美国FDA批准葛兰素史克公司的艾曲波帕片(Promacta)上市,用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少。 艾曲波帕是首个获准治疗成人慢性ITP患者的口服非肽类血小板生成素受体激动剂,临床前和临床研究显示刺激艾曲波帕可升高血小板的骨髓巨核细胞的增生和分化。 对慢性特发性血小板减少性紫癜患者随机临床研究的大量数据支持了艾曲波帕的新药申请获准。此适应证是基于2项关键的短期治疗和1项正在进行长期治疗ITP患者的临床研究数据。防止血小板被破坏一直是治疗ITP患者的主要方法。艾曲波帕临床研究的新进展显示,增加血小板的产生来治疗此种疾病也起着重要作用。 本品还正在进行治疗丙型肝炎病毒、慢性肝病引起的血小板减少症和肿瘤相关的血小板减少症的研究。 PROMACTAIndication(s):Thrombocytopenia due to chronic immune (idiopathic) thrombocytopenic purpura (ITP) in adults who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Pharmacology:Eltrombopag is an orally active thrombopoietin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. It works by interacting with the thrombopoietin receptor to cause increased platelet production. Clinical Trials:Two studies were conducted to evaluate the safety and efficacy of eltrombopag in treating chronic ITP. Patients who had completed at least one prior ITP therapy and who had a platelet count of <30x109/L were randomized to either eltrombopag or placebo daily for up to 6 weeks, then 6 weeks off therapy. The primary endpoint was the response rate, defined as a shift from baseline platelet count to ≥50x109/L at any time during treatment. The groups given eltrombopag 50mg/day had response rates of 59% and 70% in Studies 1 and 2, respectively; for those given placebo, the rates were 16% and 11%. Legal Classification:Rx Adults:Take on empty stomach. Initially 50mg once daily. Moderate to severe hepatic impairment or East Asian ancestry: initially 25mg once daily. Titrate to maintain platelet count ≥50x109/L; max 75mg once daily. Adjust dose based on platelet count: see literature. Children:Not recommended. Warnings/Precautions:Monitor CBC, platelet count, and peripheral blood smears for cytopenias and abnormal morphologies; discontinue if no increase in platelet count occurs after 4 weeks at max dose, or if excessive increase in platelet count occurs (eg, >400x109/L), or if evidence of bone marrow fibrosis occurs (eg, cytopenias, nucleated RBCs). Monitor liver function closely before, during, and after treatment (see literature); discontinue if ALT >3xULN and is progressive or persistent for ≥4 weeks, or if it occurs with evidence of hepatic injury; reinitiation of therapy: not recommended; if restarted, use lower dose and monitor carefully. Do baseline eye exam; monitor for cataracts. Thromboembolism risk factors. Myelodysplastic syndromes. Renal impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interaction(s):Do not take within 4 hours of food/drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+2, Mg+2, Se+2, Zn+2). May potentiate substrates of organic anion transporter polypeptide 1B1 (eg, benzylpenicillin, most statins, methotrexate, nateglinide, repaglinide, rifampin); monitor and consider reducing their doses. May be potentiated by strong inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine) or CYP2C8 (eg, gemfibrozil, trimethoprim), and