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易瑞沙(IRESSA)中文说明

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易瑞沙中文说明书

  易瑞沙 薄膜衣片
  Iressa
  【成分】
  吉非替尼 Gefitinib
  制造商
  阿斯利康
  包装/剂型
  剂型 包装/零售价 图片
  薄膜衣片 0.25g x 10 片
  贮藏/有效期:30°C以下保存 有效期24个月
  【性状】
  吉非替尼的化学名为 : N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉丙氧基)喹唑啉-4-胺,分子式为 :C22H24ClFN4O3,分子量为 :446.90。
  本药为褐色圆形薄膜衣片 ;一面印有"IRESSA 250"。
  【药理作用】
  吉非替尼是一种选择性表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,该酶通常表达于上皮来源的实体瘤。
  吉非替尼广泛抑制异种移植于裸鼠的人肿瘤细胞的生长,抑制其血管生成。在体外,可增加人肿瘤细胞衍生系的凋亡,并抑制血管生成因子的侵入和分泌。在动物试验或体外研究中已证实,吉非替尼可提高化疗、放疗及激素治疗的抗肿瘤活性。
  临床研究 两项大型的II期临床研究评估了本品单药治疗局部晚期或转移性非小细胞肺癌(NSCLC)的有效性和安全性。患者的WHO体力状况评分为0-2,并且必须为既往化
  疗失败者 :
  IDEAL1(研究0016),既往接受了1或2个化疗方案,并且至少有一个包括铂类治疗(中位年龄为59.6岁[28-85岁] ;n=209)。
  IDEAL2(研究0039),既往接受了2个或以上化疗方案,该化疗方案包括同时或先后接受了铂类和多西紫即嫉闹瘟?中位年龄为61岁[30-84岁];n=216)。
  两个研究设计相似,均为双盲、平行组、多中心,评估了两个吉非替尼口服剂量 :250 mg/天和500 mg/天。患者被随机分配在这两个剂量组。在IDEAL1中主要研究终点为肿瘤客观缓解率,次要研究终点为疾病相关症状改善 ;在IDEAL2中主要研究终点为肿瘤客观缓解率以及疾病相关症状改善率(每周以LCS进行测定)。
  疗效结果 对于IDEAL1和IDEAL2疗效结果的总结见下表。不考虑WHO体力状况评分(0,1或2)和既往接受的化疗次数,两个研究中得到的肿瘤客观缓解率以及疾病相关症状改善率结果相似。大多数患者肿瘤客观缓解发生于治疗的第1个月,少部分患者的客观缓解可迟至治疗的第4个月发生。 
  a 在IDEAL1试验中,无论是250 mg还是500 mg,日本患者的客观缓解率要比非日本患者的高(250 mg为27.5%:9.6%,500 mg为27.5%:11.1%),未调整的比值比(两组合并)为3.27,p=0.002。在多变量分析时,调整了性别,组织学和身体状况后,这一差异不再有统计学意义(调整后的比值比为2.13,p=0.068)。
  b 基于症状改善可评估人群(250 mg,n=67;500 mg,n=73)。
  + 数据截止时仍在继续。
  FACT-L肺癌患者生活质量测定量表。
  NC未计算。
  PFS无进展生存。
  安全性 本品的安全性情况在两项研究中是相似的,不良事件的发生率和严重程度呈剂量相关性(见“不良反应”)。
  结论 临床研究资料证明局部晚期或转移性非小细胞肺癌患者以本品进行治疗可达到持续的客观缓解。
  在中国进行的临床研究 在中国的5个临床研究基地中进行了临床研究,以评估吉非替尼片250 mg/日在既往接受过化学治疗的非小细胞肺癌患者中的客观缓解率。
  共有159名受试者至少服用了一次吉非替尼片250 mg,受试者的人口学和疾病特征情况如下 :
  男性91人(57.2),女性68人(42.8) ;
  年龄均数(标准差)为56.5岁(11.3),中位数为57岁,范围(最小值,最大值)在31.0-84.0岁。
  年龄组情况 :18-60岁组有91人(57.2%),60-70岁组有46人(28.9%),70岁以上组有22人(13.8%)。
  吸烟状况 :不吸烟者有90人(56.6%),曾吸烟者有37人(23.3%),偶尔吸烟者有3人(1.9%),经常吸烟者有29人(18.2%)。
  组织学分型 :鳞癌有29人(18.2%),腺癌有105人(66%),未分化癌有5人(3.1%),大细胞癌有1人(0.6%),腺鳞癌有7人(4.4%),细支气管肺泡癌(BAC)有12人(7.5%)。
  入选时非小细胞肺癌状态 :局部晚期MO有26人(16.4%),转移性M1有133人(83.6%)。
