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格列卫(Glivec)是什么

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【药品名称】
  通用名称:甲磺酸伊马替尼胶囊
  商品名称:格列卫(Glivec)
  英文名称:Imatinib Mesylate Capsules
  汉语拼音:Jiahuangsuan Yimatini Jiaonang
  【成份】
  本品活性成份为甲磺酸伊马替尼。
  化学名称:4-[(4-甲基-1-哌嗪)甲基]-N-[4-甲基-3-[[4-(3-吡啶)-2-嘧啶]氨基]苯基]-苯胺甲磺酸盐
  分子式:C29H31N7O.CH4SO3
  分子量:589.7
  【性状】
  本品为胶囊,内容物为白色至类白色粉末。
  【适应症】
  用于治疗慢性髓性白血病(CML)急变期、加速期或α-干扰素治疗失败后的慢性期患者。
  用于治疗不能切除和/或发生转移的恶性胃肠道间质肿瘤(GIST)的成人患者。
  【规格】
  100mg
  【用法用量】
  开始剂量:一开始治疗就应由对慢性髓性白血病或GIST有治疗经验的医师进行。
  本品应口服,宜在进餐时服药,并饮一大杯水。通常成人每日一次。儿童和青少年每日一次或分两次服用(早晨和晚上)。
  不能吞咽胶囊的病人(儿童),可以将胶囊内药物分散于水或苹果汁中。建议怀孕期和哺乳期妇女在打开胶囊时,避免药物与皮肤或眼睛接触,或者吸入(见孕妇和哺乳期妇女),接触打开的胶囊后应立即洗手。
  ——CML病人的治疗剂量
  成人
  对慢性期患者的推荐剂量为400毫克/日,对急变期和加速期患者为600毫克/日。
  只要有效,就应持续服用。
  如果血象许可,没有严重药物不良反应,在下列情况下剂量可考虑从400毫克/日增加到600毫克/日,或从600毫克/日增加到800毫克/日(400毫克,口服,分2次服用):疾病进展、治疗至少3个月后未能获得满意的血液学反应,已取得的血液学反应重新消失。
  3岁以上儿童及青少年
  到目前为止,儿童患者的用药经验有限。依据成人的剂量,推荐日剂量为:慢性期260mg/m2(最大剂量:400mg)、加速期和急变期340mg/m2(最大剂量:600mg),制订儿童患者的每日推荐剂量,计算所得剂量一般应接近或在100mg左右, 12岁以下儿童的剂量一般应尽可能接近或在50mg左右。尚无3岁以下儿童治疗的经验。
  ——GIST病人的治疗剂量
  对不能切除和/或转移的恶性GIST患者, 本品的推荐剂量为400毫克/日。
  在治疗后未能获得满意的反应,如果没有药物不良反应,剂量可考虑从400毫克/日增加到600毫克/日。 治疗时间:
  对于GIST病人,本品应持续治疗,除非病情进展。
  下列情况中必须调整剂量:
  如果接受甲磺酸伊马替尼治疗过程中出现严重非血液学不良反应(如严重水潴留),应停药,直到不良反应消失,然后再根据该不良反应的严重程度调整剂量。
  严重肝脏毒副作用时剂量的调整:
  如胆红素升高﹥正常范围上限3倍或转氨酶升高>正常范围上限5倍,宜停止服用甲磺酸伊马替尼,直到上述指标分别降到正常范围上限的1.5或2.5倍以下。
  以后甲磺酸伊马替尼治疗可以减量后继续服用。成人每日剂量应该从400毫克减少到300毫克,或从600毫克减少到400毫克;儿童和青少年从260mg/m2减少到200 mg/m2或从340 mg/m2减少到260 mg/m2。
  中性粒细胞减少或血小板减少时剂量的调整:
  加速期或急变期(起始剂量600毫克/日或儿童和青少年340mg/m2/日):如果出现严重中性粒细胞和血小板减少(中性粒细胞<0.5×109/L和/或血小板<10×109/L),应确定是否血细胞减少症与白血病有关(抽取骨髓或活检),如果血细胞减少症是由白血病引起的,建议剂量减少到400毫克/日或儿童和青少年260mg/m2/日。如果血细胞持续减少2周,则进一步减少剂量到300毫克/日或儿童和青少年200mg/m2/日,如血细胞持续减少4周,应停药,直到中性粒细胞≥1.0×109/L和血小板≥20×109/L。再用时剂量为300毫克/日或儿童和青少年200mg/m2/日。
  CML慢性期及GIST患者(起始剂量400毫克/日或儿童和青少年260mg/m2/日):当中性粒细胞<1.0×109/L和/或血小板<50×109/L时应停药,在中性粒细胞≥1.5×109/L和血小板≥75×109/L时应该恢复用药,治疗可恢复为剂量400毫克/日或儿童和青少年260mg/m2/日,如果再次出现危急数值,治疗中断后的重新治疗剂量减至300mg/日或儿童和青少年200mg/m2/日。
  肝功能衰竭患者的剂量:
  肝功能损害者甲磺酸伊马替尼的血浆浓度可能升高。由于目前尚无肝功能损害患者使用甲磺酸伊马替尼的临床资料,故无法提出剂量调整的建议。肝功能受损患者应慎用本品,严重肝功能衰竭患者应在认真权衡危险-效益比后,再使用本品。
  肾功能衰竭和老年患者的剂量:
  已知肌酐清除率可随年龄老化而降低,而年龄对本品的药代动力学无明显影响,由于尚未在肾功能损害患者中进行过临床试验,故无法提出剂量调整的建议。
  【不良反应】
  多数患者在服用本品期间会出现一些不良反应,但绝大多数属轻到中度。考虑到疾病本身也会产生症状,常难以明确它们的因果关系。
  在CML的临床试验过程中,因药物相关的不良反应而停药者,在α-干扰素治疗失败的慢性期患者中仅占1%,加速期中约占2%,急变期占5%。
  在GIST临床试验中,因药物相关的不良事件而停药者占3.4%。
  CML和GIST病人发生的不良反应相似,只有两种例外:GIST病人发生骨髓抑制较少,肿瘤内出血仅在GIST病人中观察到(见
  【注意事项】)。
  在CML和GIST病人中,最常见报告的与药物治疗相关的不良事件有轻度恶心(50~60%),呕吐,腹泻、腹痛、乏力、肌痛、肌痉挛及红斑,这些不良事件均容易处理。
  所有研究中均报告有浮肿和水潴留,发生率分别为47~59%和7~13%,其中严重者分别为1~3%和1~2%。大多数患者的浮肿表现为眶周和下肢浮肿。曾有青光眼的个别报告,与水潴留有关。也有胸水、腹水、肺水肿和体重迅速增加的报告。这些事件通常可采用暂停使用本品、使用利尿剂或给予其它支持治疗而得以缓解。但是个别患者情况严重,甚至威胁生命。有1例急变期患者因并发胸水、充血性心力衰竭和肾功能衰竭的复杂临床情况而死亡。这些不良事件的发生率与剂量有一定关系,多见于剂量>600mg/天时。
  当伊马替尼与高剂量的化疗药联合使用时,可发生一过性的肝毒性,如转氨酶升高及高胆红素血症。
  按系统器官分类及发生的频度,将不只是发生于个别患者的不良反应在下面列出。
  发生率的定义(CIOMS分类法)为:很常见:>10%;常见:>1%≤10%;不常见:>0.1%≤1%;罕见:>0.01%≤0.1%;非常罕见≤0.01%。
  全身性异常
  很常见:周围浮肿(56%)、疲劳(15%)。
  常 见:水潴留、发热、疲劳、畏寒
  不常见:不适、出血
  罕 见:全身水肿
  传染病/感染
  不常见:败血症、肺炎、单纯疱疹、带状疱疹和上呼吸道感染和胃肠炎
  血液与淋巴系统异常
  很常见:中性粒细胞减少(14%)、血小板减少(14%)和贫血(11%)
  常 见:发热性中性粒细胞减少
  不常见:全血细胞减少、骨髓抑制
