" Trombocitopenia Imune Primária: Avanços no Tratamento "

" Trombocitopenia Imune Primária: Avanços no Tratamento "
Dr. João Carlos de Campos Guerra Programa de Hematologia e TMO - HIAE

Pluripotent Stem Cell Myeloid Stem Cell B Stem Cell T Stem Cell
CFU-GEMM Pre B Cell Prothymocyte BFU-E BFU-Meg CFU-GM CFU-Bas CFU-Mast CFU-G CFU-M CFU-Eo CFU-E CFU-Meg Myeloblast Monoblast Myeloblast Myeloblast B Lymphoblast T Lymphoblast Proerytoblast Megakaryocyte Neutrophilic Myelocyte Promonocyte Eosinophilic Myelocyte Basophilic Myelocyte Erythrocyte Platelets Neutrophil Monocyte Eosinophil Basophil B Cell T Cell Macrophage Mast Cell Plasma Cell

Trombopoiese Enciclopédia Iberoamericana de Hematologia - Vol. III - Ed pág. 69

Trombopoiese Enciclopédia Iberoamericana de Hematologia - Vol. III - Ed pág. 71

Eritropoiese Ineficaz Anemia Megaloblástica
TROMBOCITOPENIA Outras Causas  Produção Destruição Transfusão Maciça Hiperesplenismo Deficiência da MO Eritropoiese Ineficaz Não Imunológica Imunológica Aplasia QT RT Infecção Toxina Drogas Infiltração Anemia Megaloblástica CIVD PTT SHU Vasculites CEC Auto Imune Drogas (TIH) Alo Imune PTI LES LP HIV HCV Trombocitopenias Hereditárias P Neonatal PPT Fig. Causas da trombocitopenia: MO= medula óssea, QT= quimioterapia, RT= radioterapia, CIVD= coagulação intravascular dissemidada, PTT= púrpura trombocitopênica trombótica, SHU= síndrome hemolítico-urêmica, P Neonatal= púrpura neonatal, PTT= púrpura pós transfusional, PTI= púrpura trombocitopênica imunológica, LES= lúpus eritematoso sistêmico, LP= doenças linfoproliferativas, HIV= vírus da imunodefifiência adquirida, HCV= hepatite por vírus C, TIH= trombocitopenia induzida por heparina.

Trombocitopenia Imune Diagnóstico de exclusão
Hemograma normal exceto isolada plaquetopenia Plaquetas gigantes no esfregaço, sem outras citopenias Exame físico normal exceto sinais de sangramento PTI secundária: Dç. Auto-imune Dç. Linfoproliferativa Infecção

Trombocitopenia Imune secundária
Auto-imune: Lupus (LES) Sindrome do anticorco anti-fosfolípides (SAFI) Dç. Tireoidiana Imune (Graves) Sindrome de Evans Dçs. Linfoproliferativas: LLC LÑH Macroglobulinemia de Waldenstron Infecções: HIV HCV H.Pylori Dengue

A prevalência de hepatite C (HCV) em pacientes adultos com trombocitopenia imune crônica (PTI).
Hematology 2008 ASH Education Program Book

Os potenciais mecanismos de trombocitopenia induzida pelo Helicobacter pylori.
A) H pylori poderia induzir anticorpos produção em resposta a antígenos, tais como cagA, que crossreact contra vários antígenos glicoproteína plaquetária. B) Plaquetas pode ser activada através da ligação da primeira-geração H Pylori anticorpos para latelet FcãRIIA ou através de uma interação entre Hpylori ligadas fator de von Willebrand (VWF) e plaquetas glicoproteína IB (GPIB). A ativação plaquetária pode promover a limpeza e apresentação antígeno, o que aumenta produção de anticorpos antibacterianos. C) Na presença de anticorpos antiplaquetários, o LPS de bactérias podem melhorar significativamente Gramnegative Fc-dependente plaquetária fagocitose. D) Epitope disseminação e mutação somática pode levar ao desenvolvimento da segunda e terceira geração de anticorpos que reconhecem quer bacterially fatores derivados ou crossreact com antígenos plaquetários. A produção destes anticorpos não está mais dependente da estimulação de antígenos bacterianos, conduzindo assim ao desenvolvimento de trombocitopenia crônica refratária à erradicação da H pylori. Abreviaturas: APC, células apresentadoras de antígeno, P, plaquetas. Cazzola et al Hematology 2008 ASH Education Program Book

Proporção de Helicobacter pylori (HP), HP-positivos e negativos de pacientes adultos com PTI alcançar uma resposta na contagem de plaquetas. Does Helicobacter pylori Eradication therapy Result in a Platelet count Improvement in Adults with Immune Thrombocytopenic Purpura Regardless of H pylori Infection ? ASH Evidence-based review 2008 Hematology 2008 ASH Education Program Book

Distribuição das Patologias encontradas nos Pacientes com Plaquetopenia
Fonte: CHSP (Jan/1997 à Mar/2004) J.C.Guerra, R.H. Kanayama, R.Kuabara, I.Y.Takihi, M.R. Yoshida, R.J.Lázaro, , C.A, Mendes, S.T.Nosawa, N.S. Bacal, E. Ferreia, J. Pasternak, M.W. Faulhaber, L.M.Rosenfeld, C.C.C.Guerra - Hospital Albert Einstein / Centro de Hematologia de São Paulo, São Paulo, Brazil – Low platelet counts: diagnosis using flow cytometry and platelet antibody – Clinical Chemistry Vol. 49, 2003

Fonte: CHSP (Jan/1997 à Mar/2004)

Fonte: CHSP (Jan/1997 à Mar/2004)
Guerra et al – Clinical Chemistry Vol. 49, 2003

Guerra et al – Clinical Chemistry Vol. 49, 2003

Detalhamento das Outras Causas
Fonte: CHSP (Jan/1997 à Mar/2004) Guerra et al – Clinical Chemistry Vol. 49, 2003

Anticorpo anti-plaquetas
Método por imunofluorescência indireta Método Direto por Citometria de Fluxo

Pesquisa de Anticorpo Anti-plaquetas (Método Direto)
Total de casos 115 pacientes com plaquetopenia. Amostra: 10 ml de sangue em EDTA. Equipamento: Citômetro de Fluxo – EPICS XL-MCL da Beckman Coulter. Material: - Anti-Human IgG FITC conjugate SIGMA (F-1641); - CD41 ou CD61 PE Immunotech (PN – IM1416); - Tampão PBS-EDTA. Método: As Plaquetas separadas do sangue total coletada em EDTA, são lavadas e marcadas com CD41PE e IgG FITC e analisadas no Citômetro de Fluxo. João Carlos C. Guerra, MD, Ruth H Kanayama, PhD, Sonia S.Nozawa, PhD, Márcia R. Ioshida, PhD, Irina Y Takiri, PhD, Robson J. Lazaro, PhD, Nelson Hamerschlak, MD, Luiz Gastão M. Rosenfeld, MD, Celso Carlos C. Guerra MD and Nydia S. Bacal, MD. Low Platelet Counts: Diagnosis Using Flow Cytometry and Anti Platelet Antibody – Blood (ASH Annual Meeting Abstracts) : abstract 3966.

0.114 1.47 Controle Negativo Plaquetas – /mm³

CSM CSM/20 anos (Masc.) Plaquetas – /mm³ 2.58 5.95

AVS AVS/31 anos (Fem.) Plaquetas – /mm³

Distribuição por Resultado Obtido
Anticorpo anti-plaquetas Guerra et al . Low Platelet Counts: Diagnosis Using Flow Cytometry and Anti Platelet Antibody – Blood (ASH Annual Meeting Abstracts) : abstract 3966.

Distribuição percentual por Diagnóstico e Resultado
Anticorpo anti-plaquetas Guerra et al . Low Platelet Counts: Diagnosis Using Flow Cytometry and Anti Platelet Antibody – Blood (ASH Annual Meeting Abstracts) : abstract 3966.

Conclusão A plaquetopenia é uma achado laboratorial freqüente.
A PTI é a causa mais comum de plaquetopenia, com maior frequência no sexo Feminino , em crianças entre 1 a 10 anos e adultos jovens entre 15 a 40 anos, conforme dados da literatura. Neste trabalho, a faixa de normalidade foi responsável por 15,7% dos casos (segunda maior causa); o que nos faz questionar os valores de normalidade para contagem de plaquetas utilizados na maioria dos laboratórios.

Conclusão A análise microscópica do “esfregaço à fresco” (sem anticoagulante) é importante na identificação de pseudotrombocitopenia, macroplaquetas e alterações morfológicas das linhagens hematopoiéticas. O anticorpo anti-plaquetas é um exame útil, quando positivo, para confirmar PTI e importante, quando negativo, para descartar diagnósticos errôneos de plaquetopenias (faixa de normalidade).

Patogênese da PTI Destruição das Plaquetas1,2
As plaquetas são prematuramente destruídas sendo fagocitadas no baço Os receptores Fc dos macrófagos ligam-se a anticorpos na superfície das plaquetas Autoanticorpos (imunoglobulinas) revestem a superfície das plaquetas Produção inadequada das Plaquetas1-4 O “turnover” das plaquetas pode estar diminuído, mesmo com níveis de TPO normais Os megacariócitos são destruído ou apresentam maturação prejudicada Autoanticorpos se ligam a megacariócitos na medula óssea. References: 1. Chang M, et al. Blood. 2003;102: Cines DB, et al. Annu Rev Med. 2005;56: von dem Borne, et al. Blood Rev. 2002;16: McMillan R, et al. Blood. 2004;103:

MO – PTI X 10

Achados Clínicos e Evolução da PTI
Crianças1-5 Adultos1-5 Crônica na maioria dos pacientes Geralmente aguda, transitória (crônica ~10 – 20%) Não possue relação direta com outras patologias Frequentemente após infecção viral ou imunização Remissão espontânea <10% Remissão espontânea 80%–90% em 2–8 semanas Refratário em 30 – 50% Refratário em 15 – 30% Mortalidade 8 -16% (refratário); 5% de hemorragia fatal (aguda) Risco muito baixo de mortalidade ou sangramento severo References: 1. Stasi R, et al. Mayo Clin Proc. 2004;79: Cines DB, et al. Annu Rev Med. 2005;56: George JN, et al. Blood. 1996;88: Kumar M, et al. Am J Hematol. 2005;78: Cines DB, et al. Blood. 2005;106:

TROMBOCITOPENIA E RISCO HEMORRÁGICO1,2
5% 20–50,000/mm3 10% 10–20,000/mm3 NÚMERO DE PLAQUETAS 21% <10,000/mm3 5 10 15 20 25 RISCO DE HEMORRAGIA References: 1. Elting LS, et al. J Clin Oncol. 2001;19: Weaver CH

Sinais e sintomas de trombocitopenia
Purpura (manchas roxas)— equimoses nas pernas Petequias 1 cm 2 cm 3 cm Escala atual:

Sinais e sintomas de trombocitopenia
Sangramento anormal e hemorragia Sangramento anormal de mucosa RNM - hemorragia em SNC pac. com trombocitopenia severa

QUAL PACIENTE DEVE SER TRATADO ?
PTI – TRATAMENTO QUAL PACIENTE DEVE SER TRATADO ?

PTI – TRATAMENTO ADULTO
Consenso: Observação em pacientes sem sangramento e cont. de plaq.> /mm3 Drogas de 1a linha: Corticosteróides Imunoglobulina Anti-D Ig Tto. de 2a linha: Esplenectomia Pacientes refratários: Rituximab Outras opções terapêutica: Vincristina, ciclosporina, azatioprina, danazol Novas terapias: Receptores agonistas de trombopoetina

Corticoesteróides: Prednisona (1mg/kg/dia): % resposta, < 20% se mantem em 1 ano5-7. Dexametasona 40 mg VO – 4 dias, < 50% se mantem em 6 meses2. IgIV 400mg/kg/dia x 5 (1g/kg x 2): > 75% resposta (mas transitório, <10% se mantem) 5-7. Pacientes com pobre resposta a IgIV podem ter alguma doença mediada por célula T1. Anti-RhD ( mcg/kg): Provavelmente tem resposta similar ao IVIG, Hemólise imune, Custo reduzido versus IgIV5-7. 1.Olsson et al. Nat Med Cheng et al. N Engl J Med 2003; 349: Godeau et al., Blood 2008; 112; Zaja F et al. Haematologica 2008; 93: Stasi R, et al. Mayo Clin Proc. 2004;79: Cines DB, et al. Annu Rev Med. 2005;56: 7.Cines DB, et al. Blood. 2005;106:

Esplenectomia Laparoscopica: Normalização inicial das plaquetas em 75 – 85% dos casos, porém 25 a 50% de recaída em anos5-7 . Rituximab: dose convencional 40% dos pacientes tiveram uma boa resposta em 1 ano, com apenas 30% exibindo uma resposta completa (plaquetas> 150 x 109 / L)3. Com dose reduzida (piloto 28 pacts), 100 mg por semana 4 x , 75% dos pacientes obtiveram uma resposta parcial ou completa , sendo que 35% apresentaram resposta completa4. Danazol, vincristina, azathioprina, ciclofosfamida, ciclosporina, MMF, etc5-7. 1.Olsson et al. Nat Med Cheng et al. N Engl J Med 2003; 349: Godeau et al., Blood 2008; 112; Zaja F et al. Haematologica 2008; 93: Stasi R, et al. Mayo Clin Proc. 2004;79: Cines DB, et al. Annu Rev Med. 2005;56: 7.Cines DB, et al. Blood. 2005;106:

International consensus report on the investigation and management of primary immune thrombocytopenia Drew Provan,1 Roberto Stasi,2 Adrian C. Newland,1 Victor S. Blanchette,3 Paula Bolton-Maggs,4 James B. Bussel,5 Beng H. Chong,6 Douglas B. Cines,7 Terry B. Gernsheimer,8 Bertrand Godeau,9 John Grainger,10 Ian Greer,11 Beverley J. Hunt,12 Paul A. Imbach,13 Gordon Lyons,14 Robert McMillan,15 Francesco Rodeghiero,16 Miguel A. Sanz,17 Michael Tarantino,18 Shirley Watson,19 Joan Young,20 and David J. Kuter21 BLOOD, 14 JANUARY VOLUME 115, NUMBER 2

DISORDERS OF PLATELET NUMBER OR FUNCTION POSTER III ASH - 2009
Abstract 3522: Time to Splenectomy Failure in Patients with Recurrent or Refractory Chronic Immune Thrombocytopenic Purpura.Gregory Cheng et al. CONCLUSION: This retrospective analysis demonstrates that success of splenectomy appears to diminish over time. In patients requiring further ITP treatment, most splenectomized patients who relapse do so within 5 years. The treatment of chronic ITP has advanced as more data on the safety and efficacy of new medications like the thrombopoietin receptor agonists have become available. As physicians and patients become more familiar with the risks and benefits of all treatments, options other than splenectomy may be preferred for certain patients.