  WHO体力状况 :0分有23人(14.5%),1分有101人(63.5%),2分有34人(21.4%),3分有1人(0.6%)。
  其中在入选前曾接受过1个化疗方案治疗的受试者有75名(47.2%),2个及3个以上(含3个)化疗方案治疗的受试者分别为50名(31.4%)和34名(21.4%)。对于159名受试者(意向性治疗人群集)进行了有效性分析。
  以下为疗效总结 :
  客观缓解率为27.0%,
  95%可信区间为20.3-34.7%,
  中位PFS为97天,
  95%可信区间为67-120天,
  中位生存期为11.1月(生存期数据截止至2004年11月22日)。
  在不同治疗亚组中客观缓解率显示有一定的差异性(根据入组时基线特征进行分组,受试者的客观缓解率情况如下表,类似的差异性同样见于其他国际临床研究。尽管在某些亚组的受试者数不够多,但吉非替尼对这些受试者的效果和预期的相一致。
  安全性 吉非替尼的总体耐受性良好。大部分不良事件为轻度,无需处理。超过10%的受试者报告的不良事件为皮疹(44.0%)、皮肤瘙痒(15.7%)和腹泻(11.3%)。所出现的不良事件严重程度及发生频率与在其他临床研究中观察到的相一致。 
  【药代动力学】
  静脉给药后,吉非替尼迅速清除,分布广泛,平均清除半衰期为48小时。癌症患者口服给药后,吸收较慢,平均终末半衰期为41小时。吉非替尼每天给药1次出现2-8倍蓄积,经7-10剂给药后达到稳态。达到稳态后,24小时间隔用药,血浆药物浓度最高和最低值之比一般维持在2-3倍范围之间。
  吸收 本品口服给药后,吉非替尼的血浆峰浓度出现在给药后的3-7小时。癌症患者的平均绝对生物利用度为59%。进食对吉非替尼吸收的影响不明显。
  分布 在稳态时吉非替尼的平均分布容积为1400 L,表明其在组织内分布广泛。血浆蛋白结合率约为90%。吉非替尼与血清白蛋白及α1-酸性糖蛋白结合。
  代谢 体外研究数据表明参与吉非替尼氧化代谢的P450同工酶主要是CYP 3A4。
  体外研究显示吉非替尼可有限地抑制CYP 2D6(见“药物相互作用”)。
  吉非替尼的代谢中三个生物转化的位点已被确定 :N-丙基吗啉基团的代谢,喹唑啉上甲氧取代基的脱甲基作用及卤化苯基基团类的氧化脱氟作用。
  在人血浆中鉴别到的主要代谢物是O-去甲基吉非替尼。它对EGFR刺激细胞生长的抑制作用比吉非替尼弱14倍,因此对吉非替尼的临床活性不太可能有显著作用。
  消除 吉非替尼总的血浆清除率约为500 mL/分。主要通过粪便排泄,少于4%通过肾脏以原型和代谢物的形式清除。
  特殊人群 人群动力学 :在以人群为基础的数据分析中,未发现预期的稳态血药谷浓度与患者年龄、体重、性别、种族、或肌酐清除率之间有任何关系。
  肝功能损害 在一项有31名实体瘤患者(他们中肝功能为正常的有14名,中度肝功能损害的有13名,由于肝转移出现重度肝功能损害的有4名)参加的临床研究中对吉非替尼进行了药代动力学评价。研究表明,日服250 mg本品28天后,达到稳态的时间,总血浆清除率及稳态值(Cmaxss,AUC24SS)在肝功能正常组和中度肝功能损害组之间是相似的。4名由于肝转移出现重度肝功能损害的患者其稳态值与肝功能正常组也相似。未在由肝硬化或肝炎引起肝功能损害的患者中进行本品的研究。
  【毒理研究】
  非临床(体外)研究资料表明,吉非替尼具有抑制心脏动作电位复极化过程(如QT间期)的可能性。但由临床研究和上市后监测获得的安全性资料未提示吉非替尼对心脏有任何不良作用。致癌,致畸和生殖毒性 未进行吉非替尼的致癌研究。在基因突变分析(细菌和体外哺乳动物细胞)和裂解试验(体外哺乳动物细胞和体内大鼠微核试验)中,
  【吉非替尼未显示基因毒性作用】
  在交配前4周至妊娠7天期间给予吉非替尼20 mg/kg/天(按体表面积计为临床用药剂量的0.7倍),可对雌鼠排卵产生影响,导致黄体量下降。
  在器官发生期给予可产生母体毒性剂量的吉非替尼,在大鼠中可观察到成骨不全的发生率升高,在家兔中可观察到胎儿体重下降。在大鼠中未观察到畸形,仅在产生严重母体毒性的剂量下可在家兔中观察到畸形。
  当给予哺乳大鼠口服5 mg/kg吉非替尼(按体表面积计为临床用药剂量的0.2倍),吉非替尼及某些代谢产物广泛分泌入乳汁。
  在大鼠妊娠及分娩期间给于吉非替尼20 mg/kg/天(按体表面积计为临床用药剂量的0.7倍)的剂量,可减少幼鼠的存活率。
  【适应症】
  本品适用于治疗既往接受过化学治疗的局部晚期或转移性非小细胞肺癌(NSCLC)。既往化学治疗主要是指铂剂和多西紫杉醇治疗。
  对于化学治疗失败的局部晚期或转移性非小细胞肺癌患者的疗效,是基于客观反应率指标而确立的,尚无对照性的研究显示改善疾病相关症状和延长生存期方面的临床受益。本品用于非小细胞肺癌二线治疗的现有数据仅基于非对照的临床研究,尚待设计良好的对照的临床试验进一步证实。