  代谢和营养失衡
  常 见:食欲不振、体重增加
  不常见:脱水、高尿酸血症、低钾血症、食欲增加、食欲降低、痛风、低磷酸盐血症、体重减轻
  罕 见:高钾血症,低钠血症
  精神异常
  不常见:抑郁、焦虑、性欲降低
  罕 见:意识模糊
  神经系统异常
  很常见:头痛(11%)
  常 见:头晕、味觉障碍、感觉异常、失眠
  不常见:脑溢血、晕厥、周围神经病变、感觉减退、嗜唾、偏头痛、
  记忆损害
  罕 见:脑水肿、颅内压增高、惊厥
  眼部异常
  常 见:结膜炎、流泪增多、视力模糊
  不常见:眼刺激症状、结膜下出血、眼干、眶周浮肿
  罕 见:黄斑水肿、视神经乳头水肿、视网膜出血、玻璃体出血、青光眼
  耳和迷路异常
  不常见:头晕、耳鸣
  心脏异常
  不常见:心力衰竭、肺水肿、心动过速。
  罕 见:心包积液、心包炎、心包填塞
  血管异常
  不常见:血肿、高血压、低血压、潮红、四肢发冷
  罕 见:血栓/栓塞
  非常罕见:过敏性休克
  呼吸道、胸和纵隔异常
  常 见:鼻衄、呼吸困难
  不常见:胸腔积液、咳嗽、咽喉痛、急性呼吸衰竭
  罕 见:肺纤维变性、间质性肺炎
  消化系统异常
  很常见:恶心(51%)、呕吐(25%)、腹泻(25%)、消化不良(13%)、
  腹痛(14%)
  常 见:腹胀、胀气、便秘、胃食道反流、口腔溃疡
  不常见:胃肠道出血、黑便、腹水、胃溃疡、胃炎、嗝逆、口干
  罕 见:结肠炎、憩室炎、肠梗阻、肿瘤出血/肿瘤坏死、胃肠穿孔、胰腺炎
  肝胆系统异常
  常 见:肝酶升高
  不常见:黄疸、肝炎、高胆红素血症
  罕 见:肝衰竭
  非常罕见:肝坏死
  皮肤和皮下组织异常
  很常见:周身浮肿(32%)、皮炎/湿疹/皮疹(26%)
  常 见:颜面浮肿、眶周浮肿、瘙痒、红皮症、皮肤干燥、毛发稀少、盗汗
  不常见:瘀斑、挫伤、多汗、荨麻疹、指甲断裂、光过敏反应、紫癜、脱发、唇炎、皮肤色素沉着过多、皮肤色素沉着过少、牛皮癣、剥脱性皮炎和大疱疹
  罕 见:血管神经性水肿、小疱疹、Stevens-Johnson综合征、急性发热性中性粒细胞皮病(Sweet 综合征)
  骨骼肌、结缔组织和骨异常
  很常见:肌痉挛、疼痛性肌痉挛(36%)、骨骼肌肉痛(14%)。
  常 见:关节肿胀
  不常见:坐骨神经痛、关节肌肉僵硬
  罕 见:无血管性坏死/髋关节坏死
  肾和泌尿系统异常
  不常见:肾衰、肾区痛、尿频、血尿
  生殖系统和乳房异常
  不常见:男性乳房女性化、乳房增大、阴囊水肿、月经过多、乳头疼痛、性功能障碍
  已经发现有晚期病人、严重感染、严重白细胞减少症和患有其它严重疾病患者死亡的病例。
  已有由胃肠道穿孔而引起死亡的报道。
  已有由肝坏死引起死亡的报道。
  不良反映的其他情况:
  有些患者眼睛会稍有一点水肿,有一段时间胃口不太好,大便次数增多,这些都是正常反应不必紧张。
  有的慢粒患者服用格列卫后应为食欲增加而体重增加,这不需要紧张,只要确定不是体液潴留即可放心。体液潴留特别容易发生在老年病人或者有心脏基础病变的人身上。
  对肝肾可能会产生损伤,应该定期做肝功能肾功能检查,也可以服用一些护肝药(如肝泰乐)。吃药的同时在吃保肝的药,肝胆方面的医生说一般肝功能正常就别吃太多的药,预防性的保肝可以吃适量的糖加上多种维生素比如善存片,施尔康就可以了。(摄入多种维生素对身体有很大益处)。
  实验室检查异常
  所有研究均报告有血细胞减少,尤其是中性粒细胞和血小板减少,以>750毫克/日的大剂量时发生率为高(I期研究),然而血细胞减少的发生率也明显取决于疾病分期,3或4度的中性粒细胞减少(ANC<1.0×109/L)和血小板减少(血小板计数<50×109/L),在急变期和加速期发生率较CML慢性期(14%中性粒细胞减少和7%血小板减少)高4和6倍(中性粒细胞减少和血小板减少分别为58~62%和42~58%)。相比之下在慢性期分别只有14%和7%,前者为后者的2~3倍。CML慢性期病人中4度中性粒细胞减少(ANC<0.5×109/L)和血小板减少(血小板计数<10×109/L)的发生率分别只有2%和1%。中性粒细胞和血小板减少发生的中位数持续时间分别为2~3周和3~4周。对于这类事件,一般情况下可通过降低剂量或暂停用药而缓解,仅个别病例需为此而长期停药。在儿科CML患儿中,多数毒性反应为3级和4级,包括有中性粒细胞减少症,血小板减少症和贫血。这些症状通常发生在首次治疗的前几个月内。
  在GIST病人,出现3级和4级贫血的发生率分别为3.4%和0.7%,这些病人中至少有一部分是与胃肠道或肿瘤内出血有关。3级和4级中性粒细胞减少的发生率分别为4.1%和3.4%,而3级血小板减少的发生率为0.7%,没有病人发生4级血小板减少。全血细胞和中性粒细胞计数降低主要发生在治疗的最初6周,以后细胞计数保持相对稳定。
  显著的转氨酶或胆红素升高不常见(<4%病例),其能够通过减量或停药(中位数持续时间约为一周)来缓解,只有不到0.5%患者因肝功能实验室检查异常而长期停药。有1例加速期CML患者死于急性肝功能衰竭,但不能排除大剂量对乙酰氨基酚与甲磺酸伊马替尼的药物相互作用的结果(见【药物相互作用】和【注意事项】)。
  偶见血碱性磷酸酶、肌酐磷酸激酶、肌酐和乳酸脱氢酶升高。
  【禁忌】
  对本品活性物质或任何赋形剂成份过敏者禁用。
  【注意事项】
  甲磺酸伊马替尼治疗第一个月宜每周查一次全血象,第二个月每两周查一次,以后则视需要而定(如每2-3个月查一次)。若发生严重中性粒细胞或血小板减少,应调整剂量(见【用法用量】)。
  开始治疗前应检查肝功能(转氨酶、胆红素和碱性磷酸酶),随后每月查一次或根据临床情况决定,必要时应调整剂量。肝功能衰竭患者甲磺酸伊马替尼的暴露量可能会增加,肝功损害者慎用本品。严重肝功能衰竭者在认真进行危险-效益比评估后,才能使用甲磺酸伊马替尼(见【用法用量】)。应谨记GIST患者可能有肝转移,从而增加肝功能的损害。曾有一位常规服用对乙酰氨基酚治疗发热的患者死于急性肝衰竭。尽管准确的死因目前尚不知,同时服用甲磺酸伊马替尼和对乙酰氨基酚时需谨慎(见【药物相互作用】)。
  同时服用甲磺酸伊马替尼和CYP3A4诱导剂(见【药物相互作用】)可显著降低伊马替尼的总暴露量,因此增加潜在治疗失败的危险。因此应避免甲磺酸伊马替尼与CYP3A4诱导剂合用。
  大约有1~2%服用本品的患者发生严重水潴留(胸水、浮肿、肺水肿和腹水),因此建议定期监测体重, 应仔细评价体重的增加,必要时采取适当的支持治疗。特别是儿童患者,水潴留可能不出现可以识别的水肿。
  水潴留可以加重或导致心衰,目前尚无严重心衰病人(按纽约心脏学会分类法的Ⅲ~Ⅳ级)临床应用本品的经验。对这些患者用本品要谨慎,青光眼的患者也应慎用(见【不良反应】)。
  在嗜酸细胞增多症(HES)及患有心脏病患者中,有个例报道发生心源性休克/左心室功能异常与伊马替尼的初始治疗有关。据报道,通过给予类固醇全身给药治疗,循环支持及暂停伊马替尼,该症状是可逆的。骨髓增生异常/骨髓增生疾病也许与高的嗜酸细胞水平有关。对患有HES/CEL以及伴有高嗜酸细胞水平的,需进行超声心动检测及监测血浆肌钙蛋白,如果任一指标是异常的,在初期使用伊马替尼治疗时应考虑使用类固醇全身给药(1-2mg/kg)进行预防治疗,连续使用1-2周。