Disorders of Platelet Number or Function: New Therapies for ITP EHA - 2010
Abstract 0603: EFFICACY OF RITUXIMAB IN COMBINATION WITH DEXAMETHASONE VS DEXAMETHASONE IN NEWLY DIAGNOSED PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA – AN INTERIM ANALYSIS OF A PROSPECTIVE RANDOMISED STUDYAuthorGudbrandsdottir, S, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark(P) Conclusion: HAEMATOLOGICA – 2010; 95 (s2)

Disorders of Platelet Number or Function: New Therapies for ITP EHA - 2010
Abstract 0604: RESULTS OF BONE MARROW EXAMINATIONS IN PATIENTS WITH CHRONIC IDIOPATHIC (IMMUNE) THROMBOCYTOPENIC PURPURA TREATED WITH ELTROMBOPAG FOR MORE THAN ONE YEAR. Bussel, James, Weill Medical College of Cornell University, New York, United States of America(P) Conclusion: Patients treated with eltrombopag ≥1 year No evidence of clinically relevant increases in bone marrow abnormalities or clinical findings typically associated with myelofibrosis based on blood smears and bone marrow biopsy data HAEMATOLOGICA – 2010; 95 (s2)

PROLONGED RESPONSE TO ELTROMBOPAG IN PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA G. Cheng1*, H. Frederiksen2, K. Bakshi3, C. Bailey3, A. Brainsky3 1Prince of Wales Hospital, Shatin, China; 2Odense University Hospital, Odense, Denmark; 3GlaxoSmithKline, Collegeville, United States of America Aim: To evaluate prolonged platelet responses to eltrombopag in the EXTEND study. Methods: Patients in EXTEND had received eltrombopag or placebo in one of the following studies: two 6-week phase 2 and phase 3 studies (TRA100773A/B), a 6-month phase 3 study (RAISE), or a phase 3 study of intermittent treatment (REPEAT). Dosing in EXTEND is individualized according to platelet counts with a goal of maintaining platelets 50,000/mL and <200,000/mL while minimizing the use of concomitant ITP medications. Patients remain in the study until withdrawal or commercial availability of eltrombopag. An adhoc analysis was conducted to evaluate the proportion of patients in EXTEND who experienced a prolonged response, defined as a platelet count 50,000/mL that was sustained for 12 weeks after the last dose of eltrombopag, without any rescue therapies. EHA

Novos Agentes Trombopoiéticos - PTI
AMG531 (Romiplostim) µg/Kg/dose IV/SC uma vez por semana Aprovado pelo FDA para PTI, estudos para plaquetopenia em SMD e pós QT ELTROMBOPAG – 50 mg VO diário Aprovado pelo FDA e ANVISA para PTI e estudos para plaquetopenia em HCV e SMD AKR-501 – 100 mg VO diário SB

O Papel da TPO na Trombopoiese
Modified with permission from Kaushansky K. Thrombopoietin. N Engl J Med. 1998;339:

O que é Trombopoetina ? Uma potente citocina endógena1,2
O principal regulador fisiológico da produção de plaquetas1,2 Influencia a proliferação e diferenciação dos megacariócitos provenientes das células progenitoras da medula óssea2-4 Produzida pelo fígado, Rins e Medula Óssea Seus níveis são regulados pelo receptor c-mpl3 Receptor Trombopoetina (TPO-R) Localizado na superfície da stem cells, células progenitoras e megacariócitos References: 1. Vadhan-Raj S, et al. J Clin Oncol. 2003; 21: Kuter DJ, Begley CG. Blood. 2002;100: Wolber E-M, Jelkmann W. News Physiol Sci. 2002;17: Kaushansky K. N Engl J Med. 1998;339:

O nível de TPO está reduzida na PTI ?
Kuwana 2005

Próxima geração de agonistas do receptor da TPO
Componentes não-imunogênicos que estimulam a produção de plaquetas pela ligação no receptor da TPO em um dos dois sítios1: Sítio de ligação da TPO1,2 Sítio de ligação para TPO peptídeo mimético e para anticorpos agonistas da TPO Domínio transmembrana do receptor da TPO2 Sítio de ligação para TPO não peptídeos mimético disponível em apresentação oral Podem complementar ao invés de competir com a TPO endógena1 TPOR TPO Binding site Transmembrane domain Cell Membrane JAK2 Kinase STAT RAS/RAF PI3K MEK The next generation TPOR agonists are non-immunogenic compounds that stimulate platelet production by binding to the TPOR The next generation of TPOR agonists comprises non-immunogenic compounds that stimulate platelet production by binding the TPOR at one of two sites: the TPO binding site,1,2 which is the binding site for TPO peptide mimetics and TPO agonist antibodies, and the TPOR transmembrane domain,2 which is the binding site for orally available TPO nonpeptide mimetics, which allows these agents to complement rather than compete with native TPO.1 Development of new TPO nonpeptide mimetics, such as AKR-501, and some TPO agonist antibodies, is rapidly progressing. Ongoing studies should soon help determine the utility of all these thrombopoietic growth factors in the treatment of thrombocytopenic patients.1 References Kuter DJ. Blood 2007; 109(11): 4607–16 Bussel JB, et al. N Engl J Med 2007; 357(22): 2237–47 AKT MAPK/ ERK NUCLEUS 1. KUTER, DJ. Blood, 109(11): 4607–16, 2007; 2. BUSSEL, JB. et al. N Engl J Med, 357(22): 2237–47, 2007. 53

Resumo da experiência clínica com eltrombopag
Desenho Estudo Descrição Desfecho primário No. de pacientes recebendo eltrombopag Duplo-cego, randomizado, placebo controlado 773A (Phase II) N=117 Estudo de escala de doses 30, 50 e 75 mg por 6 semanas†‡ Aumenta a contagem de plaquetas 50 Gi/L 88 773B* (Phase III) N=114 Tratamento a curto prazo Dose inicial de 50 mg por 6 semanas†§ 76 RAISE* (Phase III) N=197 Tratamento a longo prazo Dose inicial de 50 mg por 6 meses†§ Probabilidade de atingir a contagem de plaquetas 50400 Gi/L 135 Abertos REPEAT (Phase II) N=66 Doses intermitentes Dose inicial de 50 mg por 3 x 6 ciclos § Proporção de pacientes que alcançaram a contagem de plaquetas 50 Gi/L e 2x o valor inicial no ciclo 2 ou 3 66 EXTEND N=299 (Dec 08) Tratamento a longo prazo/segurança Dose inicial de 50 mg por >6 meses§ Segurança e eficácia a longo prazo 207‖ (em andamento) Observacional LENS Segurança ocular a longo prazo Pacientes tratados nos estudos de fase II/III Longo prazo de segurança ocularno que diz respeito a alterações na lente Em andamento eltrombopag has been investigated in two double-blind, placebo-controlled studies and two open label studies in patients with idiopathic thrombocytopaenic purpura (ITP) The safety and efficacy of eltrombopag have been demonstrated in a Phase II dose-ranging study (TRA100773A), two Phase III, randomized, double-blind, placebo-controlled studies (TRA100773B and RAISE [TRA102537]) and two open-label studies (REPEAT [TRA108057] and EXTEND [TRA105325]) in adult patients with previously treated chronic ITP. The plasma eltrombopag concentration–time data collected in 88 patients with ITP in studies TRA100773A and TRA100773B were combined for a pooled analysis of the Phase III, randomized study results. The long-term ocular safety of eltrombopag is being assessed in an observational study of patients who have received study medication (eltrombopag or placebo) in any of the Phase II or III clinical studies. The LENS study (TRA108132) will follow subjects for 2.5 years following their last ocular assessment on their prior treatment study (regardless of the therapeutic indication) and will describe long-term ocular safety with respect to changes in the lenses over time for all subjects. The study initiation date was August 2009 and the study is due for completion in 2013. Reference *Estudos de submissão pivotal; † Todos os pacientes foram autorizados a receberem tratamento padrão; ‡Escala de dosa – eltrombopag 30, 50 e 75 mg; §eltrombopag 50 mg; ‖150 dos pacientes EXTEND foram previamente expoxtos ao eltrombopag (57 tiveram a primeiro exposição no EXTEND) 54

eltrombopag estimula a diferenciação do megacariócito
Células primárias da medula óssea CD34+ à CD41+ células, 10 dias Stimulates human megakaryocyte differentiation and proliferation in a dose-dependent manner In this preclinical study, flow cytometry quantified differentiation of CD34+ cells into CD41+ megakaryocytes and platelet production in vitro. The percent of CD41+ megakaryocytic cells (expressed as a percent of that induced by 100 ng/mL TPO) detected at Day 10 increased in a dose-dependent manner following treatment with eltrombopag with an average EC50 of 200 nM in multiple experiments. The efficacy of eltrombopag relative to the maximum efficacy of TPO averaged 120% at 3 μM in more than 20 individual marrow experiments. The results of this study demonstrate that eltrombopag is capable of activating TPO-specific signal transduction, proliferation and differentiation responses in a manner similar to that of innate TPO. Reference Erickson-Miller CL, et al. Exp Hematol 2005; 33(1): 85–93 eltrombopag (μM) TPOmax= concentração máxima de trombopoetina 28. ERICKSON-MILLER, CL. et al. Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp Hematol, 33(1): 85–93, 2005.

Função plaquetária Estudos in vitro e in vivo mostraram que eltrombopag estimula o sinal plaquetário com pouco ou nenhum efeito na função geral plaquetária31 Clinical studies in vitro have shown that eltrombopag did not enhance or antagonise agonist-induced platelet aggregation compared to placebo1–3 Eltrombopag does not enhance ADP-induced aggregation of platelets.1–3 In studies conducted at subthreshold/submaximal concentrations of ADP or collagen, eltrombopag pretreatment did not result in platelet aggregation.1 This is in contrast to recombinant human (rh)-TPO, which has been shown to induce maximal platelet aggregation in synergy with submaximal concentrations of ADP or collagen.1 In the same study, rhTPO acted in synergy with submaximal concentrations of ADP or collagen to induce maximal aggregation under all conditions examined. Platelet activation as examined via surface expression of CD62P was also not enhanced by eltrombopag pretreatment as compared to rhTPO.1 Platelet function, as measured by platelet aggregation and activation, has been shown to be unaffected by the administration of eltrombopag in placebo-controlled clinical studies of healthy subjects.2 Studies with romiplostim have shown that the drug did not appear to alter platelet aggregation and platelets generated after exposure to the drug functioned normally.4,5 References Erhardt J, et al. Exp Hem 2009; 37(11): Jenkins JM, et al. Blood 2007; 109(11): 4739–41 Psaila B, et al. Blood 2007; 110(11): 391–2 Nichol JL. Pediatr Blood Cancer 2006;47: Kumagai Y, et al. J Supp Oncology 2007;5(4):76-77 ERHARDT, JA. et al. Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol, 37(9): , 2009.

Farmacodinâmica 24 Estudo clínico de fase I
Resposta plaquetária em homens sadios após a administração de eltrombopag oral (1 vez por dia) durante 10 dias Cinética da resposta plaquetária em homens sadios após 10 dias de administração oral de eltrombopag 75 mg Eltrombopag induces dose dependent increase in platelets Eltrombopag was administered as oral capsules to healthy male subjects at doses of 5 to 75 mg once daily for 10 days in a Phase I, placebo-controlled clinical trial. None of the nine subjects in the 5 or 10 mg dose groups, one of nine subjects in the 20 mg dose group, six of nine subjects in the 30 mg dose group and nine of nine in the 50 and 75 mg dose groups achieved a platelet count more than 20% above baseline. The mean increases in platelet count for the 30, 50 and 75 mg dose levels were 24.1, 42.9 and 50.4%, respectively, as shown in Figure A. A consistent increase in platelet count started after 8 days of repeat dosing with eltrombopag, and the time from first dose to peak platelet count was 16 days. By Day 22 (12 days after the last dose of eltrombopag), platelet count had returned to baseline values, as shown in Figure B. Reference Jenkins JM, et al. Blood 2007; 109: 4739–41 24.JENKINS, JM. et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood, 109: 4739–41, 2007.

Estudo TRA100773A Este estudo de variação de dose do eltrombopag mostrou que a dose diária de 50 ou 75 mg é um tratamento de curto-prazo efetivo para PTI crônica20 70% dos pacientes que receberam eltrombopag 50 mg e 81% dos pacientes que receberam eltrombopag 75 mg responderam à medicação20 A dose inicial recomendada foi de 50 mg uma vez ao dia, que poderia ser aumentada para 75 mg diários20 This was a dose-finding study in which 118 adults with chronic ITP and platelet counts of less than 30,000/μL All enrolled patients had had relapses or their platelet count had been shown to be refractory to at least one standard treatment for ITP. Patients were randomly assigned to receive the oral TPOR agonist eltrombopag (30, 50 or 75 mg once daily) or placebo. The primary endpoint was a platelet count of 50,000 or more per cubic millimetre on Day 43.1 At the first visit (Day 8), 44% of patients receiving 50 mg of eltrombopag and 62% of those receiving 75 mg had a platelet count of 50,000 or more per cubic millimeter.1 By Day 15, 88% of patients receiving 50 mg and 81% of those receiving 75 mg had a response, with the median platelet count (last observation-carried-forward data) approaching the normal range (i.e. 150,000 to 400,000 per cubic millimeter).1 The recommended initial dosage of eltrombopag was 50 mg/day, with a maximum dose of 75 mg/day.2 References Bussel JB, et al. N Engl J Med 2007; 357(22): 2237–47 Garnock-Jones KP, et al. Drugs 2009; 69(5): 567–76 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Interações alimentares
Administração concomitante de eltrombopag e alimentos com altas concentrações de cálcio ou antiácidos contendo alumínio e magnésio resulta em redução da biodisponibilidade sistêmica Biodisponibilidade de eltrombopag em pacientes sadios (n=18) que receberam um alto teor de gordura e cálcio no almoço foi reduzida (AUC0–∞) em 59% e Cmax em 65% comparados com pacientes em jejum Eltrombopag should not be administered together with high-calcium foods or antacids This study compared eltrombopag 50 mg administered in the fasted state or with a high-fat, high-calcium breakfast. The bioavailability of eltrombopag in healthy subjects (n=18) who received a high-fat, high-calcium breakfast was reduced in terms of AUC0–∞ by 59% (geometric mean ratio [GMR], 0.41; 90% confidence interval [CI]: 0.36–0.46) and Cmax by 65% (GMR, 0.35; 90% CI: 0.30–0.41) compared with subjects in a fasted state. In a similar study, investigating eltrombopag 75 mg administered in the fasted state (immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminium hydroxide and magnesium carbonate), mean plasma AUC0–∞ and Cmax values decreased by ~70% when administered with a metal cation–containing antacid. Reference Williams DD, et al. Clin Ther 2009; 31(4): 764–76 34.WILLIAMS, DD. et al. Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies. Clin Ther, 31(4): 764–76, 2009. 59

Resumo: Características e propriedades do eltrombopag
Indicação Adultos com PTI crônica com resposta insuficiente ao tratamento com corticóides, imunoglobulinas ou esplenectomia Mecanismo de ação Agonista não peptídico do receptor de TPO, estimula a diferenciação e a proliferação de células da linhagem megacariocítica e resulta no aumento na contagem de plaquetas Dose Dose inicial: 50 mg/dia Dose máxima: 75 mg/dia Freqüência 1 vez ao dia Via de administração Oral Tempo para atingir a concentração máxima 2–6 h (plasma) Meia-vida 26–35 h (plasma) Eventos adversos mais freqüentes Náusea, diarréia, dor de cabeça, fatiga Eltrombopag is an orally bioavailable, low molecular weight, synthetic nonpeptide TPOR agonist1 Eltrombopag is rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) achieved within 2–6 hours of administration in patients with ITP.1 A 75 mg single solution dose of eltrombopag was associated with a 52% or higher oral absorption of drug-related material.1 In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (>99%); eltrombopag in blood cells makes up 50–79% of the plasma concentration.1 The plasma elimination half-life of eltrombopag in patients with ITP was approximately 26–35 hours.1 Eltrombopag was generally well tolerated in clinical trials in patients with chronic ITP. The incidence of serious adverse events did not differ between eltrombopag and placebo recipients (11 vs 12%, respectively).1 Romiplostim is administered once weekly subcutaneously, at a dose that is based on weight, initiated at 1 μg/kg and titrated to the desired endpoint, with a maximum dose of 10 μg/kg.1,2 In the pivotal clinical trials, the median average weekly dose for splenectomised patients was 3 μg/kg and for non-splenectomised patients was 2 μg/kg.3 References Bussel JB, et al. N Engl J Med 2007; 357(22): 2237–47 Frampton JE, et al. Drugs 2009; 69(3): 307–17 Amgen. Nplate Summary of Product Characteristics 2009 GARNOCK-JONES, KP. et al. Eltrombopag. Drugs, 69(5): 567–76, 2009. 60