  对于非小细胞肺癌的一线治疗,两个大型的随机对照临床试验结果表明 :基于铂剂的二联化疗方案合用本品治疗后未显示任何受益,因此,吉非替尼不适用于此种治疗。
  【用法用量】
  本品的成人推荐剂量为250 mg(1片),1日1次,口服,空腹或与食物同服。
  如果有吞咽困难,可将片剂分散于半杯饮用水中(非碳酸饮料),不得使用其他液体。将片剂丢入水中,无需压碎,搅拌至完全分散(约需10分钟),即刻饮下药液。以半杯水冲洗杯子,饮下。也可通过鼻-胃管给予该药液。
  无需因下述情况不同调整给药剂量 :年龄、体重、性别、种族,肾功能,因肝转移而引起的中至重度肝功能损害。
  剂量调整 :当患者出现不能耐受的腹泻或皮肤不良反应时,可通过短期暂停治疗(最多14天)解决,随后恢复每天250 mg的剂量。
  【不良反应】
  最常见(发生率20%以上)的药物不良反应为腹泻、皮疹、瘙痒、皮肤干燥和痤疮,一般见于服药后的第1个月内,通常是可逆性的。大约8%的患者出现严重的药物不良反应(CTC标准3或4级)。因不良反应停止治疗的患者仅有1%。
  各身体系统发生的不良事件按发生频率以降序排列(多见 :≥ (greater than or equal to) 10% ;常见 :≥ (greater than or equal to) 1%且<10% ;少见 :≥ (greater than or equal to) 0.1%且<1% ;罕见 :≥ (greater than or equal to) 0.01%且<0.1% ;极罕见 :<0.01%)。
  可出现的不良事件总结如下 :
  消化系统 :
  多见腹泻,主要为轻度(CTC1级),少有中度(CTC2级),个别报道严重伴脱水的腹泻(CTC3级)。
  常见恶心,主要为轻度(CTC1级) ;呕吐,主要为轻度或中度(CTC1或2级) ;厌食,轻度或中度(CTC1或2级) ;口腔粘膜炎,多为轻度(CTC1级) ;继发于腹泻,恶心,呕吐或厌食的脱水口腔溃疡。
  少见胰腺炎。
  皮肤及附件 :
  多见皮肤反应,主要为轻度或中度(CTC1或2级) ;脓疱性皮疹,在红斑的基础上有时伴皮肤干燥发痒。常见指甲异常。极罕见中毒性表皮坏死松懈症和多形红斑的报道,过敏反应,包括血管形水肿和荨麻疹。
  代谢和营养 :
  常见肝功能异常,主要包括无症状性的轻度或中度转氨酶升高(CTC1或2级)。 
  全身 :
  常见乏力,多为轻度(CTC1级) ;脱发 ;体重下降 ;外周性水肿。
  眼科 :
  常见结膜炎和睑炎,主要为轻度(CTC1级) ;弱视。
  少见可逆性角膜糜烂,有时伴睫毛生长异常。
  极罕见角膜脱落 ;眼部缺血/出血。
  血液和淋巴 :
  常见出血,如鼻衄和血尿。
  少见在服用华法林的一些患者中出现INR(International Normalised Ratio)升高及/或出血事件 ;出血性膀胱炎。
  呼吸 :
  常见呼吸困难。
  少见间质性肺病,常较严重(CTC3-4级。在全球进行的临床研究,扩大用药/同情用药,上市后使用中,约有158348名患者接受了本品治疗,在日本以外的地区,包括约92821名患者,间质性肺病总的发生率约为0.28%,在日本其发生率约为1.70%,包括约65527名患者,数据截至2004年6月2日),已有致死性病例的报道。
  【禁忌症】
  已知对该活性物质或该产品任一赋形剂有严重过敏反应者禁用。
  警告
  【注意事项】接受本品治疗的患者,偶尔观察到发生间质性肺病,患者通常出现急性的呼吸困难,伴有咳嗽,低热,呼吸道不适和动脉血氧不饱和。短期内该症状可发展得很严重,并报告有死亡。放射学检查常显示肺浸润或间质有毛玻璃样阴影。已观察到在出现该状况的患者中,伴有原发性肺纤维化/间质性肺炎/尘肺/放射性肺炎/药物诱导性肺炎的患者死亡率较高。
  处方医生应密切监测间质性肺病发生的迹象,如果患者呼吸道症状加重,应中断本品治疗,立即进行检查。当证实有间质性肺病时,应停止使用本品,并对患者进行相应的治疗。
  已观察到无症状性肝转氨酶升高。因此,建议定期检查肝功能。肝转氨酶轻中度升高的患者应慎用本品。如果肝转氨酶升高加重,应考虑停药。
  已报道在服用华法林的一些患者中出现INR(International Normalised Ratio,国际标准化比率)升高及/或出血事件。服用华法林的患者应定期监测凝血酶原时间或INR的改变。应告诫患者当以下情况加重时即刻就医 :
  任何眼部症状 ;
  严重或持续的腹泻,恶心,呕吐或厌食 ;
  这些症状应按临床需要进行处理。
  随机对照试验证明,在晚期非小细胞肺癌患者中将本品和以铂类为基础的标准两药联合化疗方案合用,不会有额外的益处。因此,本品应单用于既往接受过细胞毒性化疗的非小细胞肺癌患者。
