特雷克斯（口服）

Trexall说明

Trexall®（甲氨蝶呤片剂USP）（以前呤）是在一定的肿瘤性疾病，严重的牛皮癣，成人和类风湿性关节炎的治疗中使用的抗代谢物。化学上的氨甲蝶呤，USP是N- [4 [[（（2,4-二氨基-6-哌啶基）甲基]甲基-氨基]苯甲酰基] -L-谷氨酸。结构式为：

C 20 H 22 N 8 O 5分子量：454.45

口服的Trexall（甲氨蝶呤片USP）有5毫克，7.5毫克，10毫克和15毫克浓度。

每片含有甲氨蝶呤钠，其含量等于标记的甲氨蝶呤，USP，并含有以下非活性成分：无水乳糖，交聚维酮，羟丙基甲基纤维素，硬脂酸镁，微晶纤维素，聚乙二醇，聚山梨酸酯80，预糊化玉米淀粉，钠一水碳酸盐，滑石和二氧化钛。

5毫克还含有：D＆C黄色。 10铝色湖水，FD＆C蓝色。 1铝色淀和FD＆C黄色编号6铝湖。

7.5毫克还包含：FD＆C蓝色1号铝色淀。

10毫克还包含：FD＆C红色编号。 40铝湖。

15毫克还包含：FD＆C蓝色。 2铝色湖面和FD＆C红色编号40铝湖。

Trexall-临床药理学

甲氨蝶呤抑制二氢叶酸还原酶。必须先用这种酶将二氢叶酸还原为四氢叶酸，然后才能将其用作嘌呤核苷酸和胸苷酸合成中的一个碳原子的载体。因此，甲氨蝶呤会干扰DNA的合成，修复和细胞复制。活跃增殖的组织，例如恶性细胞，骨髓，胎儿细胞，颊和肠粘膜，以及膀胱细胞，通常对甲氨蝶呤的这种作用更敏感。当恶性组织中的细胞增殖大于大多数正常组织时，甲氨蝶呤可能会损害恶性肿瘤的生长而不会对正常组织造成不可逆转的损害。

类风湿关节炎的作用机理尚不清楚。它可能会影响免疫功能。两项报道描述了甲氨蝶呤在体外对刺激的单核细胞对DNA前体摄取的抑制作用，另一篇报道在动物多关节炎中通过甲氨蝶呤对脾细胞低反应性和抑制IL 2产生的部分校正。但是，其他实验室无法证明类似的效果。甲氨蝶呤对免疫活性的影响及其与类风湿免疫发病机制的关系的澄清尚待进一步研究。

在类风湿关节炎患者中，甲氨蝶呤对关节肿胀和压痛的作用最早可在3至6周内见到。尽管甲氨蝶呤可明显改善炎症症状（疼痛，肿胀，僵硬），但尚无证据表明其可引起类风湿关节炎的缓解，也未显示出对骨侵蚀和其他放射学改变（导致关节使用障碍，功能障碍，和畸形。

对于风湿性关节炎患者，甲氨蝶呤的大多数研究都是相对短期的（3到6个月）。长期研究的有限数据表明，持续治疗至少可维持最初的临床改善两年。

在牛皮癣中，皮肤中上皮细胞的产生速率大大超过正常皮肤。增殖速率的这种差异是使用甲氨蝶呤控制银屑病过程的基础。

在一项为期6个月，双盲，安慰剂对照的试验中，对非风湿性关节炎的127名小儿类风湿性关节炎（JRA）患者（平均年龄10.1岁；年龄2.5至18岁，平均病程5.1年）进行了研究根据医师的整体评估或患者的综合评估，与安慰剂相比，每周口服10 mg / m 2的类固醇抗炎药（NSAIDs）和/或泼尼松，甲氨蝶呤提供了显着的临床改善（25严重程度评分降低％，并且父母和医生对疾病活动的总体评估得到了改善。）该试验中三分之二以上的患者患有多关节病程JRA，在该亚组中，使用10种药物治疗的患者在数值上最大的反应mg / m 2 /周甲氨蝶呤。其余绝大多数患者患有系统性病程JRA。所有患者对NSAIDs无反应；大约三分之一使用低剂量皮质类固醇。在该试验中，每周甲氨蝶呤剂量为5 mg / m 2并不比安慰剂有效。