Estudo fase II de eltrombopag no tratamento de púrpura trombocitopênica idiopática crônica (ITP): TRA100773A TRA100773A Phase II eltrombopag treatment of chronic ITP. 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007. 61

Pacientes com TPI <30,000/μL
Desenho do estudo Estudo fase II, multicêntrico, randomizado, duplo-cego, placebo-controlado para examinar tratamento com eltrombopag oral uma vez ao dia Placebo N=29 Screening 30 mg eltrombopag Pacientes com TPI <30,000/μL Randomização 1:1:1:1 N=30 50 mg eltrombopag Objetivo: Verificar se eltrombopag poderia seguramente aumentar a contagem de plaquetas em adultos com PTI N=30 TRA100773A: this was a Phase II, multicentre, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of eltrombopag in patients with chronic ITP Adults with chronic ITP who had a platelet count below 30,000/µL and who had received at least one prior ITP therapy were eligible. Patients receiving maintenance immunosuppressive regimens, primarily glucocorticoids, were eligible if the dose had been stable for at least 1 month. The dose had to remain unchanged throughout the study. Other treatments for ITP must have been completed at least 2 weeks before enrolment. Patients with the following conditions were excluded: secondary immune thrombocytopaenia (e.g. patients infected with human immunodeficiency virus or hepatitis C virus or patients with systemic lupus erythematosus); haemoglobin levels of less than 10 g per decilitre; congestive heart failure, arrhythmia, thrombosis within 1 year of study enrolment or myocardial infarction within 3 months before enrolment; women who were nursing or pregnant. Women of childbearing age agreed to use contraception throughout the study. Values within the normal range were required for neutrophils, reticulocyte count, creatinine and liver enzymes. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 75 mg eltrombopag N=28 Período de tratamento: 6-semanas 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007. 62

Desenho do estudo (cont.)
A randomização foi estratificada de acordo com a medicação concomitante (sim ou não), esplenectomia (sim ou não) e contagem de plaquetas inicial (>15,000 por milímetro cúbico vs ≤15,000 por milímetro cúbico Para reduzir o risco de trombocitose, o tratamento foi descontinuado quando a contagem de plaquetas excedeu por milímetro cúbico TRA100773A: patients were randomized to receive 30, 50 and 75 mg of eltrombopag Patients were randomized to receive either 30, 50 or 75 mg of eltrombopag. Randomization was stratified according to concomitant ITP medication (yes or no), splenectomy (yes or no) and the baseline platelet count (>15,000 per cubic millimetre vs ≤15,000 per cubic millimetre), with a block size of four within each stratum. To reduce the risk of thrombocytosis, treatment was discontinued when platelet counts exceeded 200,000 per cubic millimetre. The group receiving 30 mg of eltrombopag did not meet the stopping criterion for either efficacy or futility (two-sided; p=0.340); however, this dose was not continued because of high response rates for doses of 50 mg and 75 mg and a similar incidence of adverse events among patients in all four study groups. After the decision was made to stop the study, the final analysis involving data from 118 patients, including 14 patients who enrolled after the interim cut-off date (September 2005), was performed. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Desfechos do estudo Desfecho primário Desfechos secundários
Contagem de plaquetas de ≥50,000/μL no 43º dia do estudo Desfechos secundários Segurança e tolerabilidade Sinais de sangramento (escala de sangramento WHO) Níveis de trombopoietina Qualidade de vida TRA100773A: the primary endpoint of the study was a platelet count of ≥50,000/μL All patients who were treated with at least one dose of study medication and who had a baseline platelet count of less than 30,000 per cubic millimetre were included in the analyses of the primary end point. The primary endpoint of the study was a platelet count of ≥50,000/μL. The primary endpoint was analysed by use of a prospectively defined last observation carried forward imputation in which the last platelet count during treatment was carried forward to Day 43 for patients who withdrew prematurely because of a platelet count of more than 200,000/μL. Secondary endpoints included safety and tolerability, signs of bleeding, serum thrombopoietin level and health-related quality of life. The incidence and severity of bleeding were assessed at every visit using the World Health Organisation (WHO) bleeding scale (grade 0: no bleeding to grade 4: debilitating blood loss). All patients were assessed weekly for safety, tolerability and efficacy of the treatment during the 6-week treatment period and at 2-week intervals for 6 weeks after the study medication had been discontinued. Patients who withdrew prematurely for any other reason were counted as not having had a response, irrespective of the platelet count. Additional supportive analyses were performed with the use of only observed data at Day 43, with no imputations. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 WHO=World Health Organisation 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Características demográficas dos pacientes
Placebo (n=29) eltrombopag Total (n=114) p valor 30 mg (n=30) 50 mg (n=30) 75 mg (n=28) Idade (anos) Média (faixa), 42 (18–85) 51 (23–79) 45 (23–81) 55 (18–85) 50 (18–85) 0.04*† Sexo Mulheres, n (%) 16 (55) 16 (53) 21 (70) 20 (71) 73 (62) 0.33‡ Homens 13 (45) 14 (47) 9 (30) 8 (29) 44 (38) Variáveis de estratificação Esplenectomia 14 (48) 15 (50) 11 (39) 55 (47) 0.82‡ Terapia concomitante* 6 (21) 10 (33) 12 (40) 10 (36) 38 (32) 0.43‡ Contagem de plaquetas inicial ≤15,000/µL 15 (54) 56 (48) Terapia prévia ≥1 28 (97) 29 (97) 30 (100) 26 (93) 113 (97) 0.52‡‖ ≥2 21 (72) 26 (87) 24 (80) 16 (57) 87 (74) ≥3 17 (57) 18 (60) 60 (51) ≥4 12 (41) 42 (36) TRA100773A: demographic characteristics were balanced between the two treatment groups Of 153 patients screened, 118 underwent randomization and 117 were treated. The median age of enrolled patients was 50 years and 62% of patients were women. The majority of patients were of white (79%) or Asian (18%) race with a greater proportion of Asian patients in the eltrombopag 50 mg treatment arm (40%) compared with placebo (7%), 30 mg (13%) or 75 mg (11%). Forty-seven percent of the patients had undergone splenectomy, 32% were receiving concomitant medication for ITP (primarily prednisone or prednisolone) and 48% had a platelet count of 15,000/μL. Seventy-four percent of the patients had previously received two or more treatments for ITP. Only 20 of the 117 patients had received therapy for ITP other than glucocorticoids or intravenous immunoglobulins within the 3 months preceding the start of the protocol treatment, and these 20 patients were equally distributed among the four treatment groups. Significant differences in median age and race (white vs non-white) were observed between treatment groups at baseline. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 *Baseado no teste Kruskall–Wallis em todos os grupos de tratamento; †Significância em 5%‡Baseado no teste chi-square em todos os grupos de tratamento; §Raça foi auto-referida; ¶p valor foi baseado na compração entre brancos e negros;‖p valor foi baseado na proporção de pacientes que receberam pelo menos um tratamento prévio em todos os grupos do estudo 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Responders (%) (≥ 50Gi/L)
eltrombopag aumentou a contagem de plaquetas em >80% dos pacientes (p<0.001 versus placebo) p<0.001* OR=38.82 (7.62, ) p<0.001* OR=21.96 (4.72, ) p=0.07 OR=3.09 (0.69, 13.75) Responders (%) (≥ 50Gi/L) TRA100773A: eltrombopag increases platelet count to a pre-defined target of ≥50,000/L in >80% of patients (p<0.001 versus placebo) In this multicentre, randomized, double-blind, placebo-controlled, dose-ranging study in patients with ITP who had received at least one prior therapy, once-daily eltrombopag treatment at 30, 50 and 75 mg increased platelet count to a pre-defined target of ≥50,000/L in 28, 70 and 81% of patients, respectively. This response occurred in over 80% of patients within 2 weeks, was significantly greater for the 50 and 75 mg doses than among placebo-treated patients (11%; p<0.001), and was not affected by splenectomy status. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 70% 81% 11% 28% *1-sided p valor. OR=odds ratio 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Eventos adversos ocorrendo em ≥5% dos pacientes independente da causa
Evento adverso, n (%) Placebo (n=29) eltrombopag 30 mg (n=30) 50 mg (n=30) 75 mg (n=28) Qualquer evento adverso* 17 (59) 14 (47) 17 (61) Dor de cabeça 6 (21) 4 (13) 3 (10) Fadiga 5 (17) – 1 3 2 (7) Epistaxe 4 13 Artralgia 1 (3) Elevação da aminotransferase aspartato Constipação Rash Anemia 1 (4) Diarréia Edema periférico Distúrbios do paladar Distensão abdominal Hemorróida Dor nas extremidades TRA100773A: eltrombopag is associated with a low rate of mild-to-moderate, transient adverse events The incidence and severity of adverse events were similar for all the study groups. The number of patients experiencing grade 3 or 4 adverse events during the study, or within 30 days after discontinuation of the study treatment, was also similar across all four study groups. A single case of cataract progression was reported 181 days after the last dose of study medication in a 60-year-old woman with a history of glucocorticoid use and cigarette smoking who received 75 mg of eltrombopag daily for 8 days. The event was assessed by the investigator as not related to the study drug. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 *Número total de pacientes com pelo menos um evento 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Eventos adversos graus 3 e 4 independente da causa
Evento adverso, n (%)* Placebo (n=29) eltrombopag 30 mg (n=30) 50 mg (n=30) 75 mg (n=28) Qualquer evento adverso de grau 3 ou 4 4 (14) 2 (7) 4 (13) 3 (11) Náusea 1 (3) – Vômito Gastroenterite Hepatite tóxica Ruptura da veia varicosa Convulsão Dores Pneumoniti Hemorragia retal Herpes zoster Trombocitopenia Pneumonia Hepatite Insuficiência renal DPOC Dedo em gatilho hemorragia Rash TRA100773A: eltrombopag is associated with a low rate of mild-to-moderate, transient adverse events In the placebo group, one patient had nausea, vomiting, and salmonella gastroenteritis and one patient each had toxic hepatitis, varicose-vein rupture, and convulsion. In the group receiving 30 mg of eltrombopag, one patient each had pain in both legs and pneumonitis. In the group receiving 50 mg of eltrombopag, one patient each had a rectal hemorrhage, herpes zoster, and thrombocytopenia, and one patient had pneumonia, hepatitis, renal failure, and chronic obstructive pulmonary disease. In the group receiving75 mg of eltrombopag, one patient each had trigger finger, menorrhagia, and rash. Reference 1. Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 *Os pacientes podem ter tido mais de um evento 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Eventos adversos sérios relacionados à medicação em estudo
Evento adverso, n (%) Placebo (n=29) eltrombopag 30 mg (n=30) 50 mg (n=30) 75 mg (n=28) EASs não fatais 2 (7) – 1 (4) Hepatite tóxica 1 (3) Convulsão Hepatite Insuficiência renal Urticária EASs fatais TEV Embolia Pulmonar TRA100773A: severe adverse events realted to eltrombopag are relatively infrequent Three patients (3%) receiving eltrombopag experienced a non-fatal severe adverse event related to study medication compared with two patients (7%) in the placebo arm. Two patients in the eltrombopag 50mg arm experienced a fatal severe adverse event related to study medication. Reference GSK Clinical study register. Available at Last accessed Septermber 2009 20.BUSSEL, JB. et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357(22): 2237–47, 2007.

Estudo fase III de eltrombopag no tratamento de púrpura trombocitopênica idiopática crônica (PTI):TRA100773B TRA100773B Phase III eltrombopag treatment of chronic ITP. 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009. 70

Desenho do estudo Seleção Tratamento padrão + placebo Pacientes PTI ≥1 tratamento prévio, <30.000/μL N=38 Randomização 2:1 Tratamento padrão + 50 mg eltrombopag N=76 período de tratamento: 6 semanas Objetivos: Avaliar a eficácia e a segurança do eltrombopag (50 mg) Explorar a eficácia da dose aumetada para 75 mg (se necessário) TRA100773B: the objective of this Phase III randomized study was to assess the efficacy, safety and tolerability of once-daily eltrombopag 50 mg in more than 100 adults with previously treated chronic ITP who were naїve to thrombopoietic agents, and to explore the efficacy of a dose increase to 75 mg (if needed) Adults with chronic ITP who had a platelet count below 30,000/µL and who had received at least one prior ITP therapy were eligible. Patients were randomly assigned 2:1 to receive standard of care and either eltrombopag 50 mg or placebo once daily for up to 6 weeks. All patients were assessed for safety, tolerability and efficacy every week during treatment, and at 1, 2, 4 and 6 weeks after discontinuation of study drug. Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 Fase III, randomizado, duplo-cego, placebo-controlado 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009. 71