  在一项对儿科患者进行本品和放疗治疗的I/II期临床研究中,33名入选患者(这些患者为新诊断出脑干神经胶质瘤或未完全切除的幕上恶性神经胶质瘤)中,发生4例(1例死亡)中枢神经系统出血。在一项单用本品治疗的临床研究中,一位患者有室管膜瘤的儿童也出现了中枢神经系统出血。接受本品治疗的成年非小细胞肺癌患者脑出血风险不太可能增高。
  对驾驶及操纵机器能力的影响 :在本品治疗期间,可出现乏力的症状,出现这些症状的患者在驾驶或操纵机器时应给予提醒。 
  【孕妇及哺乳期妇女用药 】
  妊娠期使用 :目前尚无本品用于妊娠期女性的资料。在器官发生期给予可产生母体毒性剂量的吉非替尼,在大鼠中可观察到成骨不全的发生率升高,在家兔中可观察到胎儿体重下降。在大鼠中未观察到畸形,仅在产生严重母体毒性的剂量下可在家兔中观察到畸形。在接受本品治疗期间,要劝告育龄女性避免妊娠。
  哺乳期使用 :在接受本品治疗期间,应建议哺乳母亲停止母乳喂养。
  目前尚无本品用于哺乳期女性的资料。尚不知吉非替尼或其代谢产物是否会分泌入人乳,但当给予哺乳大鼠口服5 mg/kg吉非替尼(按体表面积计为临床用药剂量的0.2倍),吉非替尼及某些代谢产物广泛分泌入乳汁。
  在大鼠妊娠及分娩期间给于吉非替尼20 mg/kg/天(按体表面积计为临床用药剂量的0.7倍)的剂量,可减少幼鼠的存活率。
  【儿童用药】
  目前尚无本品用于儿童或青春期患者安全性与疗效的资料,故不推荐使用。
  老年患者用药
  【药物相互作用】
  对人肝微粒体进行的体外试验证实,吉非替尼主要通过肝细胞色素P-450系的CYP 3A4代谢。所以吉非替尼可能会与诱导、抑制或为同一肝酶代谢的药物发生相互作用。动物研究表明吉非替尼很少有酶诱导作用,体外研究显示吉非替尼可有限地抑制CYP 2D6。
  以下列出了与吉非替尼产生或可能产生有临床意义地药物相互作用地药物或药物类别 :影响吉非替尼的药物 :已证明的相互作用 - 抑制CYP3A4的药物 :在健康志愿者中将吉非替尼与伊曲康唑(一种CYP 3A4抑制剂)合用,吉非替尼的平均AUC升高80%。由于药物不良反应与剂量及暴露量相关,该升高可能有临床意义。虽然未进行与其他CYP 3A4抑制剂相互作用的研究,但这一类药物如酮康唑,克霉唑,利托那韦同样可能抑制吉非替尼的代谢。 
  升高胃pH值的药物
  在健康志愿者中进行临床研究,表明与能明显持续升高胃pH至≥ (greater than or equal to) 5的药物合用,可使吉非替尼的平均AUC降低47%,这可能降低吉非替尼疗效。
  利福平 :在健康志愿者中将吉非替尼与利福平(已知的强CYP 3A4诱导剂)同时给药吉非替尼的平均AUC比单服时降低83%。
  理论上可能有相互作用的药物 - 其他CYP 3A4诱导剂 :诱导CYP 3A4活性的物质可增加吉非替尼的代谢并降低其血浆浓度。因此,与CYP 3A4诱导剂(如苯妥因、卡马西平、巴比妥类或圣约翰草)合用可降低疗效。
  吉非替尼对其他药物的作用 :已证明的相互作用 - 通过CYP 2D6代谢的药物 :在一项临床试验中,吉非替尼与美托洛尔(一种CYP 2D6酶底物)合用,使美托洛尔的暴露量升高35%。吉非替尼与其他由CYP 2D6代谢的药物同服,可能会升高后者的血药浓度。
  理论上可能有相互作用的药物 - 华法林 :虽然迄今尚未进行正规的药物相互作用研究,在一些服用华法林的患者中报告了INR增高和/或出血事件。服用华法林的患者应定期监测其凝血酶原时间或INR的改变。
  【药物过量】
  对于服用过量本品还没有专门的治疗方法,现在尚不知过量服用可能的症状。在I期临床试验中,少量患者服用到每天1000 mg的剂量,观察到一些不良反应的发生频率增加和严重程度升高,主要是腹泻和皮疹。对于药物过量引起的不良反应应给予对症处理,特别是严重腹泻应给予适当的治疗。

=== 英文介绍 ==

Iressa film-coated tablets
Iressa
【Composition】
Gefitinib Gefitinib
Manufacturers
AstraZeneca
Packaging / Formulation
Dose packaging / retail price image
Film-coated tablets 0.25g x 10 Pian
Storage / Valid: 30 ° C preservation period of 24 months following
【Properties】
Gefitinib chemical name: N-(3 - chloro -4 - fluorophenyl) -7 - methoxy -6 - (3 - morpholino propoxy) quinazoline -4 - amine, molecular formula : C22H24ClFN4O3, molecular weight: 446.90.