药代动力学

在成年人中，口服吸收似乎是剂量依赖性的。一到两个小时内达到血清峰值水平。在30 mg / m 2或更小的剂量下，甲氨蝶呤通常被良好吸收，平均生物利用度约为60％。大于80 mg / m 2的剂量吸收明显更少，这可能是由于饱和作用所致。

在白血病小儿患者中，甲氨蝶呤的口服吸收也似乎是剂量依赖性的，据报道其变化很大（23％至95％）。据报道，最高和最低峰值水平之间的差异为20倍（20 mg / m 2剂量后，C max ：0.11至2.3微摩尔）。峰值浓度的时间（T max ：15 mg / m 2剂量后0.67至4小时）和吸收剂量的分数在时间上也存在明显的个体差异。据报道，大于40 mg / m 2的剂量吸收明显小于较低剂量的吸收。食物被证明会延迟吸收并降低峰值浓度。甲氨蝶呤通常从肠胃外注射途径完全吸收。肌肉注射后，峰值血清浓度在30至60分钟内出现。与白血病小儿患者一样，已报道小儿JRA患者甲氨蝶呤的血浆浓度存在很大的个体差异。在患有JRA的小儿患者中以6.4至11.2 mg / m 2 /周的剂量口服甲氨蝶呤后，在1小时时的平均血清浓度为0.59微摩尔（范围0.03至1.40），在1小时时为0.44微摩尔（范围0.01至1.00）。 2小时，在3小时后为0.29微摩尔（范围0.06至0.58）。在接受甲氨蝶呤治疗的急性淋巴细胞白血病（6.3至30 mg / m 2 ）或JRA（3.75至26.2 mg / m 2 ）的儿科患者中，终末半衰期据报道为0.7至5.8小时或0.9至0.9小时。分别为2.3小时。

静脉内给药后，初始分配体积约为0.18 L / kg（体重的18％），稳态分配体积约为0.4至0.8 L / kg（体重的40％至80％）。甲氨蝶呤与减少的叶酸竞争通过单个载体介导的主动转运过程跨细胞膜的主动转运。在血清浓度大于100微摩尔时，被动扩散成为可实现有效细胞内浓度的主要途径。血清中的甲氨蝶呤约为50％的蛋白质结合。实验室研究表明，它可能被包括磺酰胺，水杨酸酯，四环素，氯霉素和苯妥英在内的各种化合物取代血浆白蛋白。

口服或胃肠外给药时，甲氨蝶呤不能以治疗量穿透血脑脊液屏障。鞘内给药可达到药物的高CSF浓度。

在狗中，口服给药后发炎关节的滑液浓度高于未发炎关节。尽管水杨酸盐不会干扰这种渗透，但以前的泼尼松治疗可将发炎关节的渗透降低到正常关节的水平。

吸收后，氨甲蝶呤经过肝脏和细胞内代谢为多谷氨酸形式，可通过水解酶转化回甲氨蝶呤。这些聚谷氨酸盐充当二氢叶酸还原酶和胸苷酸合成酶的抑制剂。少量氨甲蝶呤多谷氨酸盐可能会长时间保留在组织中。这些活性代谢物的保留和延长的药物作用在不同的细胞，组织和肿瘤之间有所不同。通常规定的剂量可能会发生少量新陈代谢为7-羟基甲氨蝶呤。在成骨肉瘤中使用高剂量时，这种代谢产物的积累可能变得很重要。 7-羟基甲氨蝶呤的水溶性比母体化合物低3-5倍。口服后，甲氨蝶呤被肠道菌群部分代谢。

对于接受牛皮癣，类风湿性关节炎或低剂量抗肿瘤治疗（小于30 mg / m 2 ）治疗的患者，甲氨蝶呤的终末半衰期约为3至10小时。对于接受高剂量甲氨蝶呤的患者，终末半衰期为8至15小时。

肾脏排泄是消除的主要途径，并且取决于剂量和给药途径。静脉内给药后，在24小时内尿中80％至90％的剂量不变地排泄。胆汁排泄量有限，等于给药剂量的10％或更少。已经提出甲氨蝶呤的肠肝再循环。