  在GIST临床试验中,报告有8例病人(5.4%)出现胃肠道出血和4例病人(2.7%)出现肿瘤内出血。根据肿瘤的部位不同,肿瘤内出血可能发生在腹腔内,也可能发生在肝内。这类病人的肿瘤内出血也有可能表现为胃肠道出血,因此,在治疗开始阶段应监测病人的胃肠道症状。
  当伊马替尼与高剂量的化疗药联合使用时,可发生一过性的肝毒性,如转氨酶升高及高胆红素血症,因此在伊马替尼与化疗药联合使用时,应检测肝功能并了解有关的与肝功能相关的不良反应(见【不良反应】)。
  在格列卫ò治疗期间,对甲状腺切除患者用左甲状腺素治疗时,有甲状腺功能减退的报道,在这类患者中应监测其TSH水平。
  有关本药安全性和有效性的长期临床资料尚有限。
  临床前研究表明,甲磺酸伊马替尼不易通过血脑屏障。尚未在人体进行过研究。
  对驾驶员和机器操纵者能力的影响
  尚无有关对驾驶员或机器操纵者能力可能发生影响的信息和资料。该品不良反应提醒患者在治疗期间可能有头晕或视力模糊的症状,因此,当患者开车或操纵机器时应注意。
  【孕妇及哺乳期妇女用药】
  妊娠:动物研究表明本品存在生殖毒性(见临床前资料的生殖毒性部分)。
  目前尚缺乏孕妇使用伊马替尼的资料,对胎儿可能的毒性目前不详。除非确有必要,否则妊娠期间不宜应用。如妊娠期间服用甲磺酸伊马替尼,必须告诉其对胎儿可能的危害。育龄期妇女在服用甲磺酸伊马替尼期间应建议其同时进行有效的避孕。
  哺乳:在动物实验中,甲磺酸伊马替尼及其代谢产物大量从乳汁中排出,但未进行过人体研究,服用甲磺酸伊马替尼的妇女不应哺乳。
  【儿童用药】
  3岁以上儿童使用本品参见【用法用量】。
  【老年用药】
  已知肌酐清除率可随年龄老化而降低,而年龄对本品的药代动力学无明显影响。
  【药物相互作用】
  可改变甲磺酸伊马替尼血浆浓度的药物
  CYP3A4抑制剂:健康受试者同时服用单剂酮康唑(CYP3A4抑制剂)后,甲磺酸伊马替尼的药物暴露量显著增加(平均最高血浆浓度(Cmax)和伊马替尼曲线下面积(AUC)可分别增加26%和40%,尚无与其它CYP3A4抑制剂(如:伊曲康唑、红霉素和克拉霉素)同时服用的经验。
  CYP3A4诱导剂:健康志愿者服用利福平后,伊马替尼的清除增加3.8倍(90%可信区间=3.5-4.3倍),但Cmax,AUC(0-24)和AUC(0-8)分别下降54%、68%和74%。在临床研究中发现,同时给予苯妥英药物后,甲磺酸伊马替尼的血浆浓度降低,从而导致疗效减低。其它诱导剂如地塞米松、卡他咪嗪、苯巴比妥和含有St John麦汁浸膏制剂等,可能有类似问题,因此应避免伊马替尼与CYP3A4诱导剂同时服用。
  甲磺酸伊马替尼可使下列药物改变血浆浓度
  甲磺酸伊马替尼使辛伐他丁(CYP3A4底物)的平均Cmax和AUC分别增加2倍和3.5倍。应谨记伊马替尼可增加经CYP3A4代谢的其他药物(如苯二氮类、双氢吡啶、钙通道拮抗剂、和其它HMG-CoA还原酶抑制剂等)的血浆浓度。因此当同时服用本药和治疗窗狭窄的CYP3A4底物(如环孢素、匹莫齐特)时应谨慎。
  在与抑制CYP3A4活性相似的浓度下,甲磺酸伊马替尼还可在体外抑制CYP2D6的活性,因此在与甲磺酸伊马替尼同时服用时,有可能增加系统对CYP2D6底物的暴露量,尽管尚未作专门研究,建议慎用。
  甲磺酸伊马替尼在体外还可抑制CYD2C9和CYD2C19的活性,同时服用华法令后可见到凝血酶原时间延长。因此在甲磺酸伊马替尼治疗的始末或更改剂量时,若同时在用双香豆素,应短期监测凝血酶原时间。
  应警告病人避免使用含有对乙酰氨基酚的非处方药和处方药。
  【药物过量】
  体征和症状
  剂量超过800毫克/日的经验有限,也无剂量过量的病例报告。若发生过量,应密切观察病人,并给予适当的支持治疗。
  【临床试验】
  慢性髓性白血病临床研究
  对费城染色体阳性的慢性髓性白血病急变期(髓性原始细胞危象)、加速期和经α-干扰素治疗失败的慢性期患者进行了三项开放、非对照性的II期临床研究。
  在一项大规模、开放、对照的III期临床试验中,病人为新诊断的费城染色体阳性的慢性白血病(费城+CML)。对儿童和青少年的治疗在两项I期研究中进行。临床研究病例中,38%-40%患者的年龄≥60岁,10~12%≥70岁。
  新诊断的慢性期:一项在之前6个月内首次诊断为CML的1106名患者入组的III期临床试验中,比较甲磺酸伊马替尼400毫克/天和α-干扰素(INF)5百万IU/m2/天+阿糖胞苷(Ara-C)20毫克/m2/天(10天/月)的疗效。80%的病人在服用试验药物前曾接受羟基脲的治疗,在试验的最初6个月,50%服用甲磺酸伊马替尼的病人和75%服用IFN-Ara-C的病人也同时继续服用羟基脲(平均分别为15和30天)。
  在12个月后的中期分析,甲磺酸伊马替尼组和IFN-Ara-C组的完全血液学反应(CHR)分别为94.4%和54.6%,主要细胞遗传学反应为82.6%和20.3%,完全细胞遗传学反应为67.8%和7.4%。
  采用经验证的FACT-BRM问卷评价生活质量, 甲磺酸伊马替尼组所有方面的评分均高于 IFN-Ara-C 组, 生活质量数据表明, 接受甲磺酸伊马替尼治疗的病人能够保持心情愉快。
  a-干扰素治疗失败的慢性期患者:(532例,起始剂量400毫克,每日一次)60%的患者获得了主要细胞遗传学反应,42%获得了完全缓解,93%获得了完全血液学反应。
  加速期:(235例,其中63%患者在加速期已接受过其他治疗,235例患者中77例接受甲磺酸伊马替尼400毫克,每日一次;158例接受600毫克,每日一次)。结果70%患者获得确切的血液学反应,28%患者获得完全血液学反应,25%患者获得主要的细胞遗传学反应(即分裂中费城染色体阳性细胞减少到<35%)18%获得完全细胞遗传学缓解。以血液学缓解为主要终点的分析,发现400毫克和600毫克剂量组之间无明显差异,但600毫克剂量组的细胞遗传学反应改善更明显,其持续时间更长。本研究中,600毫克剂量组的至疾病出现进展时间明显不同。
  急变期(髓性原始细胞危象):(260例,95例[37%]在进入加速期或急变期后均已接受过化疗,另165例[63%]此前未接受过化疗。223例开始治疗的剂量为600毫克, 每日一次)。以不同的完全血液学反应作为主要疗效进行统计,31%的患者获得了肯定的血液学反应(未接受过治疗患者为36%,经过治疗的患者为22%),15%患者观察到主要细胞遗传学反应。未接受和接受过治疗的患者的中位生存时间分别为7.7和4.7个月。
  儿童和青少年:CML慢性期(15人)或CML急变期或费城染色体阳性的急性白血病(16人)共31名儿童患者入组一项剂量逐渐增大的I期试验, 其中28%的CML患者年龄在2-12岁, 50%在12-18岁。病人按下列剂量接受甲磺酸伊马替尼,260毫克/m2/天 (n=6)、340毫克/m2/天 (n=11)、440毫克/m2/天 (n=8) 和570毫克/m2/天 (n=6)。在获得了细胞遗传学资料的13例CML病人中,7人 (54%)获得完全细胞遗传学反应, 4人(31%)获得部分细胞遗传学反应, 其相当于85%的主要细胞遗传学反应率。另有8名患儿(3名CML, 4名急性白血病)进行另一项I期试验, 3人接受的剂量为173-200毫克/m2/天,4人接受的剂量约为260毫克/m2/天, 1人接受360毫克/m2/天的剂量。3名CML患儿中有两人获得完全细胞遗传学反应。与成人试验相比, 总共39名儿童中没有特别的安全性问题。
  胃肠道间质肿瘤(GIST)的临床研究