This medicine is a brown circular film-coated tablets; side printed with "IRESSA 250".
Pharmacological effects 【】
Gefitinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, the enzyme is usually expressed in the epithelial source of solid tumors.
Gefitinib inhibited xenograft in nude mice a wide range of human tumor cell growth, inhibit the angiogenesis. In vitro, can increase the human tumor cell lines derived from apoptosis, and inhibition of vascular endothelial growth factor and secretion of the invasion. In animal experiments or in vitro studies have confirmed that gefitinib Nicole improve chemotherapy, radiotherapy and hormone therapy anti-tumor activity.
Clinical study of two large-scale Phase II clinical study assessed the single-agent treatment of this product with locally advanced or metastatic non-small cell lung cancer (NSCLC) the effectiveness and safety. Physical status of patients with WHO score of 0-2, and must be past-oriented
Treatment failure:
IDEAL1 (Research 0016), past received one or two chemotherapy regimens, and at least one, including platinum-treated (median age 59.6 years [28-85 years]; n = 209).
IDEAL2 (Research 0039), past received two or more chemotherapy regimens, the regimen includes simultaneously or successively received platinum and multi-West purple blast that envy trouble? Median age was 61 years old [30-84 years]; n = 216).
Two studies of similar design, both double-blind, parallel group, multi-center, an assessment of two oral doses of gefitinib: 250 mg / day and 500 mg / day. Patients were randomly assigned in these two dose groups. The IDEAL1 main study endpoint was objective tumor response rate, secondary endpoint of the study of disease-related symptom improvement; in IDEAL2 main study endpoint was objective tumor response rate and disease-related symptom improvement rate (LCS were determined on a weekly basis).
IDEAL1 and efficacy findings are summarized in the table below IDEAL2 efficacy results. WHO does not consider the physical condition score (0,1, or 2) and prior number of chemotherapy treatments received, two studies to be an objective tumor response rate and disease-related symptom improvement rates were similar. The majority of patients treated tumor objective response occurred in the first 1 month, less objective response in some patients may be as late as the first 4 months of treatment took place.
a In the IDEAL1 trial, whether it is 250 mg or 500 mg, the objective response rate in Japanese patients than in non-Japanese patients with high (250 mg of 27.5%: 9.6%, 500 mg of 27.5%: 11.1%), unadjusted odds ratio (two groups combined) was 3.27, p = 0.002. In multivariate analysis, the adjusted gender, histology and physical position, this difference no longer statistically significant (adjusted odds ratio 2.13, p = 0.068).
b Based on symptom improvement to assess the population (250 mg, n = 67; 500 mg, n = 73).
+ Data cut-off time is continuing.
FACT-L scale measured the quality of life in patients with lung cancer.
NC not calculated.
PFS progression-free survival.
The security situation in the safety of this product in the two studies is similar to the incidence of adverse events and severity of dose-related (see "Adverse reactions").
Conclusion The clinical research data to prove with locally advanced or metastatic non-small cell lung cancer patients were treated with this product can achieve sustained objective response.
Clinical studies conducted in China in China, 5 Clinical Research Center conducted a clinical study to evaluate gefitinib tablets 250 mg / day in the past had received chemotherapy in non-small cell lung cancer patients with objective response rate.
A total of 159 subjects were taking at least a gefitinib tablets 250 mg, subjects demographic and disease characteristics are as follows:
Male 91 (57.2), female 68 (42.8);
Age mean (standard deviation) was 56.5 years (11.3), with a median of 57 years, range (minimum, maximum) at 31.0-84.0 years of age.
Age group of 18 to-60 age group, 91 people (57.2%) ,60-70 age group there were 46 people (28.9%), 70 + age group there were 22 people (13.8%).
Smoking status: non-smokers and 90 people (56.6%), have been smokers there were 37 people (23.3%), occasional smokers are three people (1.9%), 29 were regular smokers (18.2% ).
Histological types: squamous cell carcinoma in 29 people (18.2%), adenocarcinoma, 105 people (66%), undifferentiated carcinoma, 5 people (3.1%), large cell carcinoma, 1 person (0.6%), adeno-squamous carcinoma 7 (4.4%), bronchioloalveolar carcinoma (BAC) 12 people (7.5%).
Selected non-small cell lung cancer when the state: MO, 26 were locally advanced (16.4%), metastatic M1 133 people (83.6%).
WHO physical status: 0 minutes, 23 people (14.5%), 1 pm, 101 people (63.5%), 2 minutes, 34 people (21.4%), 3 minutes, 1 person (0.6%).
Before the selection of which received a chemotherapy treatment, 75 subjects (47.2%), 2 and 3 above (including 3) chemotherapy in the treatment of the subjects were 50 (31.4%), and 34 (21.4%). For the 159 subjects (intention to treat population set) conducted a validity analysis.
The following efficacy conclusions:
The objective response rate was 27.0%,
95% confidence interval 20.3-34.7%,
The median PFS was 97 days,
95% confidence interval of 67-120 days,
The median survival time was 11.1 months (survival data as of November 22, 2004).
