 18 dcs (11 lis l EI)-Association amiodarone et facteurs de croissance Epotine et rythroblastopnie (anmie non rgnrative svre, ne rpondant plus l potine, absence d rythroblaste dans la moelle, sans atteinte des autres lignes avec anticorps antirythropoitine) 1998: environ 250 cas (hors USA) avec potine a (Eprex) en SC avec un pic en 2001-2002 chez les IR chroniques- Hypothse d un dfaut de stabilit avec Eprex 11 cas rapports avec potine b (Neorecormion) 6 cas avec potine a aux USA 2 cas avec darbpotine (Aranesp)1(21(2/%,      Y) b     <F"0 w  @Divers0(H  0޽h ? 3f{FEɄ  $l(  $4 $ 0Hq $Pour toute information sur le mdicament Centre Midi-Pyrnes de Pharmacovigilance (Professeur JL MONTASTRUC) Tl : 05 61 25 51 12 Courriel : crpv.toulouse@cict.fr Site : www.pharmacovigilance-toulouse.com.fr Bulletin d Informations de Pharmacologie : www.bip31.fr 08s20 2* )pq  -  0 0 0H $ 0޽h ? ̙33___PPT10i.]p +D=' = @B +H"x]p[řȲcRmIR & IhOk+r, !so@ Ц-u3\˔ 3GZΐX"C;+锆\4d;-o}#*|ț3HgL)911!' {Hۀ0` hiɛi%800p`l|b6 Xp!>aŀKq+$mB>ht\ XX X q' ]nQMpp-:̀$| ig)@/H[ >VM`P47q;`e"y+½XMX`9a6 >o ?O_Ly?6@5q:C=c*Ev: O<`4Qۄ;ø+l7=}zZiAg2r>}#P1>Wk~6!kb|r,5AcQXtq$"l@:C;[bpb0fP8(,  !oٲnK@v q[l!󖦝-\:vjȿHԠC<&H8$taK榑4@bv-uWHFÑǫԿ'suw]m 1hˆŏV~z>dFCm3L>o,`h?|Gfsc`a:~OXuM{ 9/ک7Uq5Z.W֯_Y~eU~?C+i&b ɞaC+&$D:IHh |zaFa@0YŤՉ5ZF>&1dO<ž]0HB^cJ o,\iCm 3g5̽nļg?U%| NĕW% 5~dC'bxcL/st|;< x$9'oC05 Հ+̀>]x4($}i+I@/ (> |p7}=^p߀8͘]Sv<~yNN+_C_ Fx&` y}]G̅|E݀/Z$|d >:#z1^/Fo1 ;1&%ebK.+F]btl2m5ҹ %"srlDr, Bjr%hT"іk `Cޗq|i۟XT/ө`M`ȓ? x*z._LÚw& Q)G =Sg% |1BPeAIA4Ef7hٚgEtg*\w&sXQ2PӐSyLaա 6CU.K0J8z9U YjӝIay,i">40S2?<&~5LtF@Z2d)x|+EױpI撬vrnG!bJ<;ܼ[ZJ ǚj^ F`P+3% fg8st I,'E]+.GqȲΖbj/[ \CYΎ]vg[;[^ RuD"fk\9R}̶r2\ GY HMܳEMBBk62[2Ci ?@Fmz0ϫyw2<^c}#t,k9ZN%o'ALo6rs)j{gi>@:uCT11Y6M^<xށQp~Բee65<@yT?萴u0UȥchX?׻M|*&;eGtB|!QxH}-x}gΖcxv\0)ܒi+Yf2}62?tL:O`#1y䷚44ˤ۫,T_ ˆu]%0>rcGTYHc,71_ b#SzK%(1Xg!,7gal}dJo? 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