  对不能手术切除或转移的胃肠道间质肿瘤(GIST)病人进行了一项开放、随机、多国家参加的II期临床试验。在这项试验中,共入选147例病人并随机接受口服伊马替尼400 毫克或600 毫克治疗,每日一次,平均治疗6-12个月(不超过24个月)。这些病人的年龄在18-83岁范围内,病理诊断为C-Kit-阳性的恶性胃肠道间质肿瘤(GIST),且不能手术切除和/或为转移性。
  400 毫克组的缓解率为37%,600 毫克组为43.2%,没有完全缓解病例。
  截止到平均随访7个月(7天-13个月)时,所有缓解的病人未出现病情进展。
  【药理毒理】
  作用机制/药效学特性
  伊马替尼在体内外均可在细胞水平上抑制Bcr-Abl酪氨酸激酶,能选择性抑制Bcr-Abl阳性细胞系细胞、费城染色体阳性(Ph+)的慢性髓性白血病(CML)和急性淋巴细胞白血病病人的新鲜细胞的增殖和诱导其凋亡。
  此外,伊马替尼还可抑制血小板衍化生长因子(PDGF)受体、干细胞因子(SCF),c-Kit受体的酪氨酸激酶,从而抑制由PDGF和干细胞因子介导的细胞行为。
  胃肠道间质肿瘤(GIST)细胞表达活性kit突变,体外实验显示伊马替尼抑制GIST细胞的增殖并诱导其凋亡。
  临床前和临床资料提示,某些病人可能通过不同的机制产生耐药性。
  临床前安全性数据
  在经伊马替尼长期治疗后,大鼠机会性感染的发生率增加, 并且猴子体内通常被抑制的疟疾感染病情加重。
  致突变性
  在一项体外细菌(Ames test) 实验、 一项体外哺乳动物细胞分析(小鼠淋巴瘤实验)和一项体内大鼠微核实验中, 伊马替尼均没有显示任何基因毒特性。在一项体外哺乳细胞基因碎片(clastogenicity)分析中 (中国地鼠卵巢细胞染色体畸变),当代谢激活时,发现伊马替尼有阳性的基因毒作用。出现在成品中的因生产过程而产生的两个中间产物在Ames实验显示致突变性,其中一个中间产物在小鼠淋巴瘤实验中也呈阳性。
  生殖毒性
  一项生殖力实验中, 连续70天给予雄性大鼠60mg/kg(约相当于最大临床剂量800mg/天),睾丸和副睾的重量减轻, 同时精子的活动度降低。狗口服剂量>30mg/kg时,也观察到其精子的产生有轻度到中度降低。 在一项雌性大鼠的生殖力研究中, 交配和孕鼠的数量没有变化, 但是在剂量60mg/kg而不是≤20mg/kg时, 植入后胎儿的死亡明显增加, 同时活胎数降低. 
  在一项大鼠围产期的发育研究中,口服给予45mg/kg/天, 死胎的数量和出生后第0天到第4天之间死亡的数量增加。F1代仔鼠给予同样的剂量, 从出生到终点解剖, 平均体重降低。F1代的生殖力没有受到影响,但注意到45mg/kg/天剂量组吸收的数量增加, 同时能够生育的胎儿的数量降低。母代动物给予45mg/kg/天, F1代给予15mg/kg/天(临床最大剂量800mg的1/4), 是没有毒性作用的剂量水平。
  在器官形成期给予大鼠伊马替尼≥100mg/kg有致畸作用, 该剂量约相当于临床最大剂量800mg/天的1.5倍。致畸作用包括露脑和脑彭出, 以及缺失/缺损额骨和/或缺失顶骨。在≤30mg/kg组没有观察到上述作用。
  致癌性
  尚未进行致癌研究。
  【药代动力学】
  本品药代动力学是单剂量口服及达稳态后评价的,剂量范围在25~1000毫克。
  本品剂量在25~1000毫克范围内,其平均曲线下面积(AUC)的增加与剂量间存在比例性关系。重复给药的药物累积量稳态时在1.5~2.5倍。成人人群药代动力学研究表明,性别对药代动力学无影响,体重的影响也可略而不计。
  吸收
  胶囊剂的平均绝对生物利用度为98%,口服一次本品后血浆AUC的变异系数波动在40~60%之间。与空腹时比较,高脂饮食后本药吸收率减少甚微(Cmax减少11%,tmax延后),AUC略减少(7.4%)。
  分布
  约95%与血浆蛋白结合,绝大多数是与白蛋白结合,少部分与α-酸性糖蛋白结合,只有极少部分与脂蛋白结合。整个机体内的总体分布浓度较高,分布容量为4.9 l /千克体重,但红细胞内分布比率较低。体内组织中有关药物分布情况仅来源于临床前的资料。肾上腺和性腺中摄取水平高,中枢神经系统中摄取水平低。
  代谢
  人体内主要循环代谢产物是N-去甲基哌嗪衍生物,在体外其药效与原药相似。该代谢物的血浆AUC是原药甲磺酸伊马替尼AUC的16%。甲磺酸伊马替尼是CYP3A4的底物,又是CYP3A4、CYP2D6、CYP2C9和CYP2C19的抑制剂,因此,可影响同时给予药物的代谢(见【药物相互作用】)。
  消除
  甲磺酸伊马替尼的清除半衰期为18小时,其活性代谢产物半衰期为40小时,7天内约可排泄所给药物剂量的81%,其中从大便中排泄68%,尿中排泄13%。约25%为原药(尿中5%,大便中20%),其余为代谢产物,在粪便和尿中活性代谢产物和原药的比例相似。
  特殊病人群的药代动力学
  给予同样的剂量(400毫克/天),GIST患者其稳态时的药物暴露量是CML患者的1.5倍。 依据初步的GIST病人的人群药代动力学研究,伊马替尼的药代动力学有3项指标的变化(白蛋白、WBC和胆红素)在统计学上有显著性影响。 低白蛋白水平降低清除(CL/f),正如较高的WBC水平。但是这些影响并不足以断定剂量需要调整。
  儿童用药
  儿童和青少年260毫克/m2和340毫克/m2的使用剂量会产生同样的药物暴露,分别相当于成人的400毫克和600毫克。以340毫克/m2/天的剂量经每日一次重复给药后,第8天和第1天的AUC(0-24)比揭示出有1.7倍的药物蓄积。
  肝肾功能衰竭
  对肝、肾功能衰竭病人未进行过临床研究,这些患者应用甲磺酸伊马替尼时要谨慎。已知甲磺酸伊马替尼的排泄很少经肾脏,估计肾功能衰竭患者服用不会出现问题。
  【贮藏】
  30℃以下保存
  【包装】
  铝塑包装,每盒120粒或180粒
  【价格】
  24500/盒(120粒)
  【有效期】
  24个月。
  【执行标准】
  进口药品注册标准JX20010473
  【批准文号】
  进口药品注册证号:H20020169
  【生产企业】 瑞士诺华制药
  公司名称:Novartis Pharma Schweiz AG
  生产厂:Novartis Pharma Stein AG 

==== 汉译英 ====

【Drug name】
Common name: imatinib mesylate capsules
Product name: Gleevec (Glivec)
English name: Imatinib Mesylate Capsules
Pinyin: Jiahuangsuan Yimatini Jiaonang
【Ingredients】
This product is active ingredient for imatinib mesylate.
Chemical Name: 4 - [(4 - methyl -1 - piperazinyl) methyl]-N-[4 - methyl -3 - [[4 - (3 - pyridyl) -2 - pyrimidinyl] amino] phenyl] - Aniline mesylate
Molecular formula: C29H31N7O.CH4SO3
Molecular Weight: 589.7
【Properties】
This product is capsule, the contents of a white to white powder.