通过肾小球滤过和活跃的肾小管分泌物发生肾脏排泄。在银屑病患者中已观察到剂量在7.5至30 mg之间，由于肾小管重吸收饱和而导致的非线性消除。肾功能受损以及同时使用药物（例如也会通过肾小管分泌的弱有机酸）会明显增加甲氨蝶呤的血清水平。甲氨蝶呤清除率与内源性肌酐清除率之间存在极好的相关性。

甲氨蝶呤清除率变化很大，通常在高剂量时降低。延迟的药物清除被确定为引起甲氨蝶呤毒性的主要因素之一。据推测，甲氨蝶呤对正常组织的毒性更多地取决于药物暴露的持续时间，而不是所达到的峰值水平。当患者由于肾功能受损，第三次积液或其他原因而延迟药物清除时，甲氨蝶呤的血清浓度可能会长期保持升高。

在氨甲蝶呤血浆消除的最后阶段，通过施用亚叶酸钙可降低高剂量方案或延迟排泄产生毒性的可能性。甲氨蝶呤血清浓度的药代动力学监测可能有助于确定那些面临甲氨蝶呤毒性高风险的患者，并有助于适当调整亚叶酸钙剂量。下文《剂量和管理》中提供了监测血清甲氨蝶呤水平和调整亚叶酸剂量以降低甲氨蝶呤毒性风险的指南。

在人类母乳中检测到了甲氨蝶呤。达到的最高母乳与血浆浓度之比为0.08：1。

Trexall的适应症和用法

肿瘤疾病

甲氨蝶呤适用于治疗妊娠绒毛膜癌，脉络膜腺瘤和葡萄胎。

甲氨蝶呤与其他化学治疗剂联合用于维持治疗。

甲氨蝶呤可单独使用或与其他抗癌药联合使用，用于治疗乳腺癌，头颈部的表皮样癌，晚期真菌病真菌病（皮肤T细胞淋巴瘤）和肺癌，尤其是鳞状细胞和小细胞类型。甲氨蝶呤还可以与其他化疗药物联合用于晚期非霍奇金淋巴瘤的治疗。

银屑病

甲氨蝶呤适用于对严重，顽固，致残的牛皮癣的症状控制，对其他形式的治疗没有足够的反应，但仅在通过活检和/或经皮肤科咨询确定诊断后才可使用。重要的是要确保银屑病“耀斑”不是由于未诊断的伴随疾病影响免疫反应而引起的。

类风湿关节炎，包括多关节课程类风湿关节炎

甲氨蝶呤适用于患有严重，活动性，类风湿性关节炎（ACR标准）的某些成年人或对活动性多关节病，幼年类风湿性关节炎有积极治疗的儿童，这些儿童对适当的下列药物的治疗反应不足或不能耐受一线治疗，包括全剂量非甾体类抗炎药（NSAIDs）。

阿司匹林，非甾体抗炎药和/或低剂量类固醇可能会继续使用，尽管尚未充分探讨伴随使用水杨酸酯等非甾体抗炎药增加毒性的可能性。 （请参阅预防措施，药物相互作用。）对甲氨蝶呤有反应的患者，类固醇可能会逐渐减少。甲氨蝶呤与金，青霉素，羟氯喹，柳氮磺吡啶或细胞毒剂并用尚无研究，可能增加不良反应的发生率。应当继续进行休息和理疗。

禁忌症

给孕妇服用甲氨蝶呤会导致胎儿死亡或致畸作用。牛皮癣或类风湿性关节炎孕妇禁用甲氨蝶呤，只有当潜在益处超过对胎儿的风险时，才应使用甲氨蝶呤治疗肿瘤疾病。具有潜在生育能力的妇女在怀孕被排除之前，不应该开始接受甲氨蝶呤治疗；如果她们在接受治疗时怀孕，则应该对胎儿的严重危险进行充分咨询（请参阅注意事项）。如果任何一方接受甲氨蝶呤，应避免怀孕；对于男性患者，在治疗后以及至少三个月内；对于女性患者，在治疗后以及至少一个排卵周期。 （请参阅盒装警告。）