Desenho do estudo Pacientes randomizados 2:1 para receber tratamento padrão mais eltrombopag 50 mg ou placebo, uma vez ao dia por 6 semanas Randomização estratificada por Status de esplenectomia Uso de terapia concomitante Contagem de plaquetas inicial ≤15,000/µL A dose de eltrombopag poderia ser aumentada de 50 para 75 mg após 3 semanas em pacientes cuja contagem de plaquetas fosse menor que /μL Tratamento foi interrompido nos pacientes que alcançaram a contagem de plaquetas acima de /μL TRA100773B: patients were randomized to receive either once-daily eltrombopag 50 mg or placebo in addition to standard of care1 A previous Phase II study in 118 patients with chronic ITP showed that daily eltrombopag 50 mg for up to 6 weeks increased platelet counts to 50,000/μL or more in 70% of patients, and had similar efficacy to 75 mg (70 vs 81%, respectively).2 In the double-blind, placebo-controlled study presented here, patients were randomly assigned 2:1 to receive standard of care plus either eltrombopag 50 mg or placebo once daily for up to 6 weeks. Randomization was stratified by splenectomy status, use of baseline concomitant ITP therapy and baseline platelet counts of 15,000/μL or less, or greater than 15,000/μL. The eltrombopag dose could be increased from 50 to 75 mg after 3 weeks in patients whose platelet counts were less than 50,000/μL. Treatment was discontinued in patients who attained a platelet count greater than 200,000/μL.1 In line with the Summary of Product Characteristics, in all patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese or Korean), eltrombopag was initiate at a reduced dose of 25 mg once daily.3 Patients were allowed to continue on a concomitant chronic ITP medication, provided their dose had been stable for at least 1 month prior to enrollment.1 References Bussel JB, et al. Lancet 2009; 373(9664): 641–8 Bussel JB, et al. N Engl J Med 2007; 357: 2237–47 GSK. Revolade (eltrombopag), European Summary of Product Characteristics (draft). 2009 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Proporção de pacientes com contagem de plaquetas 50,000/µL após 6 semanas de tratamento Desfechos secundários Contagem de plaquetas Probabilidade de responder durante a 2ª e 6ª semanas Proporção de pacientes com contagem de plaquetas 50,000/µL e pelo menos o dobro da contagem inicial Incidência de sintomas hemorrágicos Segurança e tolerabilidade TRA100773B: the primary endpoint of the study was the proportion of patients with platelet count ≥50,000/μL after 6 weeks of treatment The primary study endpoint was the proportion of responders, defined as patients who had an increase in platelet counts to 50,000/μL or more at Day 43 (i.e. 6 weeks after the start of treatment). Patients who withdrew prematurely because of a platelet count greater than 200,000/μL were considered responders. Patients who discontinued treatment for any other reason (e.g. patient decision, lack of efficacy, adverse event) were considered non-responders irrespective of their platelet count. Secondary endpoints included platelet counts, the odds of responding during Weeks 2–6, proportion of patients with platelet counts 50,000/μL or more and at least twice the baseline amount, incidence of bleeding symptoms, safety and tolerability. The primary endpoint was a platelet count of 50,000/μL or higher after up to 6 weeks of therapy. The endpoint of 50,000/µL was selected as it was deemed to represent an unequivocal improvement in platelet levels to above the level at which treatment is usually initiated (≥30,000/μL). Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Fluxo dos participantes
114 pacientes randomizados 38 receberam placebo 76 receberam 50 mg eltrombopag 34 tiveram dose aumentada para 75 mg 8 não completaram o tratamento 1 contagem de plaquetas >200,000/μL 3 falta de eficácia 2 eventos adversos* 1 Ig-IV antes da necessidade de cirurgia 1 protocolo violado 30 completaram o tratamento 38 incluídos na análise de eficácia 6 respoderam ao placebo 52 completaram o tratamento 74 incluídos na análise de eficácia 43 responderam à medicação 24 não completaram o tratamento 18 contagem de plaquetas >200,000/μL 3 eventos adversos* 2 protocolos violado 1 excluído TRA100773B: a total of 114 patients were randomized to received either eltrombopag 50 mg or placebo A total of 114 adults with chronic ITP and baseline platelet counts of less than 30,000/µL were enrolled into the study at 63 sites in 23 countries. Eligible patients were required to have at least a 6-month history of ITP and have received at least one previous treatment of ITP. Previous treatments with immunoglobulins, immunomodulators, rituximab and cyclophosphamide must have been completed at least 2 weeks prior to enrolment into the study. Patients were randomized to either placebo (n=38) or eltrombopag 50 mg (n=76) once daily for up to 6 weeks. Eighty two (72%) patients completed 6 weeks of treatment (eltrombopag, n=52; placebo, n=30). The most common reason for not completing 6 weeks of treatment in the eltrombopag group was a platelet count greater than 200,000/μL (18 of 24 patients). Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Características demográficas e do paciente
Placebo (n=38) eltrombopag (n=76) Total (n=114) Idade (anos) Média (faixa) 51 (21–79) 47 (19–84) 48 (19–84) Média (SD) 48 (16) 51 (17) 50 (17) Sexo Mulheres 27 (71%) 43 (57%) 70 (61%) Homens 11 (29%) 33 (43%) 44 (39%) Variáveis de estratificaçãio Esplenectomia 14 (37%) 31 (41%) 45 (39%) Terapia concomitante* 17 (45%) 32 (42%) 49 (43%) Contagem de plaquetas inicial ≤15,000/µL 38 (50%) 55 (48%) Terapia prévia ≥1 38 (100%) 76 (100%) 114 (100%) ≥2 26 (68%) 56 (74%) 82 (72%) ≥3 16 (42%) 42 (55%) 58 (51%) ≥4 9 (24%) 30 (39%) 39 (34%) ≥5 7 (18%) 16 (21%) 23 (20%) TRA100773B: demographic characteristics were balanced between the two treatment groups Randomized patients had a median age of 48 years (range 19–84), nearly two-thirds were women and three-quarters were white (74% white; 25% other; <1% black). A total of 45 (39%) patients had undergone splenectomy, 49 (43%) were receiving concomitant ITP medication (most commonly prednisone) and 55 (48%) had a baseline platelet count 15,000/μL or less. Just over half of all patients had received three or more ITP therapies and 47 (41%) patients had had ITP for at least 5 years. Corticosteroids were the most commonly reported previous ITP therapy, used by 29 (76%) patients in the placebo group and 57 (75%) patients in the eltrombopag treatment group. Other common previous therapies included intravenous immunoglobulins (13 patients [34%] in placebo group and 36 patients [47%] in eltrombopag group) and rituximab (eight [21%] placebo group and 17 [22%] eltrombopag group). Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 Os dados são em porcentagem (%) exceto a indicção; *Dois pacientes reduziram a dose a medicação concomitante (prednisona e micofenolato, respectivamente) enquanto receberam eltrombopag; SD=desvio padrão; ITP=púrpura trombocitopênica idiopática 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Proporção de respostas maiores com eltrombopag do que com placebo
p<0.0001† OR=9.61 (95% IC: 3.31, 27.86) eltrombopag 50 mg Pacientes que responderam (%) TRA100773B: the primary endpoint of platelet counts ≥50,000/µL on Day 43 was achieved in more patients in the eltrombopag group than the placebo group The primary endpoint analysis, defined as percentage of patients with counts on Day 43 (after up to 6 weeks of therapy), showed a statistically significant difference in the eltrombopag 50 mg arm compared with placebo (p<0.0001). At the end of the trial, 59% of eltrombopag-treated patients on the 50 mg dose and 16% of placebo-treated patients achieved a platelet count of ≥50,000/µL. It should be noted that patients on placebo were also receiving stable ITP medication. One patient in the placebo arm included in this analysis received intravenous immunoglobulin. Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 Placebo 16% 59% *Contagem de plaquetas inicial <30,000/µL; †Indica significância de 5% (2-sided) nível de significância; Análise de regressão logística ajustada para a randomização das variáveis de estratificação; OR=odds ratio; IC=intervalo de confiança 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

eltrombopag produz aumentos sustentáveis na contagem de plaquetas
Contagem de plaquetas média (A) e alterações médias na contagem de plaquetas (B) durante a visita TRA100773B: onset of response was rapid and increases in platelet count were sustained and durable The median platelet count increased to 53,000/μL by Day 15 for patients in the eltrombopag group, and this increase was sustained for the 6-week treatment period. On Day 43, the median platelet count in eltrombopag responders (n=43) was 144,000/μL (interquartile range: 92.50–268.00). The mean percentage change from baseline in platelet counts for patients given eltrombopag was double that of those given placebo at Day 8 and several fold higher throughout the remainder of the treatment period. After completion of treatment, platelet counts returned to normal. Note that four patients in the eltrombopag arm and two in the placebo arm were still receiving study medication on or within 3 days before the assessment on Day 50 (1 week follow up) and were included in this analysis. Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 Os dados são (A) mediana (intervalo interquartil) e (B) alterações médias (95%) intervalo de confiança; FU=acompanhamento 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Resposta ao eltrombopag visto independente da contagem inicial de plaquetas, status de esplenectomia ou resposta prévia ao tratamento TRA100773B: patients responded to eltrombopag irrespective of the use of concomitant ITP drugs (p=0.77), splenectomy status (p=0.75) or baseline platelet count of 15,000/μL or less (p=0.45) There was no statistically significant interaction between treatment response and baseline stratification variables (p=0.31). The benefit of eltrombopag, in terms of the proportion of responders, was seen regardless of the use of concomitant ITP drugs (p=0.77), splenectomy status (p=0.75) or baseline platelet count of 15,000/μL or less (p=0.45). Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 Contagem de plaquetas inicial 30,000/µL; PTI=púrpura trombocitpênica idiopática 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Avaliação do risco de hemorragia com eltrombopag
O risco relativo de hemorragia no 43º dia foi 73% menor com eltrombopag comparado com placebo (p=0.029) TRA100773B: significantly fewer patients in the eltrombopag group than in the placebo group had bleeding symptoms The incidence and severity of bleeding symptoms were assessed at every study visit during therapy (Days 1–43) and after therapy (Days 50–85). Bleeding was assessed using the World Health Organization (WHO) bleeding scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; and grade 4, debilitating blood loss). Significantly fewer patients in the eltrombopag group than in the placebo group had bleeding symptoms, as measured by the WHO bleeding scale, at Day 43: 20 (39%) patients in the eltrombopag group had bleeding events versus 18 (60%) patients in the placebo group (OR=0.27 [95% confidence interval (CI) 0.09–0.88]; p=0.029), as well as at any point in time during the course of treatment (46 [61%] versus 30 patients [79%]; OR 0.49 [95% CI 0.26–0.89]; p=0.021). No patients reported clinically significant bleeding (WHO grade 2–4) while platelet counts were 50,000/μL or more during treatment. After discontinuation of eltrombopag, when the platelet counts returned to normal, the percentage of patients with any bleeding (WHO grades 1–4) increased compared with that recorded during treatment. Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 * Níveis de sangramento da Organização Mundial de Saúde 1–4; OR=odds ratio; IC=intervalo de confiança 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Eventos adversos ocorrendo em >1% dos pacientes independente da causa
Evento adverso, n (%) Placebo (n=38) eltrombopag (n=76) Qualquer evento adverso 14 (37) 45 (59) Hemorragia* 5 (13) 7 (9) Dor de cabeça 4 (11) 6 (8) Nasofaringite 3 (8) 5 (7) Náusea – Diarréia 1 (3) 4 (5) Aumento de proteínas totais 3 (4) Vômito Artralgia 2 (3) Fadiga Mialgia Distensão abdominal 1 (1) Dor na parte superior do abdomen TRA100773B: eltrombopag is associated with a low rate of mild-to-moderate, transient adverse events. A total of 59% of patients in the eltrombopag group had one or more adverse event during the treatment phase; this compared with 37% of patients treated with placebo. The most common adverse event observed in this study was headache, reported in 8 and 11% of patients receiving eltrombopag and placebo, respectively. Other common adverse events occurring in at least 5% of eltrombopag patients included nausea, nasopharyngitis, diarrhoea and vomiting. Nausea and vomiting were the only two adverse events recorded in 5% or more of patients in the eltrombopag group and not in the placebo group. Reference 1. Bussel JB, et al. Lancet 2009; 373(9664): 641–8 *Todos os eventos de sangramento foram incluídos 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Eventos adversos sérios relacionados à medicação em estudo
Evento adverso, n (%) Placebo (n=38) eltrombopag (n=76) EASs não fatais 1 (3) – Hemorragia gastrointestinal Hemorragia cerebral Hematúria EASs fatais TRA100773B: eltrombopag is associated with few serious adverse events. One patient in the placebo arm experienced a serious adverse event, reporting non-fatal gastrointestinal haemorrhage, cerebral heamorrhage and haematuria. There were no serious adverse events reported for patients in the eltrombopag arm. No deaths occurred during the study. Reference 1. Bussel JB, et al. Lancet 2009; 373(9664): 641–8 *Todos os eventos de sangramento foram incluídos 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009.

Eventos adversos de interesse especial independente da causa
Qualquer evento adverso, n (%) Placebo n=38 eltrombopag n=76 Hemorragia* 5 (13) 7 (9) Catarata 1 (3) 3 (4) Eventos hepatobiliares† 6 (8) Eventos tromboembólicos – Diminuição transitória na contagem de plaquetas 8 (11) TRA100773B: eltrombopag is associated with a low rate of mild-to-moderate, transient adverse events Among adverse events of particular interest, three patients in the eltrombopag group and one in the placebo group had reports of cataracts; two patients in the eltrombopag group and one in the placebo group had progression of existing cataracts. All patients with cataracts had been previously treated with corticosteroids. Six patients in the eltrombopag group and one in the placebo group had increases in transaminase concentrations to twice the upper limit of normal; abnormal hepatic function caused one patient given eltrombopag on long-term concomitant danazol therapy to withdraw with a platelet count of 174,000/μL. No thromboembolic events were noted in the study. Eight (11%) patients receiving eltrombopag had platelet counts less than 10,000/μL and at least 10,000/μL less than their baseline value within 4 weeks after withdrawal of study drug, compared with five (13%) patients given placebo. Two of the eight patients with a transient decrease in platelet count given eltrombopag had bleeding symptoms (menorrhagia and gum bleeding). Both patients had had similar bleeding symptoms either before entry into the study or during therapy before the rise in platelet counts. Reference Bussel JB, et al. Lancet 2009; 373(9664): 641–8 *Todos os relatos de hemorragia foram incluídos; †definido como aumento do aspartato ou aminotransferase alanina, bilirrubina ou fosfatase alcalina *Investigator-reported AEs; †Significantly (p<0.001) reduced in the eltrombopag treatment arm; ‡defined as increases in aspartate or aminotransferases, bilirubin or alkaline phosphatase; AE=adverse event 25. BUSSEL, J. et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet, 373: 641–8, 2009. 82 82

RAndomized placebo-controlled ITP Study with eltrombopag (RAISE, TRA102537)
37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 83

Objetivo: avaliar a segurança e a eficácia do eltrombopag
Desenho do estudo Tratamento padrão + 50 mg eltrombopag Pacientes com PTI, <30,000/μL Tratamento padrão + placebo N=135 N=62 Randomização 2:1 Seleção Período de tratamento: 6 meses Objetivo: avaliar a segurança e a eficácia do eltrombopag RAISE TRA102537: this was a Phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of eltrombopag in patients with chronic ITP Adults with chronic ITP who had a platelet count less than 30,000/µL and who had received at least one prior ITP therapy were eligible for RAISE. These patients were randomized 2:1 (eltrombopag: placebo) and stratified by splenectomy status, concomitant maintenance ITP therapy and baseline platelet count of 15,000/µL or less. Patients were stratified by splenectomy status, concomitant maintenance ITP therapy and baseline platelet count ≤15,000/µL. Safety assessments, bleeding and platelet counts were monitored at weekly visits during the first 6 weeks of the study, and at visits every 4 weeks thereafter. Post-therapy visits were scheduled for 1, 2, and 4 weeks following discontinuation or completion of the study. Reference Cheng G, et al. Blood 2008; 112: 400 Adultos com PTI crônica com contagem de plaquetas <30,000/µL e ≥1 com terapia(s) prévia(s) para PTI foram selecionados. Pacientes randomizados foram estratificados por: Status da esplenectomia Terapia de manutenção concomitante Contagem de plaquetas inicial ≤15,000/µL 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 84

Dosagem Os pacientes iniciaram tratamento com eltrombopag 50 mg (ou placebo correspondente) uma vez ao dia A dose foi individualizada baseada na resposta plaquetária de cada paciente, de 25 mg a um máximo de 75 mg uma vez ao dia ou com menor frquencia Os pacientes poderiam reduzir a medicação concomitante e receber terapia de resgate como ditado pelo padrão local de tratamento RAISE TRA102537: dosing was individualized based on each patient’s platelet response Patients initiated treatment with eltrombopag 50 mg (or matching placebo) once daily, and the dose was individualized based upon each patient’s platelet response, from a maximum of 75 mg once daily to 25 mg once daily or less frequently.1 If platelet counts exceeded 200 Gi/L, study medication was decreased to the next lower dose2 If platelet counts exceeded 400 Gi/L, study medication was interrupted for 7 days, and until platelet counts fell below 150 Gi/L. Once platelet counts fell below 150 Gi/L, treatment was restarted at the next lower dose2 If patients had platelet counts below 50 Gi/L for 2 successive weeks of dosing, study medication was increased to the next higher dose on or after Day 222 After Day 22, the dose of eltrombopag could be increased to 75 mg once daily or decreased to 25 mg once daily or less often based on each patient’s platelet response; after 6 weeks of treatment patients could reduce their concomitant ITP medication. Any change in eltrombopag or concomitant ITP medication dose resulted in weekly visits during the subsequent 4 weeks.1 Patients were stratified by splenectomy status, use of baseline ITP medication and platelet count of 15,000/μL or less. References Cheng G, et al. Blood 2008; 112: 400 Stasi R, et al. EHA 2009 (abstract and poster presentation) [note: awaiting journal citation] 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008.

