Rasuvo（注射剂）

Rasuvo注射剂的适应症和用法

类风湿关节炎，包括多关节青少年特发性关节炎

Rasuvo适用于患有严重，活动性类风湿关节炎（RA）（ACR标准）或患有活动性多关节性幼年特发性关节炎（pJIA）的某些成年人，这些儿童对某种药物的治疗反应不足或不能耐受一线治疗的充分试验，包括全剂量非甾体抗炎药（NSAID）。

银屑病

Rasuvo适用于成年人，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，仅在通过活检和/或经皮肤科会诊确诊后才可进行。重要的是要确保牛皮癣“爆发”不是由于未诊断的伴随疾病影响免疫反应而引起的。

使用限制

Rasuvo不适用于治疗肿瘤疾病。

Rasuvo注射剂量和给药

重要剂量信息

Rasuvo是一种单剂量手动触发式自动注射器，仅每周一次皮下使用[请参阅警告和注意事项（5.5） ]。在腹部或大腿处使用Rasuvo。 Rasuvo仅可在7.5至30毫克之间以2.5毫克的增量使用。对于需要口服，肌内，静脉内，动脉内或鞘内给药的患者，使用每周剂量少于7.5 mg，每周剂量大于30 mg，大剂量方案或剂量调整的患者，可使用另一种甲氨蝶呤制剂替代剂量小于2.5毫克的增量。

类风湿关节炎，包括多关节青少年特发性关节炎

甲氨蝶呤的推荐起始剂量：

成人RA：每周一次，单次口服或皮下注射7.5 mg。

pJIA：每周一次10 mg / m 2 。

对于从口服甲氨蝶呤转换为Rasuvo的患者，应考虑口服和皮下注射甲氨蝶呤之间生物利用度的任何差异[见临床药理学（12.3） ]。

剂量可以逐渐调整以获得最佳响应。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。在开始，定期期间和重新开始Rasuvo治疗之前，应通过病史，体格检查和实验室检查来评估血液，肝，肾和肺功能[见警告和注意事项（5.4） ]。具有潜在生育能力的女性在排除怀孕后才应开始接受Rasuvo治疗[见禁忌症（4）和警告和注意事项（5.2） ]。

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。

最大的骨髓抑制通常发生在七至十天。

银屑病

甲氨蝶呤的推荐起始剂量：

牛皮癣：10-25 mg，每周一次，一次口服，肌内，皮下或静脉内给药。

对于从口服甲氨蝶呤转换为Rasuvo的患者，应考虑口服和皮下注射甲氨蝶呤之间生物利用度的任何差异[见临床药理学（12.3） ]。

剂量可逐渐调整以达到最佳临床反应；通常不应超过30毫克/周。一旦达到最佳的临床反应，就应将剂量减少到尽可能少的药物剂量和尽可能长的休息时间。 Rasuvo的使用可允许恢复传统的局部治疗，应予以鼓励。

管理与处理

Rasuvo是一种手动触发的自动注射器，旨在在医师的指导和监督下用于皮下使用。

如果医生确定合适的话，可以接受Rasuvo的自我注射，如果他们已经接受了有关如何准备和服用正确剂量的适当培训，并且在必要时接受了医学随访。

Rasuvo每周注射一次。必须明确告知患者每周一次的给药时间表。建议确定每周的适当固定日期进行注射。

给药前目视检查Rasuvo是否有颗粒物和变色。如果密封圈破裂，请勿使用Rasuvo。

Rasuvo的处理与处置符合细胞毒性药物的处理和处置建议1 。

验孕

在开始用Rasuvo治疗之前，验证具有生殖潜能的女性的怀孕状况[请参阅在特定人群中使用（ 8.1，8.3 ） ]