由于甲氨蝶呤在母乳喂养婴儿中可能产生严重的不良反应，因此在哺乳母亲中禁用。

患有酒精中毒，酒精性肝病或其他慢性肝病的牛皮癣或类风湿性关节炎患者不应接受甲氨蝶呤治疗。

银屑病或类风湿关节炎的患者，如果有明显的或实验室缺乏免疫缺陷综合症的证据，则不应接受甲氨蝶呤治疗。

患有银屑病或类风湿性关节炎的患者，曾患有血液异常，例如骨髓发育不全，白细胞减少症，血小板减少症或严重贫血，不应接受甲氨蝶呤治疗。

对甲氨蝶呤过敏的患者不应服用该药。

警告-请参阅带框警告。

甲氨蝶呤制剂和含有防腐剂的稀释剂不得用于鞘内或高剂量甲氨蝶呤治疗。

预防措施

一般

甲氨蝶呤具有潜在的严重毒性。 （见盒装警告。）毒性作用的频率和严重性可能与剂量或给药频率有关，但在所有剂量下均可见。由于它们可能在治疗期间的任何时间发生，因此有必要密切关注甲氨蝶呤的患者。如果及早发现，大多数不良反应是可逆的。当确实发生此类反应时，应减少药物剂量或停药，并应采取适当的纠正措施。如有必要，这可能包括使用亚叶酸钙和/或高通量透析器进行急性，间歇性血液透析。 （请参阅过量） 。如果重新使用甲氨蝶呤治疗，应谨慎进行，并充分考虑对药物的进一步需求，并提高对可能的毒性复发的警觉性。

甲氨蝶呤的临床药理学尚未在老年个体中得到很好的研究。由于该人群的肝和肾功能下降以及叶酸储备减少，因此应考虑使用相对较低的剂量，并应密切监测这些患者的中毒早期迹象。

给患者的信息

应告知患者毒性的早期体征和症状，是否需要立即就医，以及是否需要密切随访，包括定期实验室检查以监测毒性。

医师和药剂师都应向患者强调，类风湿性关节炎和牛皮癣应每周服用推荐剂量，并且错误使用每日推荐剂量会导致致命的毒性。应鼓励患者阅读剂量包中的患者说明表。不得以PRN为基础书写或重新填写处方。

应告知患者使用甲氨蝶呤的潜在益处和风险。服用甲氨蝶呤的男性和女性患者均应讨论影响生殖的风险。

实验室测试

应密切监测接受甲氨蝶呤治疗的患者，以便迅速发现毒性作用。基线评估应包括全血细胞计数（包括差异和血小板计数），肝酶，肾功能检查和胸部X光检查。在类风湿关节炎和牛皮癣的治疗过程中，建议监测以下参数：至少每月一次血液学检查，每1至2个月检查一次肾功能和肝功能。通常在抗肿瘤治疗期间需要进行更频繁的监测。在初始剂量或更改剂量期间，或在甲氨蝶呤血液水平升高（例如，脱水）的风险增加期间，也可能需要更频繁地监测。

甲氨蝶呤给药后经常观察到短暂性肝功能检查异常，通常不会引起甲氨蝶呤疗法的改变。持续的肝功能检查异常和/或血清白蛋白下降可能是严重肝毒性的指标，需要评估。 （请参阅预防措施，器官系统毒性，肝脏。）

对于牛皮癣患者，尚未建立肝功能异常检查与肝纤维化或肝硬化之间的关系。在类风湿关节炎人群中，肝功能检查的持续异常可能先于出现纤维化或肝硬化。

如果怀疑是甲氨蝶呤引起的肺部疾病，特别是如果有基线测量值，肺功能检查可能会有用。

药物相互作用

据报道，某些非甾体类抗炎药与高剂量甲氨蝶呤治疗同时给药会升高并延长血清甲氨蝶呤水平，导致严重的血液和胃肠道毒性死亡。

当将NSAIDs和水杨酸酯与较低剂量的甲氨蝶呤同时给药时应谨慎。据报道，这些药物可减少动物模型中氨甲蝶呤的肾小管分泌，并可能增强其毒性。

尽管存在潜在的相互作用，但在类风湿性关节炎患者中进行甲氨蝶呤的研究通常包括同时使用非甾体抗炎药的恒定剂量方案，而没有明显的问题。然而，应该理解的是，类风湿性关节炎所用的剂量（7.5至20 mg / wk）比牛皮癣所用的剂量要低一些，较大的剂量可能导致意想不到的毒性。

甲氨蝶呤与血清白蛋白部分结合，并且由于某些药物（例如水杨酸酯，苯基丁,、苯妥英钠和磺酰胺）的取代而可能增加毒性。丙磺舒也减少了肾小管的运输。甲氨蝶呤与该药的使用应仔细监测。