In the different treatment subgroups in the objective response rate showed some differences (based on baseline characteristics of enrolled groups when the subjects of the objective response rate of the following table, a similar difference also seen in other international clinical research. Although the number of certain sub-group of the subjects are not enough, but gefitinib effectiveness of these subjects were consistent and expected.
Security gefitinib was well tolerated overall. Most adverse events were mild, no treatment. More than 10% of the subjects reported adverse events were rash (44.0%), skin itching (15.7%) and diarrhea (11.3%). Adverse events arising from the severity and frequency in other clinical studies, consistent with the observed.
Pharmacokinetics】
After intravenous administration, rapid clearance of gefitinib, widely distributed, with an average clearance half-life of 48 hours. Cancer patients after oral administration, absorbed more slowly, with an average terminal half-life of 41 hours. Gefitinib administration a day 2-8 times the accumulation occurs and, after 7-10 doses to achieve steady state after administration. Reach steady-state, 24-hour interval medication, plasma drug concentration ratio of the highest and lowest values generally maintained at between 2-3 times the range.
Absorption of this product after oral administration, gefitinib appeared in the plasma peak concentration 3-7 hours after administration. Cancer patients, the average absolute bioavailability of 59%. Eating on absorption of gefitinib was not obvious.
Distributed in the steady state of gefitinib, the average volume of distribution 1400 L, that are widely distributed in tissues. Plasma protein binding rate is about 90%. Gefitinib with serum albumin and α1-acid glycoprotein binding.
Metabolism in vitro data show that the participation of oxidative metabolism of gefitinib was mainly the P450 isoenzyme CYP 3A4.
In vitro studies have shown that gefitinib inhibited Nicole limited CYP 2D6 (see "Drug Interactions").
Gefitinib metabolism in the biotransformation of the three sites have been identified: N-propyl morpholine group metabolism, quinazoline methoxy substituents on the demethylation and halogenated phenyl group classes the role of oxidative defluorination.
Identified in human plasma to the major metabolite is the O-demethyl-Chigi non for Nepal. It stimulated cell growth inhibition of EGFR gefitinib than 14 times weaker, and therefore gefitinib clinical activity is unlikely to have significant effect.
Elimination of the total gefitinib plasma clearance rate of about 500 mL / min. Primarily through the fecal excretion, less than 4% through the kidneys in order to prototype and metabolites in the form of removal.
Special population groups Dynamics: In a population-based data analysis, not found the expected steady-state plasma trough concentration and patient's age, weight, gender, race, or creatinine clearance rate of any relationship between the.
Liver dysfunction was 31 in a solid tumor patients (normal liver function of them are 14, with moderate hepatic dysfunction were 13, due to severe liver metastasis of liver dysfunction appears there are four) to participate in clinical research against gefitinib pharmacokinetics evaluation carried out. Studies have shown that Japanese clothing 250 mg This product is 28 days, the time to reach steady-state, total plasma clearance rate and the steady-state value (Cmaxss, AUC24SS) in the group with normal liver function and moderate hepatic impairment was similar between groups. 4 due to severe liver metastasis occurs in patients with impaired liver function and liver function in the steady-state value of the normal group is also similar. Is not caused by liver cirrhosis or hepatitis in patients with impaired liver function studies carried out in this product.
【Toxicology】
Non-clinical (in vitro) study data indicate that gefitinib could inhibit the cardiac action potential repolarization process (eg, QT interval) possibilities. However, by clinical studies and post-marketing surveillance to obtain information on the safety of gefitinib not prompted any adverse effects on the heart. Carcinogenic, teratogenic and reproductive toxicity of gefitinib is not for the carcinogenicity study. In the gene mutation analysis (in vitro bacterial and mammalian cells) and lysis test (in vitro mammalian cells and in vivo micronucleus test in rats), the
【Gefitinib did not show genotoxicity】
4 weeks before mating, during pregnancy, to give seven days of gefitinib 20 mg / kg / day (according to body surface area calculated as 0.7 times the clinical dosage) can have an impact on the female ovulation, resulting in a decline in corpus luteum.
In the period of organogenesis caused maternal toxicity may be given doses of gefitinib, in rats can be observed in the incidence of osteogenesis imperfecta increased in rabbits can be observed in fetal weight loss. Is not observed in rats deformities, only a serious dose of maternal toxicity observed in rabbits deformity.
When given to lactating rats with oral administration of 5 mg / kg gefitinib (according to body surface area calculated as 0.2 times the clinical dose), gefitinib and certain metabolic products secreted into the milk of a wide range.
In rats to pregnancy and childbirth in the gefitinib 20 mg / kg / day (according to body surface area calculated as 0.7 times the clinical dose) the dose can reduce the survival rate of young rats.
【Indications】
This product is applicable in the treatment of past received chemotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). Past chemotherapy mainly refers to the platinum agent and docetaxel treatment.
For the chemical treatment failure in locally advanced or metastatic non-small cell lung cancer efficacy is based on objective response rate targets established, there is no controlled studies have shown improvement of disease-related symptoms and prolong survival in clinical benefit. This product is used for non-small cell lung cancer second-line treatment of existing data is only based on non-controlled clinical studies, yet to be well-designed controlled clinical trials further confirmed.