A probabilidade de responder com uma contagem de plaquetas entre 50,000 e 400,000/µL durante o período de 6 meses de tratamento em pacientes que recebem eltrombopag em relação ao placebo Desfechos secundários Incidência e gravidade dos sintomas hemorrágicos Proporção de pacientes com uma redução do uso de medicação concomitante desde o início Parâmetros de segurança e tolerabilidade incluindo eventos adversos reportados e testes clínicos laboratoriais A capacidade do eltrombopag de prevenir o uso de medicação de resgate Impacto do eltrombopag na qualidade de vida RAISE TRA102537: the primary endpoint was the odds of responding (platelet count of 50,000 to 400,000/μL) during the treatment period for patients receiving eltrombopag relative to placebo The primary endpoint was the odds of responding (platelet count of 50,000 to 400,000/μL) during the treatment period for patients receiving eltrombopag relative to placebo. Secondary endpoints included the incidence and severity of bleeding symptoms. Bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale: grade 0=no bleeding, grade 1=mild bleeding, grade 2=moderate bleeding, grade 3=gross bleeding, and grade 4=debilitating blood loss. Additional secondary endpoints included proportion of patients with a reduction in concomitant ITP medication use from baseline and safety and tolerability parameters, including adverse events and clinical laboratory tests. Reference Cheng G, et al. Blood 2008; 112: 400 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 86

Características iniciais e demográficas
Placebo n=62 eltrombopag n=135 Idade média (faixa), anos 52.5 (18–77) 47.0 (18–85) Sexo, n (%) Mulheres 43 (69) 93 (69) Homens 19 (31) 42 (31) Variáveis de estratificação , n (%) Contagem de plaquetas 15,000/µL 30 (48) 67 (50) Medicação concomitante 31 (50) 63 (47) Esplenectomia 21 (34) 50 (37) Terapias prévias, n (%) ≥1 62 (100) 135 (100) ≥2 50 (81) 105 (78) ≥3 32 (52) 75 (56) ≥4 20 (32) 51 (38) ≥5 11 (18) 35 (26) RAISE TRA102537: demographic characteristics were balanced between the two treatment groups Randomized patients had a median age of 47 years (range 18–85) in the eltrombopag group and 53 years (range 18–77) in the placebo group. Just over two-thirds of all enrolled patients were women. The majority (>70%) of patients in both groups were white while 21% and 15% of patients in the placebo and eltrombopag groups, respectively, were Asian. A total of 71 patients (34 and 37% in the placebo and eltrombopag groups, respectively) had undergone splenectomy, 94 (50 and 47% in the placebo and eltrombopag groups, respectively) were receiving concomitant ITP medication (most commonly prednisone) and 97 (48 and 50% in the placebo and eltrombopag groups, respectively) had a baseline platelet count 15,000/μL or less. Baseline characteristics of a platelet count of 15,000/µL or less, use of concomitant ITP medication, and history of splenectomy were used as stratification variables during patient randomization. The majority of patients (79%) in both groups had received at least two ITP therapies prior to enrollment in this study including 18% in the placebo arm and 26% in the eltrombopag arm who had undergone treatment with at least five prior ITP therapies. Reference Cheng G, et al. Blood 2008; 112: 400 PTI=púrpura trombocitopênica idiopática 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 87

Probabilidade de resposta
Probabilidade de resposta* 8 vezes melhor com eltrombopag do que com placebo Contagem de plaquetas subiu para /L após 1 semana no grupo eltrombopag RAISE TRA102537: significantly more patients receiving eltrombopag achieved a platelet count of 50,000 to 400,000/µL over the 6 month treatment period compared with patients receiving placebo (odds ratio [OR] [99% CI]=8.2 [3.59–18.73]; p<0.001) The primary endpoint in this study was response to treatment defined as a platelet count between 50,000 to 400,000/µL. The odds ratio for patients responding to treatment with eltrombopag versus placebo was 8.2 (99% CI: 3.59–18.73); p< A total of 38% of patients in the eltrombopag group responded with platelet counts 50,000 to 400,000/µL at 75% or more of their on-therapy assessments, compared with only 7% of patients in the placebo group. Patients also responded to eltrombopag treatment regardless of splenectomy status. Statistical model: Treatment groups were compared using a repeated measures model for binary data adjusted for the randomization stratification variables. Generalized estimating equations methodology was used to estimate the regression model parameters with the correlation of an individual patient’s responder status between visits being modeled as exchangeable. Definition of odds ratio (OR): The ratio of the odds of having the target response in the experimental group relative to the odds in favour of having the target response in the control group. This can give an indication of the likelihood of a response according to which group an individual is in during the course of a set time period, as opposed to at one distinct time point. OR >1: odds of being a responder in the eltrombopag group is greater than in placebo group OR=1: odds of being a responder is the same in both groups OR <1: odds of being a responder in the eltrombopag group is less than in placebo group Reference Cheng G, et al. Blood 2008; 112: 400 *Contagem de plaquetas 50,000 to 400,000/µL; IC=intervalo de confiança; BL=valor inicial 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 88

Resposta plaquetária geral
Análise post-hoc de pacientes que completaram 6 meses de tratamento e atingiram resposta geral definida como elevação na contagem de plaquetas ≥ e ≤ μL por no mínimo 4 semanas consecutivas. RAISE TRA102537: overall platelet response was achieved by 81% of patients in the eltrombopag group versus 18% of patients in the placebo group The primary efficacy analysis of this study was the proportion of patients achieving platelet count elevations ≥50,000 and ≤400,000 μL over the 6 month treatment period. Additional post-hoc analyses have been performed to ascertain the effect of eltrombopag on durable and overall response by splenectomy status. Overall response was defined as having either a durable response or a transient response with platelet count elevations ≥50,000 and ≤400,000 μL for at least 4 consecutive weeks at any time during the 6-month treatment period. In the total population, an overall platelet response was achieved by 81% of patients in the eltrombopag group versus 18% of patients in the placebo group. Reference Stasi R, et al. Haematologica 2009; 94(Suppl 2): 231 38.STASI, R. et al. Durable and overall platelet responses in patients with chronic idiopathic thrombocytopenic purpura during long-term treatment with oral eltrombopag by splenectomy status: the RAISE study. Haematologica , 94(Suppl 2): abs. 231, 2009.

Resposta plaquetária duradoura
Análise post-hoc de pacientes que atingiram resposta duradoura definida como elevação na contagem de plaquetas ≥ e ≤ μL por pelo menos 6 das últimas 8 semanas de um período de 6 meses de tratamento. RAISE TRA102537: durable platelet response was achieved by 60% of patients in the eltrombopag group versus 10% of patients in the placebo group The primary efficacy analysis of this study was the proportion of patients achieving platelet count elevations ≥50,000 and ≤400,000 μL over the 6 month treatment period. Additional post-hoc analyses have been performed to ascertain the effect of eltrombopag on durable and overall response by splenectomy status. Durable response was defined as having as having a platelet count elevation ≥50,000 and ≤400,000 μL for at least 6 of the last 8 weeks in the 6-month treatment period. In the total population, a durable platelet response was achieved by 60% of patients in the eltrombopag group versus 10% of patients in the placebo group. Reference Stasi R, et al. Haematologica 2009; 94(Suppl 2): 231 38.STASI, R. et al. Durable and overall platelet responses in patients with chronic idiopathic thrombocytopenic purpura during long-term treatment with oral eltrombopag by splenectomy status: the RAISE study. Haematologica , 94(Suppl 2): abs. 231, 2009.

Resposta geral e duradoura atingida independentemente do status da esplenectomia
Resposta plaquetária geral e duradoura em pacientes que completaram 6 meses de tratamento (análise post-hoc). RAISE TRA102537: the proportion of patients achieving a durable and overall response with eltrombopag was similar in splenectomized and non-splenectomized patients Durable response and overall response were assessed in a post-hoc analysis in patients who received 6 months of treatment (defined as at least 182 days). Durable response was defined as having a platelet count elevation ≥50 and ≤400 Gi/L for at least 6 of the last 8 weeks in the 6-month treatment period. Patients who received rescue medication at any time during the 6-month treatment period were considered not to have achieved a durable response. Overall response was defined as having either a durable response or a transient response with platelet count elevations ≥50 and ≤400 Gi/L for at least 4 consecutive weeks at any time during the 6-month treatment period. Durable platelet response was achieved by 60% of patients in the eltrombopag group versus 10% of patients in the placebo group. Fifty-one percent (51%) of splenectomized and 66% of non-splenectomized patients treated with eltrombopag achieved a durable platelet response. Overall platelet response was achieved in 81% of patients in the eltrombopag group versus 18% of patients in the placebo group. Seventy percent (70%) of splenectomized patients and 88% of non-splenectomized patients treated with eltrombopag achieved an overall platelet response. Reference Stasi R, et al. Haematologica 2009; 94(Suppl 2): 231 38.STASI, R. et al. Durable and overall platelet responses in patients with chronic idiopathic thrombocytopenic purpura during long-term treatment with oral eltrombopag by splenectomy status: the RAISE study. Haematologica , 94(Suppl 2): abs. 231, 2009.

Pacientes responderam ao eltrombopag independentemente do status da esplenectomia.
RAISE TRA102537: eltrombopag produces a rapid and sustainable increase in platelet counts in pre- and post-splenectomy ITP Figure shows the proportions of responders in each treatment group by splenectomy status at each nominal study visit. Patients responded to eltrombopag therapy regardless of splenectomy status (p value for interaction=0.562). Reference 1. Cheng G, et al. N Engl J Med 2009; In press BL=valor inicial 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008.

eltrombopag reduziu sangramento em pacientes com PTI
76% de redução na probabilidade de sangramento (p<0.001) WHO graus de escala de sangramento 1–4 RAISE TRA102537: eltrombopag reduces bleeding in patients with ITP Significantly fewer patients treated with eltrombopag had any bleeding (WHO grades 1–4; p <0.001). eltrombopag reduced the risk of any bleeding by 76% compared with placebo (odds ratio 0.24; 95% CI, 0.16–0.38). Reference Cheng G, et al. Blood 2008; 112: 400 WHO=World Health Organization 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 93

eltrombopag reduziu o sangramento clinicamente significativo
65% redução na probabilidade de sangramento clinicamente significativo (p<0.001) WHO graus de escala de sangramento 2–4 RAISE TRA102537: eltrombopag reduces clinically significant bleeding in patients with ITP Significantly fewer patients treated with eltrombopag experienced clinically significant bleeding (WHO grades 2–4; p <0.001).1 eltrombopag reduced the risk of any bleeding by 65% compared with placebo (odds ratio 0.35; 95% CI, 0.19–0.64).2 Reference Cheng G, et al. N Engl J Med 2009; In press WHO=World Health Organization 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 94

Razão de risco =3.10 (95% IC=1.24–7.75)
eltrombopag pode permitir a redução ou a descontinuação da terapia concomitamte em pacientes com PTI * Razão de risco =3.10 (95% IC=1.24–7.75) RAISE TRA102537: eltrombopag may allow patients to reduce or discontinue their concomitant ITP medications At baseline, concomitant ITP medications were used by 47% (n=63) of patients in the eltrombopag arm and 50% (n=31) of patients in the placebo arm. More patients in the eltrombopag group (n=37/63; 59%) stopped or dose-reduced their concomitant ITP medications than in the placebo group (n=10/31; 32%; p=0.016). Of the 37 patients who reduced and/or discontinued ≥1 baseline ITP medication in the eltrombopag treatment arm, 84% of patients (n = 31/37) permanently discontinued or achieved a sustained reduction in their concomitant ITP medication: 20 patients discontinued corticosteroids 6 patients achieved a sustained reduction in their corticosteroid dose 2 patients discontinued azathioprine 1 patient discontinued mycophenolate 1 patient discontinued cyclosporine A 1 patient achieved a sustained reduction in their danazol dose Overall, corticosteroids accounted for 73% of the discontinued/reduced medications In the placebo treatment arm, 60% (n = 6/10) of patients permanently discontinued or achieved a sustained reduction in their concomitant ITP medication: 3 patients discontinued corticosteroids 1 patient achieved a sustained reduction in their corticosteroid dose 1 patient discontinued danazol 1 patients reduced azathioprine Overall, corticosteroids accounted for 40% of the discontinued/reduced medications Furthermore, patients in the eltrombopag group (19%) required less rescue therapy compared with the placebo group (40%; p=0.001) during the treatment phase of the study. Reference Cheng G, et al. Blood 2008; 112: 400 *A maioria das medicações concomitantes para PTI são os corticóides; IC=intervalo de confiança; PTI=púrpura trombocitopenica idiopática 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 95

Avaliação do eltrombopag com relação a qualidade de vida do paciente
Resultado reportado de um paciente: instrumento e domínio Efeito médio de eltrombopag vs placebo na mudança da pontuação da linha de base (ITT população) Mudança de score estimada 95% IC p valor SF-36v2 Função física 2.8 -1.1, 6.7 0.154 Papel da função física 5.4 0.5, 10.3 0.030 Dor corporal 5.1 -0.5, 10.6 0.074 Saúde geral 2.4 -1.6, 6.5 0.243 Vitalidade 3.9 0.1, 7.7 0.045 Função social 4.1 -0.6, 8.9 0.089 Papel emocional 0.8, 10.1 0.023 Saúde mental 2.5 -0.9, 6.0 Resumo do componente físico 1.3 -0.2, 2.9 0.092 Resumo do componente mental 2.1 0.2, 4.0 FACIT-Fatiga 1.6 -0.2, 3.5 0.082 FACT-Th (6 itens selecionados) 1.5 0.5, 2.5 0.004 eltrombopag improves patient health-related quality of life Patient reported quality of life for patients in the RAISE study was measured using the using the SF-36v2, fatigue sub-scale of FACIT-Fatigue, and a 6-item subset of the FACT-thrombocytopenia (FACT-Th) that focuses on concern with bleeding and bruising, and limits to physical and social activities. Differences in the changes in response from baseline were estimated from a longitudinal regression model. During 6 months of eltrombopag treatment, patients reported meaningful improvements in vitality (p=0.045), emotional (p=0.023) and physical role (p=0.030) domains, and in overall mental health (as determined by the mental component summary; p=0.030). Patients consistently reported clinically and statistically significant benefits in physical and social activities and in concerns for bleeding and bruising symptoms as outlined in the FACT-Th subset (p=0.004). eltrombopag treatment also resulted in improvements in the physical function, general health and mental health component scores compared with placebo, although these improvements were not statistically significant (p>0.1).1 In addition, there were statistically significant correlations between improvements in health-related quality of life, elevations in platelet counts and reductions in bleeding symptoms (p<0.05 for all eight domain scores and both component summary scores).2 References 1. Provan D, et al. Haematologica 2009; 94(Suppl 2): 233 2. Cheng G, et al. Blood 2008; 112: 400 ITT= intent to treat (intenção detratar); IC=intervalo de confiança; SF-36=Short-Form 36; FACT-Functional Assessment of Cancer Therapy (Avaliação Funcional da Terapia do Câncer); FACIT=Functional Assessment of Chronic Illness Therapy (Avaliação Funcional da Terapia de Doenças Crônicas) 39. PROVAN, D. et al. Improvement in fatigue and health-related quality of life (HRQOL) with long-term eltrombopag therapy in chronic idiopathic thrombocytopenic purpura: results of phase 3, double-blind study(RAISE). Haematologica , 94(Suppl 2): abs. 233, 2009. 96

Resumo dos eventos adversos
Eventos adversos, n (%) Placebo n=61 eltrombopag n=135 Qualquer EA independente da causa Dor de cabeça Diarréia Náusea Nasofaringite Infecção do trato respiratório superior Fadiga Dor nas extremidades Epitasis Tonturas Edema periférico 56 (92) 20 (33) 6 (10) 4 (7) 8 (13) 7 (11) 118 (87) 41 (30) 17 (13) 16 (12) 14 (10) 13 (10) 9 (7) 7 (5) 5 (4) 2 (1) Qualquer EA relacionado com a medicação em estudo 18 (30) 48 (36) Qualquer EA sério 11 (18) 15 (11) Mortes 1 (2) RAISE TRA102537: eltrombopag is generally well tolerated with a low rate of mild, transient adverse events The incidence and severity of adverse events were similar to that of placebo treatment groups, with mild-to-moderate headache being the most common adverse event. One patient in the placebo group died due to a fatal brain stem haemorrhage. Reference 1. Cheng G, et al. Blood 2008; 112: 400 EA= EVENTO ADVERSO 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. . 97