剂型和优势

Rasuvo是一种注射浓度为50 mg / ml的甲氨蝶呤的注射剂，可以手动触发自动注射器，以以下剂量强度施用单剂量的甲氨蝶呤溶液：

• 7.5毫克
• 10毫克
• 12.5毫克
• 15毫克
• 17.5毫克
• 20毫克
• 22.5毫克
• 25毫克
• 27.5毫克
• 30毫克

禁忌症

Rasuvo禁忌症：

•怀孕
在怀孕期间服用Rasuvo会引起胚胎-胎儿毒性和胎儿死亡。 [请参阅警告和注意事项（5.2）和在特定人群中的使用（8.1） ]。

•酒精中毒或肝病
患有酒精中毒，酒精性肝病或其他慢性肝病的患者[请参阅警告和注意事项（5.1） ]。

•免疫缺陷综合症
有免疫缺陷综合症的明显或实验室证据的患者[参见警告和注意事项（5.1） ]。

•先前存在的血液异常
曾患有血液功能异常的患者，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[参见警告和注意事项（5.1） ]。

•过敏症
对甲氨蝶呤过敏的患者。甲氨蝶呤的使用已引起严重的超敏反应[见警告和注意事项（5.1）和不良反应（6.1和6.2） ]。

警告和注意事项

器官系统毒性

Rasuvo仅应由其知识和经验包括使用抗代谢药物的医生使用。由于可能会发生严重的毒性反应（可能是致命的），因此Rasuvo仅应用于患有严重，顽固，致残性疾病且对其他形式的治疗没有充分反应的牛皮癣或类风湿性关节炎的患者。

使用甲氨蝶呤治疗恶性肿瘤，牛皮癣和类风湿性关节炎已导致死亡。应密切监测患者的骨髓，肝，肺和肾毒性。

Rasuvo具有潜在的严重毒性。毒性作用的频率和严重性可能与剂量或给药频率有关，但在所有剂量下均已观察到。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Rasuvo上的患者。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[见剂量过量（10） ]。如果重新开始Rasuvo疗法，应谨慎进行，充分考虑对药物的进一步需求，并提高对可能再次发生毒性反应的警惕性。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，肾功能下降以及叶酸储备减少，应考虑使用相对较低的剂量，并应密切监测这些患者的毒性早期征兆[见在特定人群中使用（8.5） ]。

胃肠道：

腹泻和溃疡性口腔炎需要中断治疗：否则，出血性肠炎和肠道穿孔可能会导致死亡。

如果发生呕吐，腹泻或口腔炎，可能导致脱水，应停止Rasuvo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，应特别谨慎地使用Rasuvo。

甲氨蝶呤（通常以高剂量）与一些非甾体类抗炎药（NSAIDs）同时给药的报道，胃肠道毒性反应出乎意料的严重（有时是致命的）[见药物相互作用（7.1） ]。

血液学：

Rasuvo可抑制造血功能并引起贫血，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。在已有造血功能障碍的患者中，应谨慎使用Rasuvo。在使用甲氨蝶呤另一种制剂治疗风湿性关节炎（n = 128）的对照临床试验中，2例患者出现白细胞减少症（WBC <3000 / mm3），6例患者出现血小板减少症（血小板<100,000 / mm 3 ），2例发生全血细胞减少症耐心。

如果血球计数明显下降，应立即停止Rasuvo的治疗。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（通常为高剂量）与一些非甾体类抗炎药（NSAIDs）同时给药的报道，出乎意料的是严重的（有时是致命的）骨髓抑制和再生障碍性贫血[见药物相互作用（7.1） ]。

肝：

Rasuvo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Rasuvo治疗的原因，但应谨慎使用该药物。

在类风湿性关节炎中，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类似的其他危险因素，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。有64例（7％）纤维化病例和1例（0.1％）肝硬化病例。在64例纤维化病例中，有60例被认为是轻度的。网状蛋白染色对早期纤维化更敏感，其使用可能会增加这些数字。甚至更长的使用是否会增加这些风险还不得而知。

对于风湿性关节炎接受Rasuvo的患者，应在基线和每隔4至8周进行肝功能检查。有过量饮酒史，基线肝功能测试值持续异常或慢性乙型或丙型肝炎感染的患者应进行预处理肝活检。在治疗期间，如果持续存在肝功能检查异常或血清白蛋白下降至正常范围以下（在类风湿性关节炎得到良好控制的情况下），则应进行肝活检。

如果肝活检结果显示轻度变化（Roenigk，I，II，IIIa级），则可以继续使用Rasuvo并按照上述建议对患者进行监测。对于表现出持续异常肝功能检查且拒绝肝活检的任何患者，或肝活检显示中度至重度变化（Roenigk IIIb或IV级）的任何患者，应停用Rasuvo。