口服抗生素，例如四环素，氯霉素和不可吸收的广谱抗生素，可能会通过抑制肠道菌群并抑制细菌的药物代谢，从而降低甲氨蝶呤的肠道吸收或干扰肠肝循环。

青霉素可能会降低甲氨蝶呤的肾脏清除率；甲氨蝶呤已观察到甲氨蝶呤的血清浓度升高，同时伴有血液学和胃肠道毒性。甲氨蝶呤与青霉素的使用应受到认真监测。

甲氨蝶呤与其他肝毒性药物合用时，肝毒性增加的潜力尚未得到评估。然而，在这种情况下已经报道了肝毒性。因此，应密切监测接受甲氨蝶呤和其他潜在肝毒素（例如硫唑嘌呤，类维生素A，磺胺a嗪）伴随治疗的患者的肝毒性风险增加。

甲氨蝶呤可能会降低茶碱的清除率；与氨甲蝶呤同时使用时，应监测茶碱水平。

叶酸补充甲氨蝶呤可以减轻某些副作用，例如口疮。

甲氨蝶呤/磺胺甲恶唑几乎没有报道可能会通过累加抗叶酸作用增加接受甲氨蝶呤患者的骨髓抑制。

致癌，诱变和生育能力受损

没有关于甲氨蝶呤发生肿瘤的风险的受控人类数据。甲氨蝶呤已在许多动物研究中评估了潜在的致癌性，但结论尚无定论。尽管有证据表明甲氨蝶呤会对动物体细胞和人骨髓细胞造成染色体损伤，但临床意义仍然不确定。口服小剂量甲氨蝶呤的患者中有非霍奇金淋巴瘤和其他肿瘤的报道。然而，在使用小剂量口服甲氨蝶呤治疗期间，有恶性淋巴瘤发生的情况，这些症状在停用甲氨蝶呤后已完全消退，而无需积极的抗淋巴瘤治疗。在单独使用甲氨蝶呤或与其他药物联合使用之前，应权衡潜在的风险，尤其是在儿科患者或年轻人中。甲氨蝶呤在人类中引起胚胎毒性，流产和胎儿缺陷。据报道，在停止治疗期间和停止治疗后的短时间内，会导致人类的生育能力，少精子症和月经功能障碍。

怀孕

牛皮癣和类风湿关节炎：甲氨蝶呤属于妊娠X类。请参见禁忌症。

护理母亲

见禁忌症。

儿科用

小儿患者的安全性和有效性仅在癌症化疗和多关节型青少年类风湿关节炎中得到证实。

已发表的评估甲氨蝶呤在患有JRA的儿童和青少年（即2至16岁的患者）中使用的临床研究表明，其安全性与成年人类风湿关节炎中观察到的安全性相当。 （请参阅临床药理学，不良反应和用法用量）。

老人用

甲氨蝶呤的临床研究未包括足够多的65岁及以上的受试者，以确定他们是否与年轻受试者反应不同。通常，对于老年患者，应谨慎选择剂量，以反映该人群中肝和肾功能下降，叶酸储备减少，伴随疾病或其他药物治疗（即干扰肾功能，甲氨蝶呤或叶酸代谢）的发生频率较高（请参阅预防措施，药物相互作用）。由于肾功能下降可能与不良事件增加有关，并且血清肌酐测量值可能会高估老年人的肾功能，因此应考虑使用更准确的方法（即肌酸清除率）。血清甲氨蝶呤水平可能也有帮助。应密切监测老年患者的肝，骨髓和肾毒性的早期迹象。在长期使用的情况下，补充叶酸可能会降低某些毒性。上市后的经验表明，随着年龄的增长，骨髓抑制，血小板减少和肺炎的发生可能会增加。请参阅盒装警告和不良反应。

器官系统毒性

如果发生呕吐，腹泻或口腔炎，可能导致脱水，则应停用甲氨蝶呤直至恢复。在存在消化性溃疡疾病或溃疡性结肠炎的情况下，应格外小心使用甲氨蝶呤。

甲氨蝶呤可以抑制造血作用并引起贫血，再生障碍性贫血，全血细胞减少，白细胞减少，中性粒细胞减少和/或血小板减少。对于有恶性肿瘤和已有造血功能障碍的患者，应谨慎使用该药物（如果有的话）。在类风湿性关节炎（n = 128）的对照临床试验中，2例患者出现白细胞减少（WBC <3000 / mm 3 ），6例患者出现血小板减少（血小板<100,000 / mm 3 ），2例发生全血细胞减少。