Evento adverso*, n (%) Placebo n=61 eltrombopag n=135 EAs Totais 56 (92) 118 (87) EAs hemorrágicos Hemorragia durante a terapia Hemorragia grave durante a terapia Hemorragia pós-terapia Hemorragia grave pós-terapia 19 (31) 4 (7) 6 (10) 1 (2) 26 (19) 1 (<1)† 6 (4) 2 (1) EAs tromboembólicos (em terapia) – 3 (2) EAs hepatobiliares (em terapia)‡ 17 (13) Catarata 10 (7) Tumores malignos 1 (<1) Formação de reticulina na medula óssea Diminuição transitória na contagem de plaquetas 9 (7) RAISE TRA102537: eltrombopag exhibits a low rate of mild-to-moderate adverse events For bleeding adverse events, the majority were grades 1 or 2 in severity and less than 3% of patients in both groups had events considered related to treatment. The majority of events (placebo, 52 of 54 events in 19 patients; eltrombopag, 43 of 69 events in 17 patients) occurred in patients with proximal platelet counts of 50,000/µL or less. One death due to brain stem haemorrhage was reported in the placebo group. A higher incidence of hepatobiliary laboratory abnormalities were reported in the eltrombopag group (12%) compared with the placebo group (8%). In the eltrombopag group, all hepatobiliary adverse events of elevated aminotransferase levels resolved while on therapy or following dose interruption/discontinuation without clinical sequelae. There were no clinical or laboratory symptoms, such as reticulin increases, suggestive of bone marrow fibrosis. Malignancies included one patient in the placebo group with acute leukaemia and one patient in the eltrombopag group with cancer of the rectosigmoid colon. Reference Cheng G, et al. N Engl J Med 2009; In press *Investigador relatou EAs; †Significativamente (p=0.033) reduzido no braço do tratamento com eltrombopag; ‡definido como aumento do aspartato ou aminotransferases, bilirrubina ou fosfatase alcalina; EA=evento adverso 37.CHENG, G. et al. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood, 112(11): abs. 400, 2008. 98 98

eltrombopag eXTENded Dosing (EXTEND, TRA105325)
40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008. 99

Desenho do estudo Em andamento, aberto, Estudo de extensão fase III Objetivo: Avaliar a segurança e eficácia de eltrombopag a longo-prazo em pacientes com PTI crônica que completaram previamente os ensaios referentes ao eltrombopag. EXTEND TRA105325: this ongoing, open-label, Phase III extension study was designed to assess the long-term safety and efficacy of eltrombopag in patients with ITP who had previously completed another eltrombopag trial Adult patients with chronic ITP who completed a previous eltrombopag ITP study (including TRA100773A/B, RAISE and REPEAT) at least 4 weeks prior to starting EXTEND were enrolled in the study. Patients were eligible for EXTEND regardless of whether they had received eltrombopag or placebo in their previous eltrombopag study. The primary objective of the study was to assess the long-term safety and efficacy of eltrombopag in patients with chronic ITP who had previously been enrolled and completed an eltrombopag study. Exclusion criteria included eltrombopag-related intolerance or toxicity in the previous eltrombopag study; any clinically relevant abnormality, other than ITP, identified at screening; secondary immune thrombocytopenia; prior treatment with radiation or chemotherapy; a history of malignancy, cardiac disease, drug or alcohol abuse, platelet agglutination abnormalities, and arterial or venous thrombosis and at least 2 risk factors for the development of thrombosis; and women who were nursing or pregnant. The study consisted of four different stages defined by specific goals and dosing instructions: Stage 1: Identify a dose of eltrombopag that increases platelet counts to a level high enough (≥100,000 µl) to support dose reduction of concomitant ITP medication Stage 2: Reduce or eliminate comcomitant ITP medication while maintaining the platelet counts ≥50,000 µl Stage 3: Identify the minimal effective dose of eltrombopag necessary to maintain platelet counts ≥50,000 µl in conjunction with the minimal dose of concomitant ITP medication Stage 4: Monitor safety and efficacy of eltrombopag at the minimal effective dose that in conjunction with the minimal dose of concomitant ITP medications maintains platelet counts ≥50 Gi/L Reference Bussel JB, et al. Blood 2008; 112: 3432 Bussel JB, et al. Hematologica; 94(Suppl 2): 239 A Números indicam as metas de contadem de plaquetas para cada estágio. 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008. 100

Dosagem Pacientes iniciaram com uma dosagem de eltrombopag 50 mg uma vez ao dia Após 22 dias, ajustes de dose de 25 a 75 mg uma vez ao dia ou menos foram permitidos para manter a contagem de plaquetas entre e /μL Corticóides concomitante ou azatioprina numa dose estável por ≥1 mês e ciclosporina A, micofenolato de mofetil ou danazol numa dose estável por ≥3 meses foram permitidas EXTEND TRA105325: dosing was individualized for each patient, with dose adjustments used to maintain platelet counts between 50,000 and 400,000/μL Patients started at a dose of eltrombopag 50 mg once daily. After Day 22, dose adjustments to 25 to 75 mg once daily or less often were allowed to maintain platelet counts between 50,000 and 400,000/μL. Intravenous immunoglobulin and anti-D must have been completed at least 1 week before enrolment; splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks before enrolment. Concomitant corticosteroids or azathioprine at a stable dose for at least 1 month and cyclosporin A, mycophenolate mofetil, or danazol at a stable dose for at least 3 months were permitted. The average daily dose of eltrombopag was 50.6 mg (standard deviation, 16.9), with a range from 7 to 74 mg. The median number of days on eltrombopag treatment was 91.5 days (range, 2–523 days). The total number of patient–years of exposure to eltrombopag in EXTEND was 93.3 years (93 years, 104 days). Reference Bussel JB, et al. Blood 2008; 112: 3432 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008.

Desfechos do estudo Desfecho primário Desfechos secundários incluídos:
Parâmetros de segurança e tolerabilidade, incluindo testes clínicos laboratoriais, exames oculares e frequência de todos os eventos adversos Desfechos secundários incluídos: Proporção de pacientes que alcançaram contagem de plaquetas ≥50.000/μL pelo menos uma vez durante o tratamento Durabilidade da contagem elevada de plaquetas durante o tratamento Definido como contagem de plaquetas ≥50.000/μL e pelo menos o dobro do valor de base por ≥6 das últimas 8 semanas nos primeiros 6 meses do estudo EXTEND Resposta plaquetária geral Definido como resposta duradoura mais resposta transitória (contagem de plaquetas ≥50,000/μL e pelo menos o dobro do valor de base por ≥4 semanas consecutivas em qualquer momento durante os 6 primeiros meses do estudo EXTEND) Incidência e gravidade dos sintomas de sangramento mensurado pela escala de sangramento da Organização Mundial de Saúde EXTEND TRA105325: the primary endpoint of the study was safety and tolerability The key study endpoints were as follows: Proportion of patients who achieved a platelet count of 50,000/μL or higher at least once during treatment Durability of elevated platelet counts while on therapy (defined as platelet counts ≥50,000/μL and at least double the baseline value for 6 or more of the last 8 weeks in the first 6 months of EXTEND) Overall platelet response was defined as durable response plus transient response (platelet counts ≥50,000/μL and at least double the baseline value for ≥4 consecutive weeks at any point during the first 6 months of EXTEND) Incidence and severity of bleeding symptoms associated with ITP, prospectively measured using the WHO bleeding scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; grade 4, debilitating blood loss) Safety and tolerability parameters (primary endpoint) Reference 1. Bussel JB, et al. Blood 2008; 112: 3432 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008.

Características iniciais e demográficas
eltrombopag n=207 Idade média (intervalo), anos 50 (18–86) Mulheres, n (%) 138 (67) Contagem de plaquetas, n (%) <30,000/μL 30,000–50,000/μL >50,000/μL 145 (70) 37 (18) 25 (12) Medicação concomitante, n (%)* 69 (33) Esplenectomia, n (%) 82 (40) ≥3 terapias prévias para PTI, n (%) 119 (57) EXTEND TRA105325: demographic characteristics were balanced between the two treatment groups Enrolled patients had a median age of 50 years (range 18–86), nearly two-thirds were women. The majority of patients (78%) were white, 15% were Asian and 7% were classified as Other. A total of 82 (40%) patients had undergone splenectomy, 69 (33%) were receiving concomitant ITP medication (most commonly prednisone) and 145 (70%) had a baseline platelet count of less than 15,000/μL. Reference Bussel JB, et al. Blood 2008; 112: 3432 *Incluiu prednisona, prednisolona, danazol, azatioprina, dexametasona, ácido micifenólico e oximetolona; PTI =púrpura trombocitopênica idiopática 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, FOGARTY, P. et al. Oral Eltrombopag Treatment Reduces the Need for Concomitant Medications in Patients with Chronic Idiopathic Thrombocytopenic Purpura. Blood, 112(11): abs. 3424, 2008. 103

Respostas ao eltrombopag são mantidas durante todo o tratamento
Contagem média de plaquetas alcançou ≥72,000/μL na segunda semana Elevações contínuas para ≥50,000/μL e pelo menos 2x do valor inicial foram mantidas por pelo menos 10 semanas e 25 semanas em 35 e 24% dos pacientes, respectivamente. EXTEND TRA105325: eltrombopag increased platelet count within 2 weeks of treatment, and this effect was maintained over time In the EXTEND study, a durable platelet response was defined as platelet counts ≥50,000/μL and at least double the baseline value for ≥6 of the last 8 weeks in the first 6 months of the study. The median platelet count reached 72,000/μL or more by Week 2 on therapy and remained 50,000/μL or more throughout the remainder of the current 55-week observation period with three exceptions, when the median platelet counts remained 42,000/μL or more. Continuous platelet count elevations to 50,000/μL or more and at least double the baseline value were maintained for at least 10 weeks and 25 weeks in 35 and 24% of patients, respectively. Reference Bussel JB, et al. Blood 2008; 112: 3432 aLinha pontilhada indica 50,000 plaquetas/μL; barras de erro representam os valores do 25th e 75th quartis; BL=valor inicial 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008. 104

Efeitos do eltrombopag se mostram independentes dos fatores de estratificação iniciais
Esplenectomizados (n=75) Não-Esplenectomizados (n=122) Total (N=201)* Elevação na contagem de plaquetas, n (%) ≥50,000/μL pelo menos 1 vez 64 (81) 95 (78) 159 (79) >400,000/μL pelo menos 1 vez 20 (25) 12 (10) 32 (16) Durabilidade da elevação na contagem de plaquetas durante os 6 primeiros meses do estudo Pacientes recebendo a medicação em estudo por 6 meses, n 35 39 74 Pacientes sem mediçação de resgate (Linha de base–Mês 6)†, n 30 38 68 Resposta plaquetária duradoura, n (%) 17 (57) 21 (55) 38 (56) Resposta plaquetária geral, n (%) 25 (83) 31 (82) 56 (82) EXTEND TRA105325: the effect of eltrombopag on platelet levels was seen regardless of baseline platelet levels, splenectomy status or concomitant ITP medication use at baseline Seventy-nine percent (n=159) of patients responded to eltrombopag with platelet counts of 50,000/μL at least once during the study. Patients achieved platelet counts of 50,000/μL or more regardless of concomitant ITP medication use at baseline (yes, 80%; no, 79%) or splenectomy status (yes, 81%; no, 78%). Seventy-two percent of patients who had baseline platelet counts of less than 30,000/μL achieved platelet counts of 50,000/μL or more compared with 97% of patients who had baseline platelet counts 30,000 to 50,000/μL. Eighty-one and 85% of patients who responded in the RAISE and REPEAT trials, respectively, achieved a platelet count ≥50,000/μL, and double the baseline value at least once in EXTEND. Ninety-six percent of responders in the TRA100773A/B 6-week study met this response criteria in EXTEND. Similar proportions of splenectomized and non-splenectomized patients had a durable platelet response (57 and 55%, respectively) and an overall platelet response (83 and 82%, respectively). Reference Bussel JB, et al. Blood 2008; 112: 3432 *Seis pacientes não tiveram uma pós consulta inicial e não foram avaliados quanto à eficácia; †Denominador para o cálculo da resposta plaquetária geral e duradoura. 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008.

Eventos hemorrágicos foram reduzidos com o tratamento com eltrombopag
EXTEND TRA105325: treatment with eltrombopag was associated with a reduction in bleeding symptoms At baseline, 59% (n=122) of patients reported bleeding symptoms (WHO grades 1–4) and 18% (n=38) reported clinically significant bleeding symptoms (WHO grades 2–4). The proportion of patients experiencing any bleeding was reduced to approximately 30% at 1, 3 and 6 months on therapy, while clinically significant bleeding was reduced to less than 10% at 1, 3 and 6 months on therapy. Reference Bussel JB, et al. Blood 2008; 112: 3432 BL= baseline (valor inicial) 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs. 3432, 2008. 106

Redução ou descontinuação de medicações concomitantes
Pacientes recebendo medicações de referência para PTI N=69 Tentativa de reduzir ou diminuir a medicação de referência para PTI, n (%) 33 (48) Permanentemente interrompido ou teve uma redução sustentada*, n (%) 23 (70) Durante 24 semanas*† , n (%) 15 (65) Permanentemente interrompido 1 medicação de referência*, n (%) 20 (61) Permanentemente interrompido todas as medicções de referência*, n (%) 18 (55) EXTEND TRA105325: oral eltrombopag treatment reduces the need for concomitant medications At baseline, 69 (33%) patients reported the use of ITP medications; of these, 65 patients had at least one post-baseline visit by the clinical cut-off date and were evaluable for response status. Eighty percent (52/65) of these patients responded to eltrombopag with a platelet count of 50,000/L or more during the study. Forty-eight percent (33/69) of patients attempted to reduce or discontinue their concomitant ITP medications during the study. Seventy percent (23/33) of these patients discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment as of the clinical cut-off date; of these, 65% (15/23) had maintained the discontinuation or reduction for at least 24 weeks as of the clinical cut-off date. Sixty-one percent (20/33) of patients discontinued at least one baseline ITP medication, and 55% (18/33) discontinued all baseline ITP medications, without subsequent rescue treatment. Discontinued or reduced medications included prednisone (n=11), prednisolone (n=8), danazol (n=5), and azathioprine, dexamethasone, mycophenolic acid and oxymetholone (n=1 each). Reference Fogarty P, et al. Blood 2008; 112: 3424 *Exclui os pacientes que necessitaram de medicação de resgate posterior (aumento da dose da medicação de referência concomitante, nova medicação para PTI, transfusão de plaquetas, esplenectomia); † Denominador são os 23 pacientes que interromperam permanentemente ou tiveram uma redução sustentada dos medicamentos de referência para PTI; PTI = púrpura trombocitopênica idiopática 41.FOGARTY, P. et al. Oral Eltrombopag Treatment Reduces the Need for Concomitant Medications in Patients with Chronic Idiopathic Thrombocytopenic Purpura. Blood, 112(11): abs. 3424, 2008.

Eventos adversos em ≥ 5% dos pacientes independente da causa
Evento adverso, n (%) N=207 Qualquer EA 150 (72) Dor de cabeça 32 (15) Infecção do trato respiratório superior 27 (13) Diarréia 20 (10) Nasofaringite 18 (9) Artralgia 17 (8) Fatiga 14 (7) Náusea Epistaxe 13 (6) Insônia 11 (5) Anemia 10 (5) Dor nas costas Qualque EA relacionado à medicação em estudo 51 (25) Qualquer EA sério EXTEND TRA105325: eltrombopag exhibits a low rate of mild-to-moderate, transient adverse events Adverse events were reported by 72% (n=150) of patients while on therapy, the majority of which were mild-to-moderate in severity. Fifty-one (25%) patients experienced an adverse event considered by the investigator to be treatment related Thirty-four serious adverse events were reported by 17 (8%) patients while on therapy Four deaths were reported in the study (two deaths on therapy and two deaths more than 30 days after the last dose of eltrombopag); none were considered related to study medication Reference Bussel JB, et al. Blood 2008; 112: 3432 EA= EVENTO ADVERSO 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3432, 2008.