with moderate or strong inhibitors of UGT1A1 or UGT1A3. Adverse Reaction(s):Nausea, vomiting, menorrhagia, myalgia, paresthesia, cataract, ecchymosis, thrombocytopenia, increased ALT/AST, conjunctival hemorrhage, increased risk of hematologic malignancies; thrombotic events with excessive increases in platelet counts; worsened thrombocytopenia after discontinuation. Notes:Physicians, pharmacies, and patients must enroll in Promacta Cares program. Register pregnant patients taking eltrombopag by calling (888) 825-5249. How Supplied:Tabs—30 Last Updated:1/21/2009 Promacta(艾曲波帕(eltrombopag))片 批准日期:2008年11月20日;公司:GlaxoSmithKline 一般描述:艾曲波帕软膏剂是一种联苯腙。艾曲波帕软膏剂化学名是3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid - 2-aminoethanol (1:2)。其分子式是C25H22N4O4.2(C2H7NO)。艾曲波帕软膏剂和艾曲波帕游离酸相对分子量分别为442.5和564.65。艾曲波帕软膏剂结构式如下: PROMACTA是一种促血小板生成素受体激动剂适用于治疗慢性免疫性(特发性)血小板减少性紫癜患者的血小板减少,对皮质激素、免疫球蛋白或脾切除反应不佳的患者。 剂量和用法: 对大多数患者PROMACTA的起始剂量是50 mg每天1次;对东方人患者或中度或严重肝功能不全患者,起始剂量为25 mg每天1次。 禁忌证:无。 警告和注意事项: PROMACTA可能引起肝毒性。观察到血清中转氨酶水平和胆红素增加。治疗开始前和治疗期间常规必须测定肝化学。 不良反应:最常见不良反应(发生大于接受PROMACTA1例患者和相比安慰剂PROMACTA发生率较高)是: 恶心、呕吐、月经过多、肌肉痛、感觉异常、白内障、消化不良、瘀斑、血小板减少、ALT/AST增加和结膜出血。 黑框警告:肝毒性风险 开始PROMACTA治疗前测定血清丙氨酸转氨酶(AST),和胆红素,调整剂量期每2周1次和确定稳定剂量后每月1次。如胆红素升高,进行分次。 药物相互作用: 艾曲波帕是OATP1B1转运蛋白的抑制剂。紧密监查患者过量暴露于OATP1B1底物(如,罗苏伐他汀(rosuvastatin))药物征象和症状并考虑减低这些药物的剂量。 在特殊人群中的应用: 妊娠:可能引起胎儿伤害。纳入妊娠患者在PROMACTA妊娠注册。 艾曲波帕可改善血小板减少的丙肝患者的持续病毒学应答 据美国肝病研究协会(AASLD)年会上报告的ENABLE 1试验最终结果,口服促血小板生成素受体激动剂艾曲波帕(Promacta)能够使大多数慢性丙肝伴血小板减少症患者接受抗病毒药物治疗成为可能,并可改善其持续病毒学应答(SVR)率。 目前艾曲波帕仅被批准用于治疗慢性免疫性(特发性)血小板减少性紫癜患者的血小板减少症,为评价艾曲波帕对慢性丙肝患者血小板减少症的疗效和安全性,哈佛大学医学院医学副教授、贝斯以色列女执事医疗中心肝病中心主任Nezam H. Afdha博士在该项Ⅲ期随机试验中纳入了716例血小板计数<75,000/μl的慢性丙型肝炎患者。在试验前期,所有患者均接受剂量递增的艾曲波帕开放治疗,最高剂量为100 mg/d,直到血小板计数达到≥90,000/μl 的水平;在试验后期,达到上述血小板计数水平的患者开始抗病毒治疗(聚乙二醇干扰素α-2a+利巴韦林),并按2:1比例随机分组接受艾曲波帕或安慰剂双盲治疗。根据病毒基因型,治疗持续24~48 w。如果患者血小板计数降至<50,000/μl,则减少干扰素剂量或停用。允许使用生长因子治疗贫血和嗜中性粒细胞减少症。 结果显示,95%的入组患者血小板计数可达到抗病毒治疗要求的水平。随机分组治疗患者的中位年龄52岁,多数为病毒基因1型,逾2/3患者从未接受干扰素治疗。与安慰剂组相比,艾曲波帕组抗病毒治疗24周SVR率较高(23% vs. 14%,P=0.006)。根据病毒基因型、基线血小板计数和基线病毒载量进行分组分析的结果与上述结果相同。艾曲波帕组中位血小板计数从未降至需减少抗病毒药物剂量的阈值水平以下,但安慰剂组大多数时间低于该阈值,前者无需减少干扰素剂量的患者比例是后者的2倍(57% vs. 30%)。 两组不良事件发生率、类型以及严重程度均相似,副作用均为干扰素和利巴韦林治疗患者常见的副作用。艾曲波帕组未见血栓栓塞事件发生率增加(均为2%),但有更多患者发生提示肝病进展的事件(13% vs. 8%),不过多数属于慢性肝病患者典型事件。在整个研究期间两组均未见MELD(终末期肝病模型)评分、Child-Pugh评分、白蛋白、胆红素、INR(国际标准化比率)或其他标准参数发生改变。通过系列超声和多普勒成像对受试患者门静脉血栓形成进行严格监测,与既往报道不同,此次未见血小板计数提高与门静脉血栓形成显著相关。许多血栓形成事件发生在血小板计数<50,000的患者和研究结束后。 研究者指出,血小板减少症是棘手的慢性丙肝并发症,这些患者通常不适合抗病毒药物治疗。一旦出现血小板减少,通常建议减少抗病毒药物剂量或停止治疗,从而降低获得SVR的机会。艾曲波帕治疗可使95%的慢性丙肝所致血小板减少症患者能够接受抗病毒治疗,并且可改善 SVR。 研究者还报告了ENABLE 2试验的部分最新数据:758例患者SVR基本相同,艾曲波帕组优于安慰剂组(19% vs. 13%),但血栓栓塞事件发生率略有增加(4% vs. <1%)。ENABLE 2试验除用聚乙二醇干扰素α-2b替代聚乙二醇干扰素α-2a外,其他设计与ENABLE1试验完全相同。 |
血小板减少性紫癜新药-PROMACTA(艾曲波帕片)上市简介:
美国FDA批准葛兰素史克公司的艾曲波帕片(Promacta)上市,用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少。
艾曲波帕是首个获准治疗 ... 责任编辑:admin |
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