感染或免疫学状态：

在存在活动性感染的情况下，应特别谨慎地使用Rasuvo，并且在有免疫缺陷综合症的明显或实验室证据的患者中禁用Rasuvo。

在Rasuvo治疗期间给予免疫可能无效。通常不建议使用活病毒疫苗进行免疫。有报道称，接受甲氨蝶呤治疗的患者天花免疫接种后传播了牛痘感染。很少有球蛋白球蛋白血症的报道。

潜在的致命性机会性感染，特别是肺囊虫肺炎，可能与Rasuvo治疗发生。当肺部症状的患者出现，肺囊虫肺炎的可能性，应予以考虑。

神经病学：

有报道称，向颅骨脊髓照射的患者静脉注射甲氨蝶呤后，会出现白质脑病。据报道，接受中等剂量静脉氨甲蝶呤（1 gm / m 2 ）治疗的急性淋巴细胞白血病的儿科患者，严重的神经毒性通常表现为全身性或局灶性癫痫发作，其发生频率出乎意料地增加。有症状的患者在诊断成像研究中通常被发现患有白质脑病和/或微血管钙化。甚至在没有颅骨照射的情况下，接受重复剂量的大剂量甲氨蝶呤并伴有亚叶酸钙拯救的患者也有慢性白细胞性脑病的报道。

停用甲氨蝶呤并不总是能够完全恢复。在高剂量方案治疗的患者中已观察到一过性急性神经系统综合症。中风样脑病的表现可能包括精神错乱，偏瘫，短暂性失明，癫痫发作和昏迷。确切原因未知。鞘内注射甲氨蝶呤后，可能发生的中枢神经系统毒性可分类为：急性化学性蛛网膜炎，表现为头痛，背痛，颈项强直和发烧等症状。亚急性脊髓病，特征为轻瘫/截瘫，累及一个或多个脊髓神经根；慢性白质脑病表现为精神错乱，易怒，嗜睡，共济失调，痴呆，癫痫发作和昏迷。这种情况可能是进行性的，甚至是致命的。

肺：

甲氨蝶呤诱发的肺部疾病，包括急性或慢性间质性肺炎，是一种潜在的危险病灶，在治疗期间的任何时间都可能急性发生，并已报道了低剂量。它并不总是完全可逆的，并且有死亡报告。

在Rasuvo治疗期间发生的肺部症状（特别是干性非生产性咳嗽）或非特异性肺炎可能预示着潜在的危险病变，需要中断治疗并仔细检查。尽管临床上存在差异，但典型的甲氨蝶呤诱发的肺部疾病患者会出现发烧，咳嗽，呼吸困难，低氧血症和胸部X线片浸润。需要排除感染（包括肺炎）。该损伤可以在所有剂量下发生。

肾脏：

Rasuvo可能会导致肾脏损害，从而可能导致急性肾衰竭。用于治疗骨肉瘤的高剂量甲氨蝶呤可能会导致肾脏损害，导致急性肾衰竭。肾毒性主要是由于甲氨蝶呤和7-羟基甲氨蝶呤在肾小管中沉淀所致。密切注意肾脏功能，包括充分的水合作用，尿液碱化以及血清甲氨蝶呤和肌酐水平的测定对于安全给药至关重要。

皮肤：

在儿童和成人中，口服，肌肉内，静脉内或鞘内注射甲氨蝶呤的几天之内，发生了严重的，偶发性的皮肤病学反应，包括毒性表皮坏死溶解，史蒂文斯-约翰逊综合征，剥脱性皮炎，皮肤坏死和多形性红斑。在患有肿瘤和非肿瘤疾病的患者中，单次或多次低，中或高剂量甲氨蝶呤治疗后会注意到反应。

牛皮癣的病变可能会因同时暴露于紫外线辐射而加剧。

甲氨蝶呤可能会“召回”放射性皮炎和晒伤。

其他注意事项：

出现残疾时，应格外小心使用Rasuvo。

甲氨蝶呤从第三空间舱室缓慢流出（例如胸腔积液或腹水）。这导致延长的终末血浆半衰期和意外的毒性。对于有大量第三空间积聚的患者，建议在治疗前排空液体并监测血浆甲氨蝶呤水平。