Qualquer grau de EAs de interesse especial durante o tratamento de mais de 30 dias Eventos adversos, n (%) N=207 Hemorragia 30 (14) Eventos hepatobiliares* 15 (7) Tromboembólico 7 (3) Fibras de reticulina Catarata (incidência e/ou piora) 4 (2) Tumores malignos EXTEND TRA105325: eltrombopag exhibits a low rate of mild-to-moderate, transient adverse events On therapy, 15 patients reported 41 hepatobiliary adverse events starting between Days 8 and 330. The most common hepatobiliary adverse events were aminotransferase increases (22 events) and blood bilirubin increases (14 events; indirect bilirubin where fractionated); all but two events had resolved, with the majority of events resolving during treatment with eltrombopag. Thromboembolic events were experienced by seven patients while on study. Events included deep vein thrombosis (three events), pulmonary embolism (two events), transient ischaemic attack (one event) and suspected prolonged reversible ischaemic neurological deficit (one event). Three of the patients had platelet counts of less than 50,000/μL proximal to the event; the remaining four patients had platelet counts between 94,000 and 407,000/μL. Four of these events were considered related to study medication by the investigator, including deep vein thrombosis (two events [resolved, improving]), pulmonary embolism (one event [resolved]) and suspected prolonged reversible ischaemic neurological deficit (one event [resolved]). No patient reported reticulin formation as an adverse event. Seven patients had reticulin (n=5) or reticulin in conjunction with collagen fibers (n=2) documented in the bone marrow; three of these patients had documentation of pre-existing reticulin fibers. Bone marrow biopsy reports were available for 19 patients, including 17 patients for whom biopsies were obtained after 10 or more months of eltrombopag therapy. None of the biopsies were performed due to abnormal peripheral blood smears. Cataracts were reported as an on-therapy adverse event by four patients (five events). Four adverse events in three patients were cataract progression, and one adverse event was an incident cataract (traumatic cataracts). All patients with cataracts had a risk factor of chronic corticosteroid use. Reference Bussel JB, et al. Blood 2008; 112: 3432 * Definido como aumento do aspartato ou aminotransferases, bilirrubina ou fosfatase alcalina; EA = Evento Adverso 40.BUSSEL, J. et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3432, 2008.

Repeat ExPosure to eltrombopag in Adults with idiopathic Thrombocytopenic purpura (REPEAT, TRA108057) TRA108057 Repeat ExPosure to eltrombopag in Adults with idiopathic Thrombocytopenic purpura (REPEAT) 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008. 110

Desenho do estudo Multicêntrico, aberto, Fase II, estudo de dose repetida Objetivo: avaliar a consistência de resposta e segurança de doses repetidas de eltrombopag ao longo de 6 semanas com intervalos de parada de 4 semanas em pacientes com PTI crônica. REPEAT TRA108057: this open-label, Phase II study was designed to evaluate the consistency of response and safety of repeated 6-week dosing of eltrombopag The REPEAT study was a multicentre, open-label, Phase II, repeated dosing study. Consistency of response (as measured by platelet count) and safety were evaluated following repeated eltrombopag dosing over three 6-week cycles of treatment. Efficacy and safety evaluations were performed weekly throughout the on- and off-therapy periods of each cycle. Enrolled patients were adult patients with chronic ITP who had platelet counts ranging from 20,000 to 50,000/μL and who had received one or more prior therapies for ITP. Concomitant ITP medications were allowed during the study provided that the dose was stable and kept constant throughout the study. No new ITP medications were to be introduced during the study, except rescue medications if needed. Consistency of response (as measured by platelet count) and safety were evaluated following repeated eltrombopag dosing over three 6-week cycles of treatment. Reference Bussel JB, et al. Blood 2008; 112: 3431 PTI = Púrpura Trombocitopênica Idiopática 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

Dosagem A dose inicial de eltrombopag foi 50 mg
A dose poderia ser aumentada para 75 mg após o 22º dia caso a contagem de plaquetas fosse <50,000/μL por 2 semanas consecutivas Os aumentos de dose foram mantidos através dos ciclos de tratamento subsequentes A diminuição da dose não foi permitida O período fora da terapia era iniciado caso a contagem de plaquetas fosse >200,000/μL O próximo ciclo de tratamento foi iniciado quando a contagem de plaquetas era <20,000/μL antes do final de 4 semanas fora do período de tratamento REPEAT TRA108057: eltrombopag dose was individualized according to patients’ platelet levels eltrombopag 50 mg (initial starting dose) was administered for three cycles. A cycle was defined as an eltrombopag on-therapy period of up to 6 weeks followed by an off-therapy period of up to 4 weeks, with the duration of both the on- and off-therapy periods determined by the patient’s platelet count. Patients whose platelet counts were less than 50,000/μL for 2 consecutive weeks were eligible to have their eltrombopag dose increased to 75 mg on or after Day 22 of the on-therapy period; those who had their dose increased were to start the next cycle of treatment at the increased dose. No dose decreases were permitted. If a patient achieved a platelet count of more than 200,000/μL while on therapy, treatment within the cycle was interrupted, and the off-therapy period was begun. If a patient’s platelet count decreased to below 20,000/μL before completion of the 4-week off-treatment period, the next treatment cycle with eltrombopag was started. Patients who did not respond in Cycle 1 were not eligible to enter Cycles 2 or 3. Concomitant ITP medications were allowed during the study provided that the dose was stable and kept constant throughout the study. No new ITP medications were to be introduced during the study, except rescue medications if needed. Reference Bussel JB, et al. Blood 2008; 112: 3431 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

Desfechos do estudo Consistência (durabilidade) da resposta foi definida como a proporção de pacientes que responderam ao tratamento com eltrombopag nos Ciclos 2 ou 3 seguido da resposta no Ciclo 1 Resposta dentro do Ciclo foi definida como contagem de plaquetas ≥50,000/μL e pelo menos o dobro da contagem de plaquetas inicial após ≥42 dias de administração de eltrombopag Segurança e tolerabilidade foram avaliados através de eventos adversos reportados e testes clínicos laboratoriais REPEAT TRA108057: the primary endpoint of the study was the consistency (durability) of response Consistency (durability) of response was defined as the proportion of patients who responded to eltrombopag treatment in Cycles 2 or 3 following a response in Cycle 1. Response within a cycle was defined as a platelet count of 50,000/μL or more and at least double the baseline platelet count after up to 42 days of eltrombopag dosing. Patients who withdrew early because they achieved a platelet count of more than 200,000/μL were also considered responders. The incidence and severity of bleeding events were prospectively measured using the WHO bleeding scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; and grade 4, debilitating blood loss). Safety and tolerability were assessed using adverse event reporting and clinical laboratory tests. Reference Bussel JB, et al. Blood 2008; 112: 3431 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

Características clínicas iniciais e demográficas do paciente
eltrombopag (n=66) Idade média (faixa), anos 51 (20–79) Mulheres, n (%) 45 (68) Contagem inicial de plaquetas, n (%) <20,000/μL 4 (6) 20,000 to 30,000/μL 29 (44) >30,000 to 50,000/μL 31 (47) >50,000/μL 2 (3) Uso da medicação concomitante = sim, n (%) 22 (33) Esplenectomia = sim, n (%) 20 (30) REPEAT TRA108057: demographic characteristics were balanced between the two treatment groups The 66 patients enrolled in REPEAT had a median age of 51 years, and 68% were female. The majority of patients were white (80%), 15% were Asian, 3% were black and 2% were classified as Other. A total of 33% of patients were receiving concomitant ITP medication at baseline, 91% of patients had baseline platelet counts between 20,000 and 50,000/μL, and 30% of patients had undergone splenectomy. Reference Bussel JB, et al. Blood 2008; 112: 3431 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

O uso intermitente e repetido de eltrombopag produziu respostas consistentes em pacientes com PTI crônica Contagem média de plaquetas por visita nos Ciclos 1, 2 e 3 REPEAT TRA108057: onset of action was rapid and increases in platelet counts were sustained and durable Eighty percent (n=52/66) of patients responded to treatment in Cycle 1. A total of 45 (87%) patients who responded in Cycle 1 also responded in Cycles 2 or 3 (primary endpoint; 95% CI: 74–94%). More than 50% of patients had responded by Day 8 of each cycle. By Day 15, more than 79% had responded, and 19 to 31% of patients in each cycle had platelet counts of more than 200,000/μL. In each cycle, median platelet counts were similarly elevated by Day 8, and were between 79,000 and 126,000/μL after Day 8. Median platelet counts remained elevated for 1 week after discontinuation of eltrombopag treatment and returned to near baseline after 2 weeks off therapy. Reference Bussel JB, et al. Blood 2008; 112: 3431 On, on-therapy period (no período de tratamento); Off, off-therapy period (fora do período de tratamento); As barras de erro representam o percentual 25th e 75th percentual para cada grupo de tratamento 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

Pacientes apresentaram menos hemorragia após o tratamento com eltrombopag
Incidência de hemorragia durante os ciclos 1, 2 e 3 REPEAT TRA108057: decreases in bleeding (WHO bleeding scale grades 1–4) were observed at Day 43 of each on-therapy period versus baseline Decreases in bleeding (WHO bleeding scale grades 1–4) were observed at Day 43 of each on-therapy period versus baseline. No WHO grade 3 or 4 bleeding events occurred within 4 weeks of discontinuing eltrombopag. Reference Bussel JB, et al. Blood 2008; 112: 3431 aWHO bleeding scale grades 1–4; bWHO bleeding scale grades 2–4; WHO= World Health Organization 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

Avaliação do risco de alterações hemostáticas durante os procedimentos médicos
A análise foi conduzida para determinar se o tratamento com eltrombopag poderia permitir os pacientes com PTI a se submeterem a procedimentos sem hemorragia ou terapia para PTI adicional Sete pacientes foram submetidos ao desafio hemostático e todos foram controlados com sucesso sem terapia de resgate e hemorragia inesperada 2 pacientes tiveram colonoscopia 2 pacientes tiveram problema dentários 1 paciente teve cirurgia endoscópica e cateterismo cardíaco 1 paciente foi submetido à ressecação transuretral da próstata 1 paciente teve polipectomia no cólon eltrombopag may be suitable under special circumstances in ITP patients, such as short-term procedures or surgeries In the open-label REPEAT study, seven patients successfully managed haemostatic challenges without rescue therapy and unexpected bleeding (one patient had both endoscopic sinus surgery and a cardiac catheterisation, one patient each had transurethral resection of the prostate and colon polypectomy, two patients had colonoscopies, and two patients had dental work). Similar results were achieved in the EXTEND trial where 13 patients experienced haemostatic challenge during a medical procedure. The procedures included tooth repair, colonoscopies, arthroscopy, and uterine polypectomy. Two patients not responding to eltrombopag had rescue treatment (IVIg and cyclosporine) prior to the procedure; no unexpected bleeding was reported. Reference 1. Tarantino M, et al. Hematologica 2008; 93(Suppl 1): 296 51.TARANTINO, M. et al. Oral eltrombopag helps chronic idiopathic thrombocytopenic purpura (itp) patients to undergo procedures without bleeding or additional treatment to raise platelet counts. Haematologica , 93(1): abs , 2008.

Eventos adversos mais comuns independente da causa
Ciclo 1 Ciclo 2 Ciclo 3 Todos os ciclos Evento adverso, n (%) On (N=66) Off (N=65) (N=55) (N=51) Qualquer EA independente da causa Dor de cabeça Diarréia Fadiga Nasofaringite Artralgia Náusea Vômito Dor nas costas Insônia Dor nas extremidades Infecção do trato respiratório superior 29 (44) 9 (14) 5 (8) – 2 (3) 3 (5) 1 (2) 25 (38) 23 (42) 9 (16) 2 (4) 19 (35) 4 (7) 25 (49) 4 (8) 3 (6) 23 (45) 5 (10) 45 (68) 14 (21) 7 (11) 6 (9) 4 (6) 14 (63) REPEAT TRA108057: eltrombopag was generally well tolerated A total of 68% and 63% of patients reported at least 1 adverse event during the on-therapy and off-therapy periods of the study, respectively. The incidence of adverse events was similar across all three treatment cycles, with <50% of patients experiencing an on-therapy or off-therapy adverse event during any given cycle.1 Mild headache was the most common adverse event, occurring in 21% of patients during the on-therapy periods and 8% of patients during the off-therapy periods. Similar rates of headache were observed in both the placebo and eltrombopag treatment groups in previous eltrombopag chronic ITP studies.2,3 One serious adverse event of grade 2 pneumonia was reported during the on-therapy periods. Two patients each reported onw serious adverse event within 30 days post-therapy and one patient reported three serious adverse events >30 days after the last dose of eltrombopag. No grade 4 serious adverse events or deaths occurred during the study. Reference Bussel JB, et al. Blood 2008; 112: 3431 2. Bussel JB, et al. N Engl J Med 2007; 357(22): 2237–2247 3. Bussel JB, et al. Haematologica 2007; 92(Suppl 1): 390 EA = Evento Adverso 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008. . 118

Eventos adversos Evento adverso, n (%) N=66 Hemorragia 6 (9)
Diminuição transitória de plaquetas* 8 (12) Tromboembólicos – Eventos hepatobiliares† 3 (5) Catarata (incidência e/ou piora) 1 (2)‡ REPEAT TRA108057: eltrombopag was generally well tolerated Six on-therapy bleeding adverse events (5 grade 1 events, 1 grade 2 mouth hemorrhage) were reported by 6 patients; none were considered related to study medication, and no rescue therapy was required. No bleeding serious adverse events were reported within 30 days of discontinuing eltrombopag. Three patients experienced 8 hepatobiliary adverse events during treatment; all events resolved and were either grade 1 or 2. No thromboembolic events were reported during the study. Eight (12%) patients had a transient decrease in platelet count to <10,000/μL and at least 10,000/μL below baseline within 4 weeks after eltrombopag discontinuation within any cycle; none of these 8 patients experienced an off-therapy bleeding adverse event. Twenty-one (32%) patients had a transient decrease in platelet count to <20,000/μL and at least 10,000/μL below baseline within 4 weeks after eltrombopag discontinuation within any cycle; 1 of these patients had a grade 1 adverse event of petechiae. Cataract worsening was reported as a grade 1 adverse event by 1 patient with a history of corticosteroid use. Although all 66 patients received at least 1 ocular examination, there were no reports of incident cataracts. One additional patient experienced worsening of an existing cataract that was not reported as an adverse event. Reference Bussel JB, et al. Blood 2008; 112: 3431 * Contagem de plaquetas <10,000/μL e pelo menos 10,000/μL abaixo da linha de base de 4 semanas após descontinuação de eltrombopag; † definido como aumento no aspartato ou aminotransferases, bilirrubina ou fosfatase alcalina; ‡um paciente apresentou piora da catarata; EA=evento adverso 42.BUSSEL, J. et al. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood, 112(11): abs 3431, 2008.