For non-small cell lung cancer first-line treatment, two large randomized controlled clinical trial results showed that: Based on the platinum agent combined two joint program of the FDA after treatment with chemotherapy did not show any benefit, therefore, gefitinib does not apply to such treatment .
【Usage consumption】
This product is recommended adult dose is 250 mg (1 films), 1, 1, oral, fasting or with food the same clothes.
If you have difficulty swallowing tablets can be dispersed in half a glass of drinking water (non-carbonated drinks) are not allowed to use other liquids. The tablet thrown into the water, without crushing, mixing until completely dispersed (about 10 minutes), immediately drink liquid. Half a cup of water to wash the cup, drink. Also available through the nose - giving the liquid gastric tube.
No situation is different because of the following dosage adjustments: age, weight, gender, race, renal function, due to liver metastasis caused by moderate to severe liver damage.
Dose adjustment: When the patients can not tolerate adverse effects of diarrhea or skin, it can be suspended by the short-term treatment (up to 14 days) to solve, followed by resumption of a daily dose of 250 mg.
Adverse reactions 【】
The most common (more than 20% incidence) of adverse drug reactions were diarrhea, rash, itching, dry skin and acne, generally found in the first post-medication within 1 month, usually reversible. About 8% of patients had serious adverse drug reactions (CTC criteria grade 3 or 4). Stopped because of adverse reactions in patients treated with only 1%.
The adverse events occurred in the body system, according to descending order of frequency (more common: ≥ (greater than or equal to) 10%; common: ≥ (greater than or equal to) 1% and "10%; rare: ≥ ( greater than or equal to) 0.1% and the "1%; rare: ≥ (greater than or equal to) 0.01% and the" 0.1%; extremely rare: "0.01%).
Adverse events, there may be summarized as follows:
Digestive System:
Prevalent diarrhea, mostly mild (CTC1 level), a rare moderate (CTC2 level), individual reports of serious diarrhea with dehydration (CTC3 level).
Commonly nausea, mainly mild (CTC1 level); vomiting, mainly mild or moderate (CTC1 or 2); loss of appetite, mild or moderate (CTC1 or 2); oral mucositis, mostly for mild (CTC1 level); secondary to diarrhea, nausea, vomiting or dehydration anorexia oral ulcers.
Rare pancreatitis.
Skin and accessories:
More common skin reactions, mainly mild or moderate (CTC1 or 2); pustular rash, erythema on the basis of the dry skin is sometimes accompanied by itching. Common nail abnormalities. Toxic epidermal necrosis in a very rare disease and erythema multiforme lax reports, allergic reactions, including blood vessel-shaped edema and urticaria.
Metabolism and nutrition:
Common abnormal liver function, mainly asymptomatic mild or moderately elevated aminotransferases (CTC1 or 2 level).
Body:
Common fatigue, mostly mild (CTC1 level); hair; weight loss; peripheral edema.
Eye:
Common conjunctivitis and blepharitis, mainly mild (CTC1 level); amblyopia.
Rare reversible corneal erosion, and sometimes accompanied by abnormal growth of eyelashes.
Rare corneal off; ocular ischemic / bleeding.
Blood and lymph:
Common bleeding, such as epistaxis, and hematuria.
Rarely taking warfarin for some patients, appear in INR (International Normalised Ratio) increase and / or bleeding events; hemorrhagic cystitis.
Respiratory:
Common difficulty breathing.
Rare interstitial lung disease, and often more serious (CTC3-4 Ji. In clinical studies conducted worldwide to expand the drug / sympathy medication, post-marketing use, there are about 158,348 patients receiving treatment of this product in Japan outside of areas, including about 92821 patients, the overall incidence of interstitial lung disease is about 0.28% in Japan, its occurrence rate is about 1.70%, including about 65527 patients, data as of June 2, 2004), has died of cases reported.
【Contraindications】
Known to the active substance or any excipients of the product of serious allergic reactions were banned.
Warning
【Note】 acceptance of the goods in patients treated with interstitial lung disease occurs occasionally observed, patients usually present with acute dyspnea, accompanied by cough, fever, respiratory discomfort and arterial oxygen unsaturation. The short-term symptoms can develop very serious, and to report the death. Radiological examination often shows interstitial pulmonary infiltration or a ground-glass shadows. Has been observed in patients that situation, associated with primary pulmonary fibrosis / interstitial pneumonia / pneumoconiosis / radiation pneumonitis / pneumonia in patients with drug-induced higher mortality rate.
Prescribing doctor should closely monitor the signs of interstitial lung disease occur, if the increase in patients with respiratory symptoms, the treatment should be interrupted in this product immediately be checked. When confirmed interstitial lung disease, they should stop so that the FDA, and patients treated accordingly.
Have been observed in asymptomatic elevated liver transaminase. Therefore, we recommend regular check liver function. Elevated liver transaminases in patients with mild to moderate the FDA should be cautious. If elevated liver transaminase increase, you should consider stopping.
Have been reported taking warfarin for some patients, appear in INR (International Normalised Ratio, the international normalized ratio) increased and / or bleeding events. Patients taking warfarin should be regular monitoring of prothrombin time or INR change. Patients should be warned immediately if the following conditions increase the time for medical treatment:
Any eye symptoms;
Severe or persistent diarrhea, nausea, vomiting or anorexia;
These symptoms should be clinical needs for processing.