在牛皮癣和类风湿关节炎中，如果血细胞计数明显下降，应立即停用甲氨蝶呤。在赘生性疾病的治疗中，只有在潜在的获益有可能导致严重的骨髓抑制的风险时，才应继续使用甲氨蝶呤。严重粒细胞减少和发烧的患者应立即进行评估，通常需要肠胃外广谱抗生素治疗。

甲氨蝶呤具有潜在的急性（转氨酶升高）和慢性（纤维化和肝硬化）肝毒性。慢性毒性可能致命。它通常是在长时间使用（通常为两年或更长时间）后以及总剂量至少为1.5克之后发生的。在银屑病患者的研究中，肝毒性似乎是总累积剂量的函数，并且似乎因酗酒，肥胖，糖尿病和高龄而增强。尚未确定准确的发病率；病变的进展率和可逆性尚不清楚。如果存在先前存在的肝损害或肝功能受损，则应特别注意。

在牛皮癣中，应在给药前定期进行肝功能检查，包括血清白蛋白检查，但面对纤维化或肝硬化时通常是正常的。这些病变仅可通过活检来检测。通常的建议是在1）治疗前或治疗开始后不久（2至4个月），2）1.5克总累积剂量和3）每增加1.0至1.5克进行肝活检。中度纤维化或任何肝硬化通常会导致药物停用；轻度纤维化通常建议在6个月内再次进行活检。较轻的组织学发现（例如脂肪变化和低度门脉炎症）是相对常见的预治疗。尽管这些轻微变化通常不是避免或终止甲氨蝶呤治疗的原因，但应谨慎使用该药物。

在类风湿关节炎中，首次使用甲氨蝶呤的年龄和治疗时间已被报告为肝毒性的危险因素。类风湿性关节炎中可能存在与牛皮癣中观察到的危险因素相似的其他危险因素，但迄今为止尚未得到证实。在该人群中，肝功能检查的持续异常可能先于出现纤维化或肝硬化。据报道，在治疗前和治疗期间（累计剂量至少1.5 g后），有217名类风湿性关节炎患者接受肝活检，仅在治疗过程中有714例活检。 There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.

Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis).

If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).

Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.

Hypogammaglobulinemia has been reported rarely.

Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.

Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.

Methotrexate may cause renal damage that may lead to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration.

Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.

Methotrexate should be used with extreme caution in the presence of debility.

Methotrexate exits slowly from third space compartments (eg, pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.

Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.

不良反应

IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.

Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.

Blood and Lymphatic System Disorders: suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely.

Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).

Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Hepatobiliary: disorders, hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations.

Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, and disseminated H. simplex.

Musculoskeletal System: stress fracture.

Ophthalmic: conjunctivitis, serious visual changes of unknown etiology.

Pulmonary System: respiratory fibrosis, respiratory failure, interstitial pneumonitis; deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.

Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis.

Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.

Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.

Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies

The approximate incidences of methotrexate attributed (ie, placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. （请参阅注意事项。）

Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.

Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 100,000/mm 3 ).

Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm 3 ), pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. （请参阅注意事项。）

Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.

Adverse Reactions in Psoriasis

There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear.

Adverse Reactions in JRA Studies

The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (eg, nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m 2 /wk in JRA, the published data for doses above 20 mg/m 2 /wk are too limited to provide reliable estimates of adverse reaction rates.

过量

Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis28(6): 846-854, 1996).

In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported.

Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported.

Trexall Dosage and Administration

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.

Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m 2 in combination with 60 mg/m 2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m 2 . It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

在Burkitt的I至II期肿瘤中，氨甲蝶呤在某些情况下可延长缓解期。建议剂量为每天10至25毫克/天，持续4至8天。在阶段III中，甲氨蝶呤通常与其他抗肿瘤药物同时使用。在所有阶段的治疗通常包括几个疗程的药物以及7至10天的休息时间。 III期淋巴肉瘤可能对甲氨蝶呤的联合药物治疗有反应，剂量为每天0.625至2.5 mg / kg。

