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123-5-第五节 来氟米特的不良反应及处理
来氟米特的主要不良反应有:腹泻、痰痒、皮疹、一过性转氨酶升高和白细胞下降、可逆性脱发等。一般为轻度和中度,严重的不良反应少见 。
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3 d& z* R* A- p! V1 a 在国内多中心治疗类风湿关节炎的临床试验中,来氟米特的不良反应、胃肠道反应、重度不良反应发生率和不良反应撤药率分别为16.8%,5.2%,0.7%和 0.3%,均显著低于MTX组 28.2%,21.1%,6.1%和6.1% (P<0.01)。来氟米特所产生的不良反应一般是可逆的,其对白细胞和转氨酶的影响呈一过性,大部分患者在继续用药过程中恢复正常,部分患者在改变剂量或中断一定的时间后继续服用过程中恢复正常。国外 Strand等人报道来氟米特组、MTX组和安慰剂组分别有1.1%,2.7%和1.7%发生严重不良事件。国外另一组大样本随机、双盲、对照临床试验结果显示:在2年的观察期间,MTX组有21例由于肝酶升高退出,来氟米特组有8例退出;同时,MTX组有2例患者死亡,且与药物有关,而来氟米特组无上述情况。在用来氟米特治疗的76,000多例患者中,16例发生可能与药物有关的全血细胞减少,9例严重皮疹,无1例死亡。
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; ~0 [. y/ P+ W 文献证实来氟米特长期用药安全可靠。Scott等人报道采用来氟米特治疗2年,患者的耐受性良好,腹泻、恶心、脱发的发生比例更少。国内劳志英报道,在3年的治疗观察期间,先后发生不良反应的比例为19%,且不良反应均在继续治疗过程中或者给予对症处理后好转。国外治疗类风湿关节炎的5年随访资料表明,在治疗过程中来氟米特并没有出现新的不良反应。目前已有的动物实验及临床资料还没有发现长期使用来氟米特导致肿瘤发生率增高的情况。随着来氟米特用药剂量的增加,副反应的发生也会有所增加。来氟米特用来治疗系统性红斑狼疮的剂量常大于类风湿关节炎。国外两组小样本临床研究中,因不良反应停药分别为3例/18例(2例腹泻,1例皮疹)和4例/20例(2例腹泻,1例皮疹、1例肝功能异常)。国内张凤山等采用激素和来氟米特治疗31例狼疮肾炎,有1例因严重的胃肠道反应退出治疗。
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r1 I" d- h, y1 f. b' w# v& x 在来氟米特的用药过程中,少数病人可出现一过性的ALT升高和白细胞下降,因此,来氟米特用药前及用药后应每月检查肝功能和血常规,如果比较稳定,检测时间间隔视患者具体情况而定。ALT升高的处理原则为:如果ALT升高在正常值的2倍以内,继续观察;ALT升高在正常值的2一3倍,减半量服用,继续观察;ALT继续升高或仍然维持在 80一120U/L之间,应中断治疗;ALT升高超过正常值的3倍,应停药观察。停药恢复正常后可继续用药,同时加强护肝治疗及随访,多数患者ALT不会再次升高。如果服药期间出现白细胞下降,处理原则如下:白细胞下降不低于3.0 x 1护几,继续服药观察;白细胞下降在((2.0--3.0) x 109/L之间,减半量观察,多数患者可以恢复正常,复查白细胞仍低于3.0 x 109/L,中断治疗;白细胞下降低于2.0 x 109/L,中断治疗。9 l( R5 v; o, V( }2 K5 o, s% I
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来氟米特禁用于妊娠或即将妊娠的妇女,因为动物试验发现它具有致畸作用。对于绝经前的妇女,在服用来氟米特前应避免妊娠,并做好安全的避孕措施。由于药物有较长的半衰期,其潜在的致畸作用可能在停药后继续存在,因此对于服药的年轻妇女更应引起注意。A771726的血浆水平低于0.02tg/ml时其危险性极小,因此,对于即将妊娠的妇女,应立即停用该药,并服用消胆胺8g,每日3次,坚持用药11天,以消除血浆中的药物,并使A771726的血浆浓度低于0.02f.g/ml,否则需增加消胆胺的剂量。虽然目前无足够的临床资料证实男性服用来氟米特与胎儿致畸的相关性,但为了避免可能的毒性作用,男性也应在相应时期停止应用来氟米特,同时加用消胆胺治疗。3 Y/ ?6 @) U( ~' t9 r& U, {
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