【Indications】
For the treatment of chronic myeloid leukemia (CML) blast crisis, accelerated phase or α-interferon therapy in patients with chronic phase after failure.
For the treatment of unresectable and / or metastasis of malignant gastrointestinal stromal tumors (GIST) in adult patients.
【Specification】
100mg
【Usage consumption】
Start dose: one should begin treatment on chronic myeloid leukemia or to treat GIST experienced doctors.
This product should be taken orally, appropriate medication during meals, and drink a large glass of water. Usually once a day for adults. Children and young people taking once-daily or twice (morning and evening).
Can not swallow capsules of patients (children), can be capsules of drug dispersed in water or apple juice. Recommended during pregnancy and breastfeeding women, when opening the capsules to avoid drugs and skin or eye contact, or inhalation (see pregnant and lactating women), access to open capsules to wash their hands.
- CML patient dose
Adult
Chronic phase patients on the recommended dose is 400 mg / day, on the blastic phase and accelerated phase patients was 600 mg / day.
As long as effective, it should continue to take.
If the blood such as permits, no serious adverse drug reactions, in the following circumstances could be considered dose from 400 mg / day to 600 mg / day, or from 600 mg / day to 800 mg / day (400 mg, oral, sub-2 taking): disease progression, treatment for at least 3 months after the failed to obtain a satisfactory hematologic response, hematologic response has been made to re-disappear.
Children and young people over the age of 3
So far, children have limited experience in patients with medication. Based on the adult dose, recommended daily dose as follows: chronic phase 260mg/m2 (maximum dose: 400mg), accelerated phase and blastic phase 340mg/m2 (maximum dose: 600mg), formulation of a child patient's daily recommended dose, the calculated dose of a general should be close to or in the 100mg about dose for children under the age of 12 should generally be about as close as possible or at 50mg. There is no treatment of children under 3 years of experience.
- GIST patient dose
That can not be removed and / or transfer of patients with malignant GIST, the product's recommended dose is 400 mg / day.
After treatment failed to obtain a satisfactory response, the absence of adverse drug reactions, the dose could be considered from 400 mg / day to 600 mg / day. Treatment time:
For GIST patients, this product should continue treatment, unless progression.
Must adjust the dose of the following situations:
If we accept the imatinib mesylate in the treatment of serious non-hematologic adverse reactions (such as severe water retention), should be discontinued until the adverse reactions disappeared, and then according to the severity of adverse reactions to adjust dosage.
Severe liver toxicity when the dose adjustments:
Such as bilirubin elevated "upper limit three times the normal range or elevated aminotransferases," upper limit five times the normal range, and are advised to stop taking imatinib mesylate, until the above-mentioned indices dropped to the normal range of 1.5 or 2.5 times the upper limit below.
After imatinib mesylate treatment can continue taking after reduction. Adult daily dose should be reduced from 400 milligrams to 300 milligrams, or from 600 mg reduced to 400 mg; children and adolescents from 260mg/m2 reduced to 200 mg/m2 or 340 mg/m2 from the reduced to 260 mg/m2.
Neutropenia or thrombocytopenia during dose adjustments:
Accelerated phase or blastic phase (starting dose of 600 mg / day or children and adolescents 340mg/m2 / day): If there is severe neutropenia and thrombocytopenia (neutrophils <0.5 × 109 / L and / or platelet <10 × 109 / L), should determine whether Pancytopenia and leukemia related (bone marrow or biopsy), if Pancytopenia caused by leukemia, the recommended dose reduced to 400 mg / day or children and adolescents 260mg/m2 / day. If the blood cells continued to decrease 2 weeks, then further reduce the dose to 300 mg / day or children and adolescents 200mg/m2 / day, such as blood cells continued to decrease for 4 weeks, should be discontinued until neutrophils ≥ 1.0 × 109 / L and platelets ≥ 20 × 109 / L. Then when the dose of 300 mg / day or children and adolescents 200mg/m2 / day.
In patients with chronic phase CML and GIST (starting dose of 400 mg / day or children and adolescents 260mg/m2 / day): Among granulocytes <1.0 × 109 / L and / or platelets <50 × 109 / L should be discontinued In neutrophils ≥ 1.5 × 109 / L and platelets ≥ 75 × 109 / L should be restored when the medication, treatment restore a dose 400 mg / day or children and adolescents 260mg/m2 / day, if the critical value again treatment after the interruption to re-dose reduced to 300mg / day or children and adolescents 200mg/m2 / day.
Dose in patients with liver failure:
Liver dysfunction by imatinib mesylate, may increase the plasma concentrations. Because there were no patients with impaired liver function and the use of imatinib mesylate in the clinical data, we are unable to submit proposals to adjust dosage. Impaired liver function should be cautious in patients with the FDA, patients with severe liver failure should be carefully weighed the risk - benefit ratio, and then to the FDA.
Renal failure and elderly patients dose:
Known creatinine clearance rate can decrease with age aging, but age on the pharmacokinetics of this product had no significant effect, since patients with impaired renal function has not yet been carried out in clinical trials, it impossible to make dose adjustment proposals.
Adverse reactions 【】
The majority of patients served during the FDA will be some adverse reactions, but most are mild to moderate. Taking into account also have symptoms of the disease are often difficult to clarify their causal relationship.
In the CML clinical trials process, the result of drug-related adverse reactions and withdrawal will, in α-interferon treatment failure in patients with chronic phase only 1%, speed up the period about 2%, 5% of CML.
In the GIST clinical trials, due to drug-related adverse events and withdrawal accounted for 3.4%.
CML and GIST patients with adverse reactions occurred in similar, there are only two exceptions: GIST patients experienced less bone marrow suppression, tumor hemorrhage is only observed in GIST patients (see
【Note】).
In the CML and GIST patients, the most commonly reported drug-treatment-related adverse events were mild nausea (50 ~ 60%), vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle spasm, and erythema, these adverse events are easy to treatment.
All studies reported in both the swelling and water retention, rates were 47 to 59% and 7 ~ 13%, respectively, a serious of which ~ 3% and 1 ~ 2%. Most patients showed periorbital edema and lower limb swelling. There have been isolated reports of glaucoma, and related water retention. Have pleural effusion, ascites, pulmonary edema, and rapid increase in body weight reported. These events can usually be suspended from the FDA, the use of diuretics or give other support to treatment was defused. However, individual patients in serious condition, and even life-threatening. 1 case of CML patients complicated with pleural effusion, congestive heart failure and renal failure in a complex clinical condition died. The incidence of these adverse events and dose have a certain relationship, more common in doses> 600mg / day.
When the high-dose imatinib with the combination of chemotherapy drugs, can occur a transient liver toxicity, such as elevated transaminases and hyperbilirubinemia.
According to system organ classification and the frequency of occurrence will not just occur in the individual patient's adverse reactions are listed below.
Occurrence rate is defined (CIOMS classification) as follows: very common: "10%; common:> 1% ≤ 10%; not common:> 0.1% ≤ 1%; rare:> 0.01% ≤ 0.1%; very rare ≤ 0.01 %.
Systemic abnormalities
Very common: peripheral edema (56%), fatigue (15%).
Common: water retention, fever, fatigue, chills
Not common: discomfort, bleeding
Rare: systemic edema
Infectious disease / infection
Uncommon: sepsis, pneumonia, herpes simplex, shingles and upper respiratory tract infections and gastroenteritis
Abnormal blood and lymphatic system
Very common: neutropenia (14%), thrombocytopenia (14%) and anemia (11%)
Common: febrile neutropenia
Uncommon: pancytopenia, bone marrow suppression
Metabolic and nutritional imbalance
Common: loss of appetite, weight gain
Not common: dehydration, hyperuricemia, hypokalemia, increased appetite, reduced appetite, gout, hypophosphatemia, weight loss
Rare: Hyperkalemia, hyponatremia
Psychosis
Uncommon: depression, anxiety, reduced sex drive
Rare: Confusion
Nervous system abnormalities
Very common: headache (11%)
Common: dizziness, taste disturbance, paresthesia, insomnia,
Not common: stroke, syncope, peripheral neuropathy, sensory impaired, addicted to spit, migraine headaches,
Memory impairment
Rare: Brain edema, increased intracranial pressure, convulsions
Ocular anomalies
Common: conjunctivitis, lacrimation increased, blurred vision
Not common: eye irritation symptoms, subconjunctival hemorrhage, dry eyes, periorbital edema
Rare: macular edema, papilledema, retinal hemorrhage, vitreous hemorrhage, glaucoma
Ear and labyrinth abnormalities
Less common: dizziness, ringing in the ears
Cardiac abnormalities
Not common: heart failure, pulmonary edema, tachycardia.