胚胎-胎儿毒性

根据已发表的报道和甲氨蝶呤的作用机理，甲氨蝶呤可对孕妇产生胚胎-胎儿毒性，包括胎儿死亡。在孕妇中禁用Rasuvo。启动Rasuvo之前，请验证具有生殖潜力的女性的怀孕状况。建议有生殖潜力的女性在接受Rasuvo治疗期间以及最终剂量后的6个月内使用有效的避孕方法。劝告有生殖潜力的男性在Rasuvo治疗期间和最终剂量后3个月内使用有效的避孕方法[请参阅禁忌症（4） ，在特定人群中使用（ 8.1、8.3 ） ，临床药理学（12.1） ]。

对繁殖的影响

根据已发表的报道，氨甲蝶呤可导致生育力，少精子症和月经功能障碍。尚不清楚在受影响的患者中不育是否可以逆转。讨论具有生殖潜力的男性和女性患者对生殖的影响的风险[参见“在特定人群中的使用（8.3） ”。

实验室测试

接受Rasuvo治疗的患者应受到严密监测，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个月一次肾功能和肝功能[请参阅警告和注意事项（5.1） ]。

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，也可能需要进行更频繁的监测。

肝功能检查

甲氨蝶呤给药后经常观察到暂时性肝功能检查异常，通常不会引起甲氨蝶呤治疗方法的改变。持续的肝功能检查异常和/或血清白蛋白降低可能是严重肝毒性的指标，需要评估[见警告和注意事项（5.1） ]。

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。

肺功能检查

如果怀疑有甲氨蝶呤引起的肺部疾病，特别是如果可以进行基线测量，则肺功能检查可能会有用[请参阅警告和注意事项（5.1） ]。

剂量不当带来的风险

医师和药剂师都应向患者强调Rasuvo每周给药一次，并且错误的每日使用已导致致命的毒性[参见剂量和用法（2） ]。

肾功能，腹水或胸腔积液受损的患者

肾功能受损，腹水或胸腔积液的患者甲氨蝶呤的消除减少。此类患者需要特别仔细地监测毒性，并需要降低剂量，或者在某些情况下需要中断Rasuvo的给药。

头晕和疲劳

头晕和疲劳等不良反应可能会影响驱动或操作机械的能力。

恶性淋巴瘤

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。首先终止Rasuvo，如果淋巴瘤没有消退，应采取适当的治疗措施。

肿瘤溶解综合征

像其他细胞毒性药物一样，甲氨蝶呤可能会在肿瘤迅速增长的患者中诱发“肿瘤溶解综合征”。

伴随放射治疗

甲氨蝶呤与放疗同时给予可能增加软组织坏死和骨坏死的风险。

不良反应

标签的其他部分将详细讨论以下不良反应。

• 器官系统毒性[请参阅警告和注意事项（5.1） ]
• 胚胎胎儿毒性[请参阅警告和注意事项（5.2） ]
• 对繁殖的影响[见警告和注意事项（5.3） ]
• 恶性淋巴瘤[请参阅警告和注意事项（5.8） ]

最常见的不良反应包括溃疡性口腔炎，白细胞减少症，恶心和腹部不适。其他经常报告的不良反应包括全身乏力，过度疲劳，发冷和发烧，头晕和对感染的抵抗力下降。

临床试验经验

本节概述了在使用Rasuvo以及甲氨蝶呤注射液和口服甲氨蝶呤进行的临床研究中报告的受试者不良反应。

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物的临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

类风湿关节炎

在小剂量口服甲氨蝶呤口服治疗（7.5至15毫克/周）风湿性关节炎患者（n = 128）的12至18周双盲研究中，甲氨蝶呤引起的不良反应（即减去安慰剂率）的近似发生率，在下面列出。实际上，所有这些患者都在服用非甾体类抗炎药，有些还服用低剂量的皮质类固醇。在这些短期研究中未检查肝组织学。