Administração de eltrombopag – Segundo aprovação ANVISA
A dose inicial recomendada de eltrombopag é 50 mg uma vez ao dia Se a contagem de plaquetas é menor que 50,000/L após 2 a 3 semanas, a dose pode ser aumentada para o máximo de 75 mg uma vez ao dia Pacientes com descendência asiática ou que possuam insuficiência hepática devem receber uma dose inicial de 25 mg/dia A dose deve ser ajustada para alcançar e manter a contagem de plaquetas ≥50,000/L eltrombopag deve ser administrado uma vez ao dia, por via oral, de estômago vazio Pode ser 1 hora antes ou 2 horas após as refeições The starting dose of eltrombopag of 50 mg should be adjusted to achieve and maintain a platelet count of ≥50,000/μL The recommended starting dose of eltrombopag is 50 mg/day, except in patients of East-Asian ancestry, in whom a starting dose of 25 mg/day should be used. The dosage should be adjusted to achieve and maintain a platelet count of ≥50,000/μL, up to a maximum of 75 mg once daily, which should not be exceeded. Treatment should be discontinued if the platelet count does not increase to a level that avoids clinically important bleeding after 4 weeks at the maximum dosage. Eltrombopag should be taken once a day by mouth on an empty stomach, either 1 hour before or 2 hours after a meal. Eltrombopag should be taken at least 4 hours before or after any products such as antacids, dairy products, or mineral supplements containing polyvalent cations (e.g. iron, calcium). Systemic exposure of eltrombopag is increased in patients with mild or moderate-to-severe hepatic impairment (41% and 80–93% increases in AUCinf, respectively) compared with healthy individuals. As a consequence, the initial eltrombopag dosage should be reduced to 25 mg/day in patients with moderate-to-severe hepatic impairment. The safety and efficacy of eltrombopag have not be established in patients with varying degrees of renal function, and therefore close monitoring of safety and platelet counts is recommended for all patients with renal impairment. Reference Garnock-Jones KP, Keam SJ. Drugs 2009; 69(5): 567–76 33.GARNOCK-JONES, KP. et al. Eltrombopag. Drugs, 69(5): 567–76, 2009. 120

Interações alimentares e medicamentosas com eltrombopag
eltrombopag apresenta atividade quelante frente a cátions polivantes (e.g. ferro, cálcio, magnésio, alumínio, selênio, zinco)33,34 Para evitar redução significativa na absorção, eltrombopag deve ser administrado pelo menos 4 horas antes ou depois de quaisquer produtos contendo estes cátions, como antiácidos, laticínios ou suplementos minerais33,34 eltrombopag deve ser utilizado com alimentos contendo pouco(<50 mg) ou preferencialmente nenhum cálcio34 Quando eltrombopag é administrado juntamente com rosuvastatina, uma dose reduzida de rosuvastatina deve ser considerada e deve ser feito monitoramento33 Eltrombopag is associated with a number of important drug and food interactions Polyvalent Cations (Chelation): Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc. Antacids, dairy products and other products containing polyvalent cations, such as mineral supplements, must be administered at least 4 hours apart from eltrombopag dosing to avoid significant reduction in eltrombopag absorption due to chelation.1,2 Food Interaction: Administration of a single 50 mg dose of eltrombopag with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC0- by 59% (90% CI: 54%, 64%) and Cmax by 65% (90% CI: 59%, 70%). Food low in calcium (<50 mg calcium) including fruit, lean ham, beef and unfortified (no added calcium, magnesium, iron) fruit juice, unfortified soy milk and unfortified grain did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.1,2 Rosuvastatin: In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter. When eltrombopag and rosuvastatin were co-administered in a clinical drug interaction study there was an increase in plasma rosuvastatin exposure. A twofold increase in plasma rosauvastatin Cmax was seen, as was a 1.5-fold increase in AUCinf. When co‑administered with eltrombopag, a reduced dose of rosuvastatin should be considered and careful monitoring should be undertaken.1 References Garnock-Jones KP, Keam SJ. Drugs 2009; 69(5): 567–76 33.GARNOCK-JONES, KP. et al. Eltrombopag. Drugs, 69(5): 567–76, WILLIAMS, DD. et al. Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies. Clin Ther, 31(4): 764–76, 2009.

Evitando interações alimentares potenciais com eltrombopag
Os seguintes alimentos devem ser evitados 4 horas antes e após a administração de eltrombopag: Laticínios, como manteiga, queijo, iogurte e sorvetes Leite, milkshakes ou bebida lácteas Bebidas e alimentos enriquecidos com cálcio, como por exemplo, alguns tipos de sucos, cereais e barras de cereais Antiácidos, medicamentos e suplementos que contenham cálcio, alumínio, ferro, magnésio, selênio ou zinco, incluindo alguns medicamentos OTC, minerais, multivitamínicos e shakes protéicos Calcium-containing foods, and medicines containing polyvalent ions, should be avoided four hours before and after taking eltrombopag Administration of a single 50 mg dose of eltrombopag with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC0- by 59% (90% CI: 54%, 64%) and Cmax by 65% (90% CI: 59%, 70%). Food low in calcium (<50 mg calcium) including fruit, lean ham, beef and unfortified (no added calcium, magnesium, iron) fruit juice, unfortified soy milk and unfortified grain did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content. The following foods should, therefore, be avoided 4 hours before and after taking eltrombopag: dairy foods, such as butter, cheese, yogurt and ice cream, milk, milkshakes or drinks made with milk, yoghurt or cream, calcium-rich or fortified foods and drinks, such as some types of juices, cereals, energy bars and antacids, and medicines and supplements that contain calcium, aluminium, iron, magnesium, selenium or zinc. This includes some over-the-counter medicines, mineral and multivitamin supplements and protein shakes. Reference Garnock-Jones KP, Keam SJ. Drugs 2009; 69(5): 567–76 27. Adaptado a partir de Revolade® (eltrombopag olamina). Bula do Produto.

Esquemas de dose matinal e vespertino
Esquema Matinal Permite que pacientes tenham almoço e refeição noturna normais Esquema vespertino Permite que pacientes tenham café da manhã normal na manhã seguinte Different medication plans can be devised to meet the needs of the individual patient If the patient takes their medication in the morning when they get up, although they will need to avoid dairy products, calcium-rich or fortified foods, antacids and supplements for breakfast, a they will be able to have a normal lunch and a normal evening meal. If the patient takes their medication in the evening before they go to bed, although they will need to avoid dairy products, calcium-rich or fortified foods, antacids and supplements for their evening meal, they will be able to have a normal breakfast the following morning. Dairy products, calcium-rich or fortified foods, antacids and supplements need to be avoided with the meal following or preceding eltrombopag dose, regardless of which medication plan is chosen. Reference GSK. eltrombopag® (eltrombopag) Patient Food Guide (version 1.3; pending update), 2009 27. Adaptado a partir de Revolade® (eltrombopag olamina). Bula do Produto.

Conveniência do tratamento oral
Estudos em oncologia demonstram a preferência dos pacientes por terapia oral sobre terapia intravenosa43–45 eltrombopag é administrado oralmente, uma vez ao dia33 respeitando a programação da dieta do paciente27 eltrombopag está disponível em duas apresentações (25 e 50 mg), facilitando a dose para atender às necessidades individuais dos pacientes27 Eltrombopag is an oral treatment that improves treatment convenience Patients with thrombocytopaenia may require several concomitant medications, including some that are administered by injection.1 Limited information is available on ITP patients’ preferences regarding oral medications; however, studies in oncology have shown patient preference for oral over injected therapy, which may be mirrored by patients in other therapy areas.2–4 Eltrombopag is administered orally once daily5 at a time each day that fits into the patient’s own daily dietary schedule.6 Eltrombopag is available in two tablet sizes (25 and 50 mg),5 facilitating dose to meet the individual needs of the patient.7 References Stasi R, et al. Drugs 2008; 68(7): 901–12 Aisner J. Am J Health Syst Pharm 2007; 64(9 Suppl 5): S4–7 Twelves C, et al. Ann Oncol 2006; 17(2): 239–45 Findlay M, et al. Ann Oncol 2008; 19(2): 212–22 Garnock-Jones KP, kean SJ. Drugs 2009; 69(5): 567–76 GSK. eltrombopag® (eltrombopag) Patient Food Guide (version 1.3; pending update), 2009 Bussel JB, et al. N Engl J Med 2007; 357(22): 2237–47 27.Revolade® (eltrombopag olamina). Bula do Produto. 33.GARNOCK-JONES, KP. et al. Eltrombopag. Drugs, 69(5): 567–76, AISNER, J. Overview of the changing paradigm in cancer treatment: oral chemotherapy. Am J Health Syst Pharm, 64(9): S4–7, TWELVES ,C. et al. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens In patients with advanced colorectal cancer. Ann Oncol, 17(2): 239–45, FINDLAY, M. et al. Effective oral chemotherapy for breast cancer: pillars of strength. Ann Oncol, 19(2): 212–22, 2008.

Tratamento em populações especiais
Modificação de dose em pacientes com disfunção hepática: Exposição sistêmica ao eltrombopag é aumentada em pacientes com insuficiência hepática branda ou moderada a severa, 41 e 80–93% de aumento em AUCinf, respectivamente Uma dose inicial de 25 mg/dia deve ser usada em pacientes com insuficiência hepática moderada a severa Monitoramento de pacientes com insuficiência renal Segurança e eficácia de eltrombopag não foram estabelecidas Monitoramento da segurança e da resposta plaquetária é recomendado em pacientes com insuficiência renal Eltrombopag should be used cautiously in patients with renal or hepatic impairment Dose modification in patients with hepatic impairment is recommended in patients receiving eltrombopag. Systemic exposure to eltrombopag is increased in patients with mild or moderate-to-severe hepatic impairment, with increases of 41 and 80–93% in AUCinf, respectively. As a consequence, an initial dose of 25 mg/day should be used in patients with moderate-to-severe hepatic impairment. Monitoring of patients with renal impairment is also recommended. Safety and efficacy of eltrombopag have not been established and, therefore, close monitoring of safety and platelet responses is recommended in patients with renal impairment. Reference Garnock-Jones KP, Keam SJ. Drugs 2009; 69(5): 567–76 27.Revolade® (eltrombopag olamina). Bula do Produto.

Segurança em populações especiais
Formação de reticulina e risco de fibrose na medula óssea Agonistas do receptor de Trombopoietina (TPO), incluindo eltrombopag, podem aumentar o risco de desenvolvimento ou progressão das fibras de reticulina da medula óssea46 Eventos Trombóticos/tromboembólicos: Precaução deve ser tomada ao administrar eltrombopag em pacientes com fatores de risco para tromboembolismo46 Toxicidade hepática Eltrombopag pode estar associado à toxicidade hepática: 10% dos pacientes apresentam anormalidades de enzimas hepáticas (≤ Grau 2)33 Apenas 1% dos pacientes interrompem o tratamento em função destas anormalidades33 Cataratas Reportada em 5 e 3% dos pacientes com eltrombopag e placebo, respectivamente2 Monitoramento é recomendado46 Clinical studies with eltrombopag have revealed a number of safety concerns that warrant consideration Bone Marrow Reticulin Formation and Risk of Bone Marrow Fibrosis: Thrombopoietin (TPO)-receptor agonists, including eltrombopag, may increase the risk for development or progression of reticulin fibers within the bone marrow. Prior to initiation of eltrombopag, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, perform complete blood count with white blood cell (WBC) count differential monthly. If immature or dysplastic cells are observed, examine peripheral blood smears for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature WBCs) or cytopaenias. If the patient develops new or worsening morphological abnormalities or cytopaenias, discontinue treatment with eltrombopag and consider a bone marrow biopsy, including staining for fibrosis.1 Thrombotic/thromboembolic events: Thromboembolic events may occur in patients with ITP. Use caution when administering eltrombopag to patients with known risk factors for thromboembolism (e.g. Factor V Leiden, ATIII deficiency, antiphospholipid syndrome).1 Hepatic toxicity: Eltrombopag may be associated with hepatotoxicity. The overall rate of serum liver test abnormalities in the controlled clinical trials was 10 and 8% of eltrombopag and placebo recipients, respectively; these were predominantly grade 2 or less in severity. Few patients (1 and 3%) discontinued treatment due to hepatobiliary abnormalities.2 Cataracts: Cataracts were observed in toxicology studies of eltrombopag in rodents. In the clinical studies with eltrombopag, only 5% of patients receiving eltrombopag had cataracts compared with 3% receiving placebo.2 Routine monitoring of patients for cataracts is recommended.1 Photosensitivity: In preclinical studies with eltrombopag, in vitro data suggest that a potential photosensitivity risk may exist; however, there was no evidence of in vivo cutaneous or ocular phototoxicity. A study of skin responses to ultraviolet (UV) and visible radiation has not been conducted in humans treated with eltrombopag. As a precaution, patients receiving eltrombopag should avoid being in strong direct sunlight and/or UV exposure or use protective clothing, sunscreen and sun glasses. References GSK. eltrombopag® (eltrombopag) EU SPC. 2009 Garnock-Jones KP, Keam SJ. Drugs 2009; 69(5): 567–76 46.Revolade® (eltrombopag olamina). UK Prescribing Information. Disponível em: < Acesso em: 26 jul GOLDENBERG, MM. Pharmaceutical approval update. Pharmacy and Therapeutics, 34(1): 26–50, 2009.

Segurança em populações especiais (2)
Neoplasias hematológicas Há um risco teórico de aumento de neoplasias hematológicas e progressão da neoplasia em pacientes com neoplasia pré-existente ou síndrome mielodisplásica47 Gravidez e lactação Não há dados sobre uso de eltrombopag em mulheres grávidas ou em lactação46 Clinical studies with eltrombopag have revealed a number of safety concerns that warrant consideration Haematological malignancies1 The stimulation of the TPO receptor on the surface of haematopoietic cells by eltrombopag may increase the risk of haematological malignancies. In clinical studies, no haematological malignancies were reported for patients receiving eltrombopag for a maximum of 6 weeks. One haematological malignancy (non-Hodgkin’s lymphoma) was reported in the extension study. Eltrombopag is not indicated for the treatment of thrombocytopaenia resulting from etiologic factors (e.g. myelodysplasia or chemotherapy) other than chronic ITP. Pregnancy and lactation2 There are no adequate data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Eltrombopag should not be used during pregnancy unless clearly necessary. Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with eltrombopag. The safe use of eltrombopag during lactation has not been established. It is not known whether eltrombopag is excreted in human milk. Breast feeding must be discontinued in women who are receiving therapy with eltrombopag. References Goldenberg MM. Pharmacy and Therapeutics 2009; 34(1): 26–50 GSK. eltrombopag® (eltrombopag) European SPC. 2009 46.Revolade® (eltrombopag olamina). UK Prescribing Information. Disponível em: < Acesso em: 26 jul GOLDENBERG, MM. Pharmaceutical approval update. Pharmacy and Therapeutics, 34(1): 26–50, 2009.

Curso Educacional Teórico - Prático de Hemostasia e Trombose
International Society on Thrombosis and Haemostasis (ISTH) VI Simpósio Sobre Trombose e Hemostasia Hospital Israelita Albert Einstein - HIAE ABRIL de 2012, Sao Paulo, Brasil Apóio: Educational Committee of the ISTH Organização: Educational Committee of the ISTH, Comité Educacional del Grupo CLAHT, CLAHT - Brasil, GETH , Departamento de Patología Clínica – HIAE, Programa de Hematologia - HIAE e Comitê de Hemostasia – ABHH Coordenadores : Dr. Joao Carlos de Campos Guerra - CLAHT Dra.Joyce M. Annichino Bizzacchi - ABHH Dr. Francisco Humberto Maffei - GEHT Dr. Raul Altman (Argentina) – ISTH - America latina ISTH Advisory Member: Frits Rosendaal (The Netherlands) Comitê Científico: Convidados Estrangeiros: Dr. Raul Altman Dr. Fritz Rosendal Dr. Raul Altman Dr. Uri Seligson Dr. João Carlos de Campos Guerra Dra. Alicia Blanco Dr. Marjorie Paris Colombini Dr. Nelson Hamerchlak Dra.Joyce M. Annichino Bizzacchi Dra. Vânia Morelli Dr. Francisco Humberto Maffei Dr. Cyrillo Cavalheiro Filho Dr. Edison F. de Paiva Dra. Andrea Kondo Apóio Institucional: ABHH, SBACV, SBPC SAVE DATE

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OBRIGADO DR. JOÃO CARLOS DE CAMPOS GUERRA

" Trombocitopenia Imune Primária: Avanços no Tratamento "

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