Rare: pericardial effusion, pericarditis, pericardial tamponade
Vascular anomalies
Not common: hematoma, hypertension, hypotension, flushing, cold extremities
Rare: thrombosis / embolism
Very rare: anaphylactic shock
The respiratory tract, chest and mediastinal abnormalities
Common: epistaxis, dyspnea
Not common: pleural effusion, cough, sore throat, acute respiratory failure
Rare: pulmonary fibrosis, interstitial pneumonia
Gastrointestinal Disorders
Very common: nausea (51%), vomiting (25%), diarrhea (25%), dyspepsia (13%),
Abdominal pain (14%)
Common: abdominal distension, flatulence, constipation, gastroesophageal reflux, mouth ulcers
Not common: gastrointestinal bleeding, melena, ascites, gastric ulcer, gastritis, hiccup reverse, dry mouth
Rare: colitis, diverticulitis, intestinal obstruction, tumor hemorrhage / tumor necrosis, gastrointestinal perforation, pancreatitis
Hepatobiliary system abnormalities
Common: elevated liver enzymes
Not common: jaundice, hepatitis, hyperbilirubinemia
Rare: liver failure
Very rare: hepatic necrosis
Skin and subcutaneous tissue abnormalities
Very common: whole body edema (32%), dermatitis / eczema / rash (26%),
Common: facial edema, periorbital edema, pruritus, erythroderma, skin dry, sparse hair, night sweats
Uncommon: ecchymosis, contusion, sweating, urticaria, nail breakage, light allergic reactions, purpura, alopecia, cheilitis, skin pigmentation too much, too little skin pigmentation, psoriasis, exfoliative dermatitis and large herpes
Rare: angioneurotic edema, small herpes, Stevens-Johnson syndrome, acute febrile neutrophil dermatosis (Sweet syndrome)
Skeletal muscle, connective tissue and bone abnormalities
Very common: muscle spasm, pain, muscle cramps (36%), skeletal muscle Routong (14%).
Common: joint swelling
Not common: sciatica, joint and muscle spasm
Rare: avascular necrosis / hip necrosis
Kidney and urinary system anomalies
Uncommon: renal failure, kidney area pain, frequent urination, hematuria
Reproductive system and breast abnormalities
Not common: the feminization of male breast, breast increased scrotal edema, menorrhagia, nipple pain, sexual dysfunction
Have been found in patients with advanced, severe infections, severe leukopenia and death in patients suffering from other serious cases.
Have been caused by the death of gastrointestinal perforation coverage.
Causing death by liver necrosis have been reported.
Reflected in the other bad situation:
Some patients will be slight edema of the eyes, there is a period of time is not very good appetite, stool frequency increased, these are not a normal reaction to stress.
Some CML patients taking Gleevec should be increased appetite, after which weight gain, which does not require tension, as long as fluid retention can be determined not to worry. Fluid retention is particularly likely in elderly patients or patients with heart disease-based people.
May produce damage to the liver and kidney, should have regular liver function kidney function tests, you can also take a number of hepatoprotective drugs (such as Glucurolactone). Medication at the same time eating liver protection medicine, says Dr. Fang Miandi hepatobiliary liver function is normal in general do not eat too much medicine, preventive Liver can eat the right amount of sugar, plus a variety of vitamins such as Centrum tablets, Shi Er Kang on it. (Intake of vitamins have significant benefits to the body).
Laboratory abnormalities
All the studies have reported reduction of blood cells, particularly neutropenia and thrombocytopenia, in order to "750 mg / day incidence of large doses as high (I phase study), but blood cells significantly reduced the incidence of the disease depends on the sub - period, 3 or 4 degrees of neutropenia (ANC <1.0 × 109 / L) and thrombocytopenia (platelet count <50 × 109 / L), in the blastic phase and accelerated phase compared with the incidence of CML chronic phase (14% neutropenia and thrombocytopenia 7%) high 4 and 6 times (neutropenia and thrombocytopenia were 58 ~ 62% and 42 ~ 58%). By contrast in the chronic phase were only 14% and 7%, the former for the latter 2 ~ 3 times. CML chronic phase patients, 4 degrees neutropenia (ANC <0.5 × 109 / L) and thrombocytopenia (platelet count <10 × 109 / L) respectively, the incidence of only 2% and 1%. Neutropenia and thrombocytopenia occurred in the median duration was 2 ~ 3 weeks and 3 ~ 4 weeks. For such events, under normal circumstances may be suspended by lowering the dosage or medication which alleviated the need for this purpose only a few cases long-term withdrawal. Children in the pediatric CML, the majority of toxicity for the three and four, including the neutral neutropenia, thrombocytopenia and anemia. These symptoms usually occur within a few months before the first treatment.
In GIST patients, there 3 and 4 The incidence of anemia were 3.4% and 0.7%, at least some of these patients is related to gastrointestinal bleeding or a tumor. 3 and 4 neutropenia incidence rates were 4.1% and 3.4%, and 3 The incidence of thrombocytopenia was 0.7%, no patients developed Grade 4 thrombocytopenia. Whole blood cell and neutrophil counts decrease occurred mainly in the treatment of the first 6 weeks, after cell counts remained relatively stable.
A significant increase in transaminase or bilirubin is not common ( "4% of cases), which can be through reduction or withdrawal (median duration of approximately one week) to ease, and only less than 0.5% of patients due to liver function laboratory check the abnormal long-term withdrawal. 1 case of accelerated phase CML patients died of acute liver failure, but we can not rule out the high-dose acetaminophen with imatinib mesylate, the results of drug-drug interactions (see drug interactions 【】 and 【Cautions】) .
Occasionally blood alkaline phosphatase, creatinine phosphokinase, creatinine, and lactate dehydrogenase increased.
【Taboo】
Active substances in this product or any other excipient ingredients banned allergies.
【Note】
Imatinib mesylate, the first month of treatment should check once a week, such as whole blood, the first month investigation once every two weeks and, thereafter, as may be required (for example, check once every 2-3 months). In case of severe neutropenia or thrombocytopenia, should be adjusted dose (see the usage and consumption).
Should be checked before starting treatment, liver function (transaminases, bilirubin and alkaline phosphatase), and then check once a month or according to clinical decisions, if necessary adjust the dose. Liver failure in patients with imatinib mesylate, may increase the amount of exposure, liver damage were careful the FDA. Severe liver failure to engage in serious danger in the - benefit ratio assessment in order to use imatinib mesylate (see the usage and consumption). Should bear in mind that there may be liver metastases in patients with GIST, thereby increasing the liver function damage. There have been a routine to take paracetamol for fever patients died of acute liver failure. Although the exact cause of death is still unknown at present, while taking imatinib mesylate and the need to be cautious when acetaminophen (see】 【drug interactions).
At the same time taking imatinib mesylate and CYP3A4 inducers (see】 【drug interactions) can significantly reduce the total imatinib mesylate exposure, thereby increasing the potential risk of treatment failure. Should be avoided imatinib mesylate and CYP3A4 inducer combination.
About 1 ~ 2% of patients the FDA serve a serious water retention (pleural effusion, edema, pulmonary edema, and ascites), it is suggested regular monitoring of weight, weight gain should be carefully evaluated, if necessary, take appropriate supportive care. Patients, especially children, water retention may not appear edema can be identified.
Water retention can increase or lead to heart failure, there were no patients with severe heart failure (according to New York Heart Association classification grade Ⅲ ~ Ⅳ) should be the FDA clinical experience. Caution the FDA for these patients, glaucoma patients should also be used with caution (see adverse reactions 【】).
In the eosinophilia (HES) and those with heart disease, there is a reported occurrence of cases of cardiogenic shock / left ventricular dysfunction and imatinib mesylate for initial treatment of the. It was reported that systemic administration by giving steroid therapy, circulatory support and suspension of imatinib, the symptoms are reversible. Myelodysplastic / myeloproliferative disease, perhaps related to the level of high eosinophils. Right with HES / CEL, as well as eosinophils accompanied by a high level, and in need of echocardiography testing and monitoring of plasma troponin, if any one indicator is the exception, in the initial use of imatinib in the treatment should consider the use of systemic steroids administration (1-2mg/kg) for prevention and treatment, 1-2 weeks of continuous use.