甲氨蝶呤作为单一药物的治疗似乎可在多达50％的患者中产生临床反应。早期剂量通常为每周一次5至50毫克。剂量减少或停止应以患者反应和血液学监测为指导。对于每周治疗反应不佳的患者，甲氨蝶呤也每周两次给药，剂量范围为15至37.5 mg。

银屑病，类风湿关节炎和青少年类风湿关节炎

建议的起始剂量时间表

1. 每周一次单次口服7.5毫克。
2. 间隔12小时间隔2.5毫克口服剂量，每周一次，每次3剂。

推荐的起始剂量为每周一次10 mg / m 2 。

对于成人RA或多关节病程，JRA剂量可逐渐调整以达到最佳反应。有限的经验表明，成人剂量大于20 mg / wk时，严重毒性反应（尤其是骨髓抑制）的发生率和严重性显着增加。尽管有经验表明儿童剂量最高为30 mg / m 2 / wk，但很少有公开的数据来评估剂量超过20 mg / m 2 / wk可能对儿童产生严重毒性的风险。但是，经验确实表明，如果通过肌肉内或皮下注射甲氨蝶呤，则接受20至30 mg / m 2 / wk（0.65至1.0 mg / kg / wk）的儿童可能具有更好的吸收作用，并且胃肠道副作用较小。

治疗反应通常在3至6周内开始，患者可能会继续改善12周或更长时间。

最佳治疗时间未知。成人长期研究的有限数据表明，持续治疗至少可维持最初的临床改善两年。停用甲氨蝶呤后，关节炎通常在3至6周内恶化。

应充分告知患者所涉及的风险，并应在医师的不断监督下。 (See Information for Patients under PRECAUTIONS .) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS .) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS .)

所有的时间表都应针对每个患者不断进行调整。可以在常规给药方案之前给予初始测试剂量，以检测对不良反应的任何极端敏感性。 (See ADVERSE REACTIONS .) Maximal myelosuppression usually occurs in seven to ten days.

1. 每周单次口服，IM或IV剂量方案：每周10至25 mg，直至获得足够的应答。
2. 分口服剂量方案：每12小时间隔2.5 mg，共三剂。

每个时间表中的剂量可以逐渐调整以达到最佳的临床反应。通常不应超过30毫克/周。

一旦达到最佳的临床反应，应将每种给药方案减少到尽可能少的药物用量和尽可能长的休息时间。甲氨蝶呤的使用可以允许恢复到传统的局部治疗，应予以鼓励。

HANDLING AND DISPOSAL

应考虑适当处理和处置抗癌药物的程序。关于此主题的一些指南已经发布。 1-5 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How is Trexall Supplied

Trexall ® (methotrexate tablets USP) is available as:

5 mg: Green, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 927/5 on the other side. Each 5 mg tablet contains an amount of methotrexate sodium equivalent to 5 mg of methotrexate, USP. They are available in bottles of 30 tablets.

NDC 51285-366-01

7.5 mg: Blue, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 928/7½ on the other side. Each 7.5 mg tablet contains an amount of methotrexate sodium equivalent to 7.5 mg of methotrexate, USP. They are available in bottles of 30 tablets.

NDC 51285-367-01

10 mg: Pink, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 929/10 on the other side. Each 10 mg tablet contains an amount of methotrexate sodium equivalent to 10 mg of methotrexate, USP. They are available in bottles of 30 tablets.

NDC 51285-368-01

15 mg: Purple, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 945/15 on the other side. Each 15 mg tablet contains an amount of methotrexate sodium equivalent to 15 mg of methotrexate, USP. They are available in bottles of 30 tablets.

NDC 51285-369-01

存放在20°至25°C（68°至77°F）[请参阅USP控制的室温]。

避光。

分配在USP所定义的密封，耐光的容器中，并带有防儿童进入的盖（根据需要）。

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

参考资料

1. Controlling occupational exposure to hazardous drugs (OSHA Work-Practice Guidelines). Am J Health Syst Pharm 1996: 53: 1669-1685.
2. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
3. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1983; 1:426-428.
4. Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. CA -A Cancer Journal for Clinicians Sept/Oct 1983; 258-263.
5. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1049.

Manufactured In Czech Republic By:
Teva Czech Industries, sro
Opava-Komarov, Czech Republic

Manufactured For:
Teva Select Brands , North Wales, PA 19454
Division of Teva Pharmaceuticals USA, Inc.

Rev. A 7/2016