Randomized controlled trials shows that in patients with advanced non-small cell lung cancer will be the goods and to the standard platinum-based two-drug combination chemotherapy combination, there will be no additional benefits. Therefore, the product should be single for the past received cytotoxic chemotherapy for patients with non-small cell lung cancer.
In a study of pediatric patients and radiotherapy treatment of this product I / II clinical study, 33 selected patients (these patients for the newly diagnosed brain stem glioma or a complete resection of supratentorial malignant glioma ), the occurrence of 4 cases (1 fatal) central nervous system bleeding. In a single treatment of the FDA clinical studies, patients have an ependymoma of the children also appeared in the central nervous system bleeding. Acceptance of the product treatment of adult patients with non-small cell lung cancer is unlikely to increase the risk of cerebral hemorrhage.
Pairs of driving and the ability to manipulate the impact of the machine: in the product during the treatment, there may be weakness of the symptoms, patients with these symptoms occur while driving or manipulation of the machine should be given to remind.
【Pregnant and lactating women drug】
Pregnancy Use: This product is currently no information for women during pregnancy. In the period of organogenesis caused maternal toxicity may be given doses of gefitinib, in rats can be observed in the incidence of osteogenesis imperfecta increased in rabbits can be observed in fetal weight loss. Is not observed in rats deformities, only a serious dose of maternal toxicity observed in rabbits deformity. In an interview with this product during the treatment, to advise women of childbearing age to avoid pregnancy.
Lactation use: In an interview with this product during the treatment should be recommended for nursing mothers to stop breastfeeding.
This product is currently no information on breast-feeding women. Gefitinib is not known, or whether the secretion of its metabolites into human milk, but when given to lactating rats with oral administration of 5 mg / kg gefitinib (according to body surface area calculated as 0.2 times the clinical dose), gefitinib Nigeria and certain metabolic products secreted into the milk of a wide range.
In rats to pregnancy and childbirth in the gefitinib 20 mg / kg / day (according to body surface area calculated as 0.7 times the clinical dose) the dose can reduce the survival rate of young rats.
Pediatric Use
This product is not currently available for the child or adolescent patient safety and efficacy information, it is not recommended.
Medication in elderly patients
【Drug interactions】
Carried out on human liver microsomes in vitro experiments showed that gefitinib primarily by the liver cytochrome P-450 Department of CYP 3A4 metabolism. Therefore, gefitinib may be induced or inhibited drug metabolism in the same liver enzymes interact. Animal studies in Table gefitinib little enzyme induction, in vitro studies have shown that gefitinib inhibited Nicole limited CYP 2D6.
Following is a list with gefitinib or may arise clinically meaningful drug-drug interactions to drug or class of drugs: the impact of drug gefitinib: the interaction has been proven - inhibit CYP3A4 drug: in healthy volunteers to gefitinib and itraconazole (a CYP 3A4 inhibitor) combination of gefitinib, the average AUC increased 80%. Due to adverse drug reactions associated with the dose and exposure, the increase may have clinical significance. Although it is not carried out with the other CYP 3A4 inhibitors interaction research, but this type of drugs such as ketoconazole, clotrimazole, ritonavir also may inhibit the metabolism of gefitinib.
Elevated gastric pH, the drug
In healthy volunteers in clinical studies and indicates a marked and continuous increase in gastric pH can be between ≥ (greater than or equal to) 5 of the drug combination will enable the average gefitinib AUC decrease 47%, which may reduce gefitinib Imatinib effect.
Rifampicin: In healthy volunteers will gefitinib with rifampicin (a known strong CYP 3A4 inducer) at the same time administration of gefitinib, the average AUC lower than single-serving, when 83%.
In theory there may be interactions of drugs - other CYP 3A4 inducers: induced CYP 3A4 active substances can increase the metabolism of gefitinib and decrease its plasma concentrations. Thus, CYP 3A4 inducers (eg phenytoin, carbamazepine, barbiturates, or St. John's Wort) may reduce the efficacy of combination.
Gefitinib on the role of other drugs: the interaction has been proven - through the CYP 2D6 metabolism of drugs: In a clinical trial, gefitinib with metoprolol (a CYP 2D6 enzyme substrate) combination, exposure to metoprolol increased 35%. Gefitinib and other drugs by CYP 2D6 metabolism in the same clothes, you may increase plasma concentrations of the latter.
In theory there may be interactions of drugs - warfarin: Although the date has not yet been formal drug interaction studies, in some patients taking warfarin, reported increased INR and / or bleeding events. Patients taking warfarin should regularly monitor the prothrombin time or INR change.
Overdosage
An overdose of this product for no special treatment, and now I do not know yet the possible symptoms of overdose. In Phase I clinical trials, a small amount of patients taking 1000 mg per day dose, a number of adverse reactions were observed to increase the frequency and severity increased, primarily diarrhea and rash. For the adverse reactions caused by drug overdose symptomatic treatment should be given, especially severe diarrhea should be given appropriate treatment.

Tags: 易瑞沙(IRESSA)

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更新日期: 2014-06-29 11:52
作者: : mcyclub
修订: 1.9

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