发生率大于10％：肝功能检查升高15％，恶心/呕吐10％。

发生率3％至10％：口腔炎，血小板减少症（血小板计数少于100,000 / mm3）。

发病率1％至3％：皮疹/瘙痒/皮炎，腹泻，脱发，白细胞减少症（白细胞少于3000 / mm3），全血细胞减少症，头晕。

另两项风湿性关节炎患者（n = 680）口服剂量为7.5 mg至15 mg / wk的对照研究表明，间质性肺炎的发生率为1％。

其他较不常见的反应包括血细胞比容降低，头痛，上呼吸道感染，厌食，关节痛，胸痛，咳嗽，排尿困难，眼睛不适，鼻epi，发烧，感染，出汗，耳鸣和白带。

多关节青少年特发性关节炎

每周口服甲氨蝶呤（5至20 mg / m 2 / wk或0.1至0.65 mg / kg / wk）治疗的pJIA患儿的不良反应的大致发生率如下（几乎所有患者均同时接受非甾体类抗炎药，有的还服用低剂量的皮质类固醇）：肝功能检查升高14％；胃肠道反应（例如恶心，呕吐，腹泻），占11％；口腔炎2％;白细胞减少症，2％；头痛1.2％；脱发0.5％;头晕0.2％;和皮疹，为0.2％。尽管在pJIA中有高达30 mg / m 2 / wk剂量的经验，但已公布的剂量高于20 mg / m 2 / wk的数据太有限，无法提供可靠的不良反应率估算。

银屑病

有两篇文献报道（Roenigk，1969； Nyfors，1978）描述了甲氨蝶呤治疗的大范围（n = 204、248）牛皮癣患者。剂量高达每周25毫克，治疗长达四年。除了脱发，光敏性和“皮肤损伤烧伤”（每例3％至10％）外，这些报告中的不良反应率与类风湿关节炎研究中的不良反应率非常相似。很少会出现痛苦的斑块侵蚀（Pearce，HP和Wilson，BB：Am Acad Dermatol 35：835-838，1996）。

其他不良反应

以下按器官系统列出了甲氨蝶呤在肿瘤，RA，pJIA和牛皮癣患者中报告的其他不良反应。

消化系统：牙龈炎，咽炎，口腔炎，厌食，恶心，呕吐，腹泻，呕血，黑便，胃肠道溃疡和出血，肠炎，胰腺炎。

血液和淋巴系统疾病：造血功能减退，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，血小板减少，粒细胞缺乏症，嗜酸性粒细胞增多，淋巴结病和淋巴增生性疾病（包括可逆性疾病）。少有球蛋白球蛋白血症的报道。

心血管疾病：心包炎，心包积液，低血压和血栓栓塞事件（包括动脉血栓形成，脑血栓形成，深静脉血栓形成，视网膜静脉血栓形成，血栓性静脉炎和肺栓塞）。

中枢神经系统：服用甲氨蝶呤后，还会出现头痛，嗜睡，视力模糊，暂时性失明，言语障碍（包括构音障碍和失语症），偏瘫，轻瘫和抽搐。低剂量后，偶尔有短暂的认知功能障碍，情绪改变或异常的颅骨感觉，白脑病或脑病的报道。

肝胆疾病：肝毒性，急性肝炎，慢性纤维化和肝硬化，肝功能衰竭，血清白蛋白降低，肝酶升高。

感染：有病例报告说，接受甲氨蝶呤治疗肿瘤和非肿瘤疾病的患者有时会发生致命的机会性感染。肺炎支原体肺炎是最常见的机会性感染。也有感染，肺炎，巨细胞病毒感染的报告，包括巨细胞病毒性肺炎，败血症，致命性败血症，诺卡氏病，组织胞浆菌病，隐球菌病，带状疱疹，单纯疱疹肝炎和弥散性单纯疱疹。

肌肉骨骼系统：应力性骨折。

眼科：结膜炎，病因不明的严重视觉改变。

Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, 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, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, 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, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.

药物相互作用

Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids

Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity [see Warnings and Precautions (5.1) ].

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including Rasuvo. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.

Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate.

Proton Pump Inhibitors (PPIs) and H2 Blockers

Use caution if high-dose methotrexate is administered to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

Oral Antibiotics

Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of Rasuvo with penicillins should be carefully monitored.

Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect.

Hepatotoxins

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with Rasuvo and other potential hepatotoxins (eg, azathioprine, retinoids, and sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

茶碱

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Rasuvo.