In the GIST clinical trial, reported in 8 patients (5.4%) had gastrointestinal bleeding and 4 patients (2.7%) of tumor hemorrhage. According to a different tumor site, tumor may occur in intra-abdominal hemorrhage may also occur in the liver. Bleeding tumors of these patients may also be manifested as gastrointestinal bleeding, therefore, should be monitored in the treatment of early stage patients with gastrointestinal symptoms.
When the high-dose imatinib with the combination of chemotherapy drugs, can occur a transient liver toxicity, such as elevated transaminases and hyperbilirubinemia, so imatinib in combination with chemotherapy drugs, we should Detection of liver function and learn more about liver function associated with adverse reactions (see adverse reactions 【】).
Ò In the Gleevec treatment, resection of the thyroid were treated with levothyroxine therapy, there are reports of hypothyroidism in such patients should monitor their TSH levels.
About the drug safety and efficacy of long-term clinical data is still limited.
Preclinical studies have shown that imatinib mesylate is not easy through the blood-brain barrier. Has not yet been studied in humans.
Pairs of drivers and the ability of the machine manipulators
Yet the ability of the driver or machine manipulator possible impact of information and data. The goods to remind patients with adverse reactions during treatment may have symptoms of dizziness or blurred vision, therefore, when patients should pay attention to driving or manipulation of the machine.
【Pregnant and lactating women drug】
Pregnancy: Animal studies have shown that the existence of reproductive toxicity of this product (see the pre-clinical data of the reproductive toxicity section).
There is currently a lack of imatinib mesylate for pregnant women information on the possible toxicity of the fetus is currently unknown. Unless it is necessary, otherwise, should not be applied during pregnancy. As during pregnancy taking imatinib mesylate, have to tell their potential harm to the fetus. Women of childbearing age taking imatinib mesylate during the same time should be recommended to its effective contraception.
Breast-feeding: In animal experiments, imatinib mesylate and its metabolites excreted in large numbers from the milk, but no human studies carried out, taking imatinib mesylate in women should not breast-feeding.
Pediatric Use
Children over 3 years old so that the FDA see the usage and consumption.
【Old medication】
Known creatinine clearance rate can decrease with age aging, but age on the pharmacokinetics of this product had no significant effect.
【Drug interactions】
Can change imatinib mesylate plasma concentrations of drugs
CYP3A4 inhibitors: Healthy subjects were also taking a single dose of ketoconazole (CYP3A4 inhibitor), the imatinib mesylate, the drug exposure increased significantly (mean maximum plasma concentration (Cmax), and imatinib under the curve of area (AUC) can be increased by 26% and 40%, there is no other CYP3A4 inhibitors (such as: itraconazole, erythromycin and clarithromycin) also taking experience.
CYP3A4 inducers: rifampin in healthy volunteers taking after the clearance of imatinib mesylate to increase 3.8-fold (90% confidence interval = 3.5-4.3 times), but the Cmax, AUC (0-24) and AUC (0-8 ) decreased by 54%, 68% and 74%. In clinical studies found that while giving the drugs phenytoin, after imatinib mesylate plasma concentration decreased, leading to reduced efficacy. Other inducing agents such as dexamethasone, Kata microphone triazine, phenobarbital and products containing St John Wort extract preparations, may have similar problems and therefore should be avoided imatinib with CYP3A4 inducers at the same time taking.
Imatinib mesylate make the following changes in plasma concentrations of drugs
Imatinib mesylate to simvastatin (CYP3A4 substrate), the average Cmax and AUC increased 2-fold and 3.5-fold. Nicole should bear in mind that an increase imatinib metabolism of other drugs via CYP3A4 (eg, benzodiazepines, dihydrocodeine pyridine, calcium channel antagonists, and other HMG-CoA reductase inhibitors) in plasma concentrations. Thus, when at the same time taking the drugs and the narrow therapeutic window CYP3A4 substrate (eg, cyclosporin, pimozide) should be cautious.
Inhibited CYP3A4 activity with a similar concentration, imatinib mesylate could inhibit CYP2D6 activity in vitro, and therefore with imatinib mesylate, at the same time taking, there are likely to increase the system's exposure of CYP2D6 substrates volume, although not yet made specific recommendations to the caution.
Imatinib mesylate in vitro can inhibit the activity of CYD2C9 and CYD2C19 the same time, it can be seen after taking warfarin prolonged prothrombin. Therefore, imatinib mesylate treatment of the circumstances leading to or change the dose, if the same time, double-coumarin, should be short-term monitoring of prothrombin time.
Patients should be warned to avoid the use of paracetamol containing the non-prescription drugs and prescription drugs.
Overdosage
Signs and symptoms
Doses greater than 800 mg / day experience is limited, and no case report of excessive doses. In case of overdose, the patient should be closely observed and given appropriate supportive care.
【Clinical trials】
Clinical study of chronic myeloid leukemia
Of Philadelphia chromosome-positive chronic myeloid leukemia blast crisis (myeloid blast cell crisis), accelerated phase, and by α-interferon treatment failure in patients with chronic phase of the three open, non-controlled Phase II clinical study of nature.
In a large-scale, open, placebo-controlled Phase III clinical trials for newly diagnosed patients with Philadelphia chromosome-positive chronic leukemia (Philadelphia + CML). Of children and adolescents in the treatment of two Phase I studies carried out. Clinical study cases, 38% -40% of patients aged ≥ 60 years old, 10 ~ 12% ≥ 70 years of age.
Newly diagnosed chronic phase: one in the previous 6 months for the first time diagnosed patients with CML in 1106 into the group phase III clinical trial to compare imatinib mesylate 400 mg / day and α-interferon ( INF) 5 1 million IU/m2 / day + cytarabine (Ara-C) 20 mg / m2 / day (10 days / month) efficacy. 80% of patients taking the drug test before receiving hydroxyurea treatment, the test the first 6 months, 50% taking imatinib mesylate and 75% of patients taking IFN-Ara-C patients also continued to taking hydroxyurea (an average of respectively 15 and 30 days).
12 months after the interim analysis, imatinib mesylate group and the IFN-Ara-C group of complete hematologic response (CHR), respectively 94.4% and 54.6%, major cytogenetic response was 82.6% and 20.3 %, complete cytogenetic response was 67.8% and 7.4%.
Use of proven FACT-BRM questionnaire evaluation of quality of life of imatinib mesylate in all aspects of group ratings were higher than IFN-Ara-C group, quality of life data show that the acceptance of imatinib mesylate treatment of patients be able to maintain a good mood.
a-interferon treatment failure in patients with chronic phase: (532 cases, the starting dose of 400 mg once daily) 60% of the patients have a major cytogenetic response, 42% obtained complete remission, 93% received a complete blood chemical reaction.
In accelerated phase: (235 cases, of which 63% of patients in accelerated phase had received other treatment, 235 patients, 77 patients received imatinib mesylate 400 mg once a day; 158 patients received 600 mg once a day ). Results 70% of the patients have the exact hematologic response, 28% of patients achieved complete hematologic response, 25% of patients have a major cytogenetic response (ie, split with Philadelphia chromosome-positive cells decreased to "35%) 18% achieved complete cytogenetic school mitigation. With hematologic response as the primary endpoint of the analysis, we found 400 mg and 600 mg dose was no significant difference between groups, but the 600 mg dose group to improve the cytogenetic response is more evident, its duration longer. In this study, 600 mg dose group time to progression to disease occurs significantly different.
CML (myeloid blast cell crisis): (260 cases, 95 cases [37%] into the accelerated phase or blast crisis period have received chemotherapy, and the other 165 cases [63%] have not previously received chemotherapy. 223 cases starting treatment, the dose of 600 mg once a day). Complete hematologic response in different statistics as the primary efficacy, 31% of patients have been positive hematologic response (non-treated patients received 36% of patients treated 22%), 15% of the patients observed in the main cell genetic response. Had not received and accepted by patients, the median survival time was 7.7 and 4.7 months.
Children and adolescents: CML chronic phase (15) or blastic phase CML or Philadelphia chromosome-positive acute leukemia (16) a total of 31 children into the group of patients with gradually increasing doses of a Phase I trial, of which 28% of CML Patients aged 2-12 years, 50% in the 12-18 years of age. Patients received the following doses of imatinib mesylate, 260 mg / m2 / day (n = 6), 340 mg / m2 / day (n = 11), 440 mg / m2 / day (n = 8) and 570 mg / m2 / day (n = 6). In the obtained information on 13 cases of cytogenetics in CML patients, 7 (54%) achieved complete cytogenetic response, 4 (31%) partial cytogenetic response, which is equivalent to 85% of major cytogenetic response rates. Another eight patients (three CML, 4 with acute leukemia) in a separate Phase I trial, three people received a dose of 173-200 mg / m2 / day, four people received doses of approximately 260 mg / m2 / day, a person receiving 360 mg / m2 / day dose. Three children with two of CML achieved complete cytogenetic response. Compared with the adult trials, a total of 39 children, no special security issues.
Gastrointestinal stromal tumors (GIST) in Clinical Research
Pairs of unresectable or metastatic gastrointestinal stromal tumors (GIST) patients had an open, randomized, multi-country participation in Phase II clinical trials. In this trial, 147 patients were enrolled and randomized to receive oral imatinib 400 mg or 600 mg once a day, with an average treatment of 6-12 months (not more than 24 months). These patients range in age from 18-83 years of age, the pathological diagnosis of C-Kit-positive malignant gastrointestinal stromal tumors (GIST), and can not be surgery and / or metastatic.
400 mg group remission rate of 37%, 600 mg group, 43.2%, no cases of complete remission.
As an average follow-up of 7 months (7 days -13 months), all patients does not appear to alleviate disease progression.
【Pharmacology and toxicology】
Mechanism / pharmacodynamics properties
Imatinib in vitro and in vivo at the cellular level may inhibit Bcr-Abl tyrosine kinase, can selectively inhibit Bcr-Abl-positive cell lines, Philadelphia chromosome-positive (Ph +) chronic myeloid leukemia (CML) and acute lymphocytic leukemia patients with fresh cell proliferation and induce their apoptosis.
In addition, imatinib can also inhibit platelet-derived growth factor (PDGF) receptor, stem cell factor (SCF), c-Kit receptor tyrosine kinase, which inhibit PDGF and stem cell factor-mediated cell behavior.
Gastrointestinal stromal tumors (GIST) cells activity kit mutation, in vitro experiments showed that imatinib inhibited the proliferation of GIST cells and induce their apoptosis.
Pre-clinical and clinical data suggest that some patients may arise through different mechanisms of drug resistance.
Preclinical safety data
In the long-term treatment by imatinib, the rats the incidence of opportunistic infections increase, and monkeys in vivo inhibition of malaria infection are usually sicker.
Mutagenicity
In an in vitro bacterial (Ames test) experiment, an in vitro analysis of mammalian cells (mouse lymphoma test), and an in vivo micronucleus test in rats, imatinib did not show any genetic-toxicity. In an in vitro mammalian cell gene fragments (clastogenicity) Analysis (Chinese hamster ovary cell chromosome aberration), when metabolic activation, we found that imatinib mesylate with positive genetic toxicity. Appear in the finished product in the process of production resulting from the two experiments showed intermediate products in the Ames mutagenicity, in which an intermediate product in the mouse lymphoma test was also positive.
Reproductive toxicity
A fertility experiment, male rats were given 70 days in a row 60mg/kg (equivalent to approximately maximum clinical dose of 800mg / day), testicles and reduce the weight of the Deputy testis, while lower sperm activity. Dog oral dose> 30mg/kg, we also observed that the sperm produced mild to moderate lower. In a study of fertility in female rats, mating, and no change in the number of pregnant rats, but not ≤ 20mg/kg dose of 60mg/kg, the death of the fetus after implantation, a marked increase in the same time reduce the number of live births.
In a rat prenatal developmental studies, oral giving 45mg/kg / day, the number of stillbirths and postnatal day 0 to the first 4 days of death between the increase in the number. F1 generation rat given the same dose of anatomy from birth to finish, with an average weight loss. F1 generation of fecundity was not affected, but noted that 45mg/kg / day increase in the number of absorbed dose at the same time be able to reduce the number of fetal birth. Mother on behalf of the animals, giving 45mg/kg / day, F1 generation given 15mg/kg / day (maximum dose 800mg of clinical 1 / 4), there is no toxic effect dose levels.
In the period of organ formation in rats given imatinib ≥ 100mg/kg have teratogenic effects, the dose is about equivalent to the clinical maximum dose of 800mg / day of 1.5 times. Teratogenic effects, including Lu Peng out of the brain and the brain, as well as missing / defects in the frontal bone and / or deletion of the parietal bone. In the ≤ 30mg/kg group did not observe these effects.
Carcinogenicity
Carcinogenicity studies have not yet carried out.
Pharmacokinetics】
This product is a single-dose pharmacokinetics of oral and achieve a steady-state after the evaluation, the dose range of 25 ~ 1000 mg.
This product is 25 ~ 1000 mg dose range, the average area under the curve (AUC) increased dose-proportional between the existence of sexual relations. Repeated administration of drug accumulation at steady-state 1.5 to 2.5 times. Adult population pharmacokinetic studies have shown that gender on the pharmacokinetics of no effect on body weight may also be negligible.
Absorption
Capsules, the average absolute bioavailability of 98%, oral plasma AUC after the last of this product fluctuations in the coefficient of variation of 40 ~ 60%. When compared with the fasting, and after high-fat diet have little to reduce drug absorption rate (Cmax reduction of 11%, tmax delayed), AUC decreased slightly (7.4%).
Distribution
About 95% and plasma protein binding, most with albumin, a small number of α-acid glycoprotein and protein binding, only a very small part of the combination with the lipoprotein. The overall distribution of the body as a whole a higher concentration and distribution capacity of 4.9 l / kg body weight, but the red blood cell distribution was low. In vivo tissue distribution of the drug only from pre-clinical data. Adrenal and gonadal levels of intake of a high intake of low levels of the central nervous system.
Metabolism
In the human body is the main circulating metabolite N-demethyl-piperazine derivatives, in vitro efficacy similar to the original drug. The plasma AUC of the metabolite is the original drug imatinib mesylate AUC of 16%. Imatinib mesylate is a CYP3A4 substrate, but also CYP3A4, CYP2D6, CYP2C9 and CYP2C19 inhibitors, therefore, can affect the metabolism of drugs at the same time to give (see】 【drug interactions).
Elimination
Imatinib mesylate clearance half-life of 18 hours, its active metabolite half-life of 40 hours, 7 days, some can excrete the given dose, 81%, of which 68% of excretion from stool, urine excretion 13%. About 25% of the original drug (5% in urine, stool, 20%), the rest of metabolites in the faeces and urine in the active metabolite, and the proportion similar to the original drug.
Special patient groups Pharmacokinetics
Given the same dose (400 mg / day), GIST patients whose steady-state drug exposure was 1.5 times that of patients with CML. GIST patients based on preliminary population pharmacokinetic study, imatinib mesylate pharmacokinetics are three indicators of change (albumin, WBC and bilirubin) in the statistically significant impact. Reduce the level of the low albumin clearance (CL / f), as a higher level of WBC. But these effects is not sufficient to conclude that doses need to be adjusted.
Child medication
Children and adolescents 260 mg / m2 and 340 mg / m2 for the use of doses will produce the same drug exposure, respectively, equivalent to 400 mg for adults and 600 mg. To 340 mg / m2 / day dose after repeated once-daily administration, the first 8 days and 1 day AUC (0-24) reveals that there are 1.7 times more than the drug accumulation.
Liver and kidney failure
The liver and kidney failure patients and did not conduct clinical studies, these patients with imatinib mesylate, be careful when. Imatinib mesylate is known to excrete very little through the kidney, it is estimated renal failure patients treated with no problem.
【Storage】
Stored under 30 ℃
【Packing】
Aluminum packaging, 120, or 180 per box
【Price】
24500 / Box (120)
【Valid Period】
24 months.
【Executive Standard】
Imported drug registration standards JX20010473
【Approval number】
Imported drug registration 证号: H20020169
【Manufacturer】 Novartis Pharmaceuticals
Company Name: Novartis Pharma Schweiz AG
Manufacturer: Novartis Pharma Stein AG

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更新日期: 2009-11-27 10:47
作者: : mcyclub
修订: 1.0

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