Folic Acid and Antifolates

Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity.

Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect.

巯基嘌呤

Methotrexate increases the plasma levels of mercaptopurine. The combination of Rasuvo and mercaptopurine may therefore require dose adjustment.

Nitrous oxide

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid the simultaneous use of nitrous oxide and methotrexate.

Other Drugs

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides.

Renal tubular transport is also diminished by probenecid; use of Rasuvo with this drug should be carefully monitored.

Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.

在特定人群中的使用

怀孕

风险摘要

Based on published reports, and methotrexate's mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. In pregnant women with psoriasis or rheumatoid arthritis, Rasuvo is contraindicated [see Contraindications (4) ]. There are no animal data that meet current standards for nonclinical developmental toxicity studies.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.所有怀孕都有出生缺陷，流产或其他不良后果的背景风险。 In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4 % and 15 – 20 %, respectively.

数据

人数据

Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.

A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8-29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]) (2.9%).Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

哺乳期

风险摘要

Limited published literature report the presence of methotrexate in human breast milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, including myelosuppression advise women not to breastfeed during treatment with Rasuvo and for one week after the final dose.

生殖潜力的男性和女性

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Rasuvo .

Contraception

女性

Rasuvo can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Rasuvo.

Males

Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final dose of Rasuvo.

不孕症

女性

Based on the published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that Rasuvo can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after treatment with methotrexate, advise males of reproductive potential that Rasuvo can cause infertility or oligospermia during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

儿科用

The safety and effectiveness of methotrexate, including Rasuvo, have not been established in pediatric patients with psoriasis.

The safety and effectiveness of Rasuvo have not been established in pediatric patients with neoplastic diseases.

The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis [see Clinical Studies (14.2) ].

Published clinical studies evaluating the use of methotrexate in children and adolescents (ie, patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis [see Adverse Reactions (6.1) ].

Rasuvo does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal 'gasping syndrome' in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol.症状包括喘气，低血压，心动过缓和心血管衰竭。

Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ) [see Warnings and Precautions (5.1) ].

老人用

Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (ie, that interfere with renal function, methotrexate or folate metabolism) in this population [see Warnings and Precautions (5.1) , Drug Interactions (7.7) and Use in Specific Populations (8.6) ]. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (ie, creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation.

Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age [see Warnings and Precautions (5.1) ].

肾功能不全

Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of Rasuvo administration.

肝功能不全

The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. Rasuvo is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely [see Warnings and Precautions (5.1) ].

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 has 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 Dis 28 (6): 846-854, 1996).

Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion.

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.

Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported.

There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.

Rasuvo Injection Description

Rasuvo contains methotrexate, a folate analog metabolic inhibitor.

Chemically, methotrexate is [N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-Lglutamic acid.结构式为：

C 20 H 22 N 8 O 5 MW= 454.45

Rasuvo contains methotrexate in a sterile, preservative-free, non-pyrogenic solution for a single subcutaneous injection. Rasuvo is an isotonic, clear, yellow to brown solution.

Rasuvo contains the following inactive ingredients: sodium chloride 0.4% w/v; water for injections, sodium hydroxide and, if necessary, hydrochloric acid are added to adjust the pH to approximately 8.5.

Rasuvo Injection - Clinical Pharmacology

作用机理

Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.

Pharmacodynamics

Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate's effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies.

In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.

Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non- metastatic osteosarcoma. The original rationale for high dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown.

药代动力学

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In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/m 2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m 2 is significantly less, possibly due to a saturation effect.

In a relative bioavailability study in healthy subjects, the systemic exposure of methotrexate (AUC) from Rasuvo at doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg, was higher than that of oral methotrexate administered at the same doses by 35%, 49%, 51%, and 68%, respectively. In a relative bioavailability study in psoriasis patients, the systemic exposure (AUC) of methotrexate from Rasuvo at a dose of 30 mg, was similar to that of methotrexate administered at the same dose by the intramuscular route.

In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (C max : 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) has been reported.

Significant interindividual variability has also been noted in time to peak concentration (T max : 0.67 to 4 hrs after a 15 mg/m 2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration.

Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes.

As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JIA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m 2 /week in pediatric patients with JIA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours.

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After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds i