温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

产品特性摘要

1.药品名称

Skilarence 30毫克抗胃片

斯基拉伦斯120毫克抗胃片

2.定性和定量组成

Skilarence 30毫克

每个抗胃溃疡的片剂均含有30 mg富马酸二甲酯。

Skilarence 120毫克

每个抗胃溃疡的片剂均包含120毫克富马酸二甲酯。

具有已知作用的赋形剂

Skilarence 30毫克

每个抗胃溃疡的片剂均含有34.2 mg乳糖（一水合物）。

Skilarence 120毫克

每个抗胃溃疡的片剂均含有136.8 mg乳糖（一水合物）。

有关赋形剂的完整列表，请参见第6.1节。

3.药物形式

耐胃片。

Skilarence 30毫克

白色薄膜包衣的圆形双凸片剂，直径约6.8毫米。

Skilarence 120毫克

蓝色，薄膜包衣，圆形，双凸片剂，直径约11.6毫米。

4.临床特点

4.1治疗适应症

对于需要全身药物治疗的成人，中度至重度斑块状牛皮癣的治疗适用斯基拉伦斯治疗。

4.2给药方式和方法

Skilarence旨在在牛皮癣的诊断和治疗经验丰富的医师的指导和监督下使用。

剂量

为了提高耐受性，建议以低初始剂量开始治疗，然后逐渐增加剂量。 在第一周，每天服用30毫克Skilarence（晚上1片）。 在第二周，每日两次服用Skilarence 30 mg（早晨1片，晚上1片）。 在第三周，每日服用30毫克Skilarence 30毫克（早晨1片，中午1片，晚上1片）。 从第四周起，晚上改用1片Skilarence 120毫克的治疗剂。 然后，在接下来的5周中，每天在一天的不同时间每周增加1个Skilarence 120 mg片剂，如下表所示。 允许的最大每日剂量为720 mg（3 x 2片Skilarence 120 mg）。

如果不容许特定的剂量增加，则可以暂时将其减少至最后的容许剂量。

如果在达到最大剂量之前观察到治疗成功，则无需进一步增加剂量。在达到皮肤损伤的临床相关改善后，应考虑逐步将Skilarence的每日剂量降低至个人所需的维持剂量。

如果观察到实验室参数异常（见第4.4节），也可能需要调整剂量。

老年患者

Skilarence的临床研究没有包括足够多的65岁及以上的患者来确定他们与65岁以下的患者相比是否有不同的反应（请参阅5.2节）。根据富马酸二甲酯的药理学，预计老年人无需调整剂量。

肾功能不全

轻度至中度肾功能不全的患者无需调整剂量（见5.2节）。尚未对患有严重肾功能不全的患者进行skilarence的研究，并且在这些患者中禁止使用skilarence（请参阅第4.3节）。

肝功能不全

轻度至中度肝功能不全的患者无需调整剂量（见5.2节）。尚未对严重肝功能不全的患者进行skilarence的研究，并且在这些患者中禁止使用skilarence（请参阅第4.3节）。

小儿人口

尚未确定Skilarence在18岁以下儿童患者中的安全性和有效性。没有有关小儿患者Skilarence的数据。

给药方法

Skilarence是口服的。进餐期间或饭后立即将整洁片剂全部倒入液体。胃抗性片剂的包衣旨在防止胃刺激。因此，不应将片剂压碎，分散，溶解或咀嚼。

4.3禁忌症

‒ 对活性物质或第6.1节中所列的任何赋形剂过敏。

‒ 严重的胃肠道疾病。

‒ 严重的肝或肾功能损害。

‒ 怀孕和哺乳。

4.4特殊警告和使用注意事项

血液学

飞雪可能会减少白细胞和淋巴细胞计数（请参阅第4.8节）。尚未对白细胞或淋巴细胞计数低的患者进行过研究。

治疗前

在开始使用Skilarence治疗之前，应可获得当前的全血细胞计数（包括差异血细胞计数和血小板计数）。如果发现白细胞减少症低于3.0x109 / L，淋巴细胞减少症低于1.0x109 / L或其他病理结果，则不应开始治疗。

治疗期间

在治疗过程中，应每3个月进行一次全血细胞计数和鉴别。在以下情况下需要采取行动：

白细胞减少症：如果发现白细胞总数明显减少，则应仔细监测情况，并以低于3.0x109 / L的水平停止使用Skilarence治疗。

淋巴细胞减少症：如果淋巴细胞计数降至1.0x109 / L以下但≥0.7x109 / L，则应每月进行一次血液监测，直到两次连续的血液检查水平回到1.0x109 / L或更高为止，此后可再次进行监测3个月。如果淋巴细胞计数降至0.7x109 / L以下，则必须重复血液检查，并且如果确认水平低于0.7x109 / L，则必须立即停止治疗。停药后应监测出现淋巴细胞减少的患者，直到淋巴细胞计数恢复到正常范围（参见第4.8节）。

其他血液系统疾病

应停止治疗，如果发生其他病理结果，则应谨慎。在任何情况下，都应监测血细胞计数，直到其值回到正常范围。

传染病

飞雪是一种免疫调节剂，可能会影响免疫系统对感染的反应方式。对于已存在临床相关感染的患者，医师应决定是否仅在感染解决后才开始使用Skilarence治疗。如果患者在使用Skilarence治疗期间发生感染，应考虑暂停治疗，并应在重新开始治疗之前重新评估其益处和风险。应指导接受Skilarence的患者向医生报告感染症状。

机会感染/进行性多灶性白质脑病（PML）

其他含富马酸二甲酯的产品也有机会感染的病例，特别是进行性多灶性白质脑病（PML）的病例（见4.8节）。 PML是由约翰·坎宁安病毒（JCV）引起的机会性感染，可能致命或导致严重残疾。 PML可能是由多种因素引起的。

先前感染JCV被认为是发展PML的先决条件。危险因素可以包括先前的免疫抑制治疗和某些伴随疾病的存在（例如某些自身免疫疾病或恶性血液病）。免疫系统的改变或减弱以及遗传或环境因素也可能构成危险因素。

富马酸二甲酯治疗期间持续的中度或严重淋巴细胞减少也被认为是PML的危险因素。应监测发生淋巴细胞减少症的患者的机会感染的体征和症状，尤其是指示PML的症状。与PML相关的典型症状多种多样，在数天至数周内会变得更糟，包括身体一侧的进行性无力或四肢笨拙，视力障碍以及思维，记忆力和方向改变，从而导致混乱和性格改变。如果怀疑是PML，应立即停止使用Skilarence治疗，并进行进一步的适当的神经和放射检查。

免疫抑制或免疫调节疗法的先前和伴随治疗

关于Skilarence在先前已接受其他免疫抑制或免疫调节疗法治疗的患者中的功效和安全性的有限数据。在将患者从此类疗法转为Skilarence时，应考虑另一种疗法的半衰期和作用方式，以避免对免疫系统产生累加效应。

与其他免疫抑制或免疫调节疗法同时使用时，没有关于Skilarence的功效和安全性的数据（请参阅第4.5节）。

既往胃肠道疾病

既往已有胃肠道疾病的患者尚未研究过斯基拉伦斯病。患有严重胃肠道疾病的患者忌讳skilarence（请参见第4.3节）。遵循开始剂量的剂量滴定方案以及与食物一起服用斯基伦斯，可以改善胃肠道耐受性（参见第4.2和4.8节）。

肾功能

由于肾脏消除在从血浆中清除Skilarence的过程中起着很小的作用，因此肾脏损害不太可能会影响药代动力学特征，因此，预计轻度至中度肾损害的患者无需调整剂量（请参见第4.2和5.2）。

在III期安慰剂对照临床试验中，各治疗组在治疗期间均未见肾功能恶化。但是，尚未对患有严重肾功能不全的患者进行Skilarence的研究，在富马酸酯的上市后监测期间已报告了一些肾毒性病例。因此，严重肾功能不全的患者忌用斯基拉伦斯治疗（参见第4.3节）。

开始治疗前应检查肾功能（例如肌酐，血尿素氮和尿液分析），此后每3个月检查一次。如果肾功能发生临床相关变化，尤其是在没有其他解释的情况下，应考虑减少剂量或停止治疗。

范可尼综合征

Fanconi综合征的早期诊断和Skilarence治疗的中止对于预防肾功能不全和骨软化症的发作很重要，因为该综合征通常是可逆的。最重要的体征是：蛋白尿，糖尿（血糖水平正常），氨基酸尿过多和血尿（可能与低磷血症并发）。病情进展可能涉及多尿，多饮和近端肌肉无力等症状。在极少数情况下，低血磷性骨软化症伴有非局部性骨痛，血清中碱性磷酸酶升高和应力性骨折。重要的是，在没有肌酐水平升高或肾小球滤过率低的情况下可以发生范可尼综合征。如果症状不明确，则应考虑Fanconi综合征，并应进行适当的检查。

肝功能

在严重肝功能不全的患者中尚未研究过斯基拉仑（skilarence），并且禁忌在这些患者中（参见第4.3节）。

建议在开始治疗之前及其后每3个月监测肝功能（SGOT，SGPT，γ-GT，AP），因为在III期研究中发现某些患者肝酶升高。如果肝参数发生临床相关变化，尤其是在没有其他解释的情况下，应考虑减少剂量或停止治疗。

冲洗

应该使患者意识到，他们在服用Skilarence的最初几周内可能会出现潮红（见4.8节）。

乳糖

臭味中含有乳糖。患有半乳糖不耐受，总乳糖酶缺乏症或葡萄糖-半乳糖吸收不良的罕见遗传病的患者不应服用这种药物。

4.5与其他药品的相互作用以及其他形式的相互作用

尚未进行相互作用研究。

应谨慎地与其他全身性抗银屑病疗法（例如甲氨蝶呤，类维生素A，补骨脂素，环孢菌素，免疫抑制剂或细胞抑制剂）联合使用skilarence。在Skilarence治疗期间，应避免同时使用其他富马酸衍生物（局部或全身使用）。

同时服用肾毒性物质（例如甲氨蝶呤，环孢素，氨基糖苷类，利尿剂，非甾体抗炎药或锂）可能会增加患斯基拉仑斯的患者发生肾脏不良反应（例如蛋白尿）的可能性。

如果使用Skilarence治疗期间出现严重或长期腹泻的情况，可能会影响其他药物的吸收。处方具有狭窄治疗指数，需要在肠道吸收的药物时，应谨慎行事。口服避孕药的功效可能会降低，建议使用替代性屏障避孕方法来预防可能的避孕失败（请参阅口服避孕药的处方信息）。

应避免食用大量的烈性酒精饮料（按体积计酒精含量超过30％），因为这可能会导致Skilarence的溶出度增加，并因此增加胃肠道不良反应的发生率。

Skilarence治疗期间的疫苗接种尚未进行研究。免疫抑制是使用活疫苗的危险因素。应当权衡接种疫苗的风险与收益。

没有证据表明Skilarence与细胞色素P450以及最常见的外排和摄取转运蛋白发生相互作用，因此，预计不会与这些系统代谢或运输的医药产品发生相互作用（参见5.2节）。

4.6生育，怀孕和哺乳

有生育能力的妇女

不建议有生育能力的妇女不使用适当的避孕措施，要讲究技巧。对于在Skilarence治疗期间出现腹泻的患者，口服避孕药的效果可能会降低，并且可能需要采取其他避孕措施（见4.5节）。

怀孕

富马酸二甲酯在孕妇中的使用的数据有限。动物研究表明有生殖毒性（见5.3节）。怀孕期间禁止雪橇（请参阅第4.3节）。

哺乳

富马酸二甲酯或其代谢产物是否会从人乳中排泄尚不清楚。不能排除新生儿或婴儿的危险。因此，母乳喂养期间忌讳Skilarence（请参阅第4.3节）。

生育能力

没有关于斯基拉伦斯对生育力影响的人类或动物数据。

4.7对驾驶和使用机器的能力的影响

尚未进行有关驱动和使用机器的能力的研究。机灵可能会对驾驶和使用机器的能力产生较小的影响。施用Skilarence后可能会出现头晕和疲劳（请参阅第4.8节）。

4.8不良影响

安全概要摘要

在III期临床研究（1102）中，使用Skilarence观察到的最常见的不良反应是胃肠道事件（62.7％），潮红（20.8％）和淋巴细胞减少（10.0％）。大多数不良反应被认为是轻度的，并没有导致研究治疗中断。导致> 5％的患者中止治疗的唯一不良反应是胃肠道反应。有关不良反应的监测建议和临床处理，请参阅第4.4节。

不良反应列表

以下是在临床研究期间接受Skilarence治疗的患者和Fumaderm（一种包含富马酸二甲酯和其他富马酸酯的相关药物）的不良反应的清单。

不良反应的发生频率使用以下约定定义：非常常见（≥1/ 10）； 普通（≥1/ 100至＜1/10）； 不常见（≥1/ 1,000至<1/100）； 稀有（≥1/ 10,000至＜1 / 1,000）； 非常稀有（＜1 / 10,000）； 并且未知（无法根据可用数据进行估算）。

所选不良反应的描述

肠胃不适

来自III期临床研究和文献的数据表明，含富马酸二甲酯产品的胃肠道疾病最有可能在开始治疗后的前2至3个月内发生。没有发现明显的剂量关系，也没有发现发生这些不良反应的危险因素。腹泻是服用Skilarence的患者中常见的不良反应（36.9％），导致约10％的患者停药。这些腹泻事件中有90％以上是轻度到中度的严重程度（请参阅第4.4节）。

冲洗

根据III期临床研究的观察结果以及文献数据，潮红最有可能在治疗的最初几周内发生，并且随着时间的流逝会逐渐减少。在临床研究中，总共有20.8％的接受Skilarence的患者出现潮红，在大多数情况下是轻度的（参见4.4节）。含富马酸二甲酯产品的已发表临床经验表明，每次服用药片后通常会在短期内开始出现潮红，并在数小时内消失。

血液学改变

来自III期临床研究的数据以及来自文献的数据表明，血液学参数的变化最有可能在开始用富马酸二甲酯治疗后的前3个月内发生。特别是，在临床研究中，平均淋巴细胞计数略有下降，从第3周到​​第5周开始，在第12周达到最大值，约有三分之一的患者淋巴细胞值低于1.0x109 / L。在临床研究期间，淋巴细胞的平均值和中位数保持在正常范围内。在第16周（治疗结束），淋巴细胞计数没有进一步下降。在治疗的第16周，有13/175（7.4％）患者的淋巴细胞水平＜0.7x 109 / L。随访时仅在异常情况下进行血液取样以进行安全的临床实验室检查。在无治疗的随访中，停止治疗后6个月的1/29（3.5％）患者和停止治疗12个月的0/28（0％）患者的淋巴细胞水平＜0.7x 109 / L。停止治疗后12个月，有3/28（10.7％）的患者淋巴细胞值低于1.0x109 / L，这代表开始使用Skilarence的患者中有3/279（1.1％）。

对于总白细胞计数，在治疗的第12周时明显下降。在治疗的第16周（治疗结束）它又缓慢增加；停止治疗后12个月，所有患者的值均高于3.0x109 / L。

早在第3周，嗜酸性粒细胞的平均值便出现短暂增加，在第5和8周达到最大值，并在第16周恢复到基线值。

有关血液学不良反应的监测建议和临床处理，请参阅第4.4节。

报告疑似不良反应

重要的是在药物授权后报告可疑的不良反应。它允许继续监视药品的利益/风险平衡。要求医疗保健专业人员通过附录V中列出的国家报告系统报告任何可疑的不良反应。

4.9过量

服药过量时需对症治疗。没有特定的解毒剂。

5.药理特性

5.1药效学性质

药物治疗组：其他免疫抑制剂，ATC代码：L04AX07

作用机理

富马酸二甲酯及其代谢产物富马酸单甲酯的抗炎和免疫调节作用尚未完全阐明，但据认为主要是由于与直接参与牛皮癣发病机理的细胞的胞内还原型谷胱甘肽相互作用所致。与谷胱甘肽的这种相互作用导致对易位到核内的抑制以及激活的B细胞核因子κ轻链增强子（NF-κB）的转录活性。

富马酸二甲酯和富马酸单甲酯的主要活性被认为是免疫调节的，导致T辅助细胞（Th）从Th1和Th17谱型转变为Th2表型。炎性细胞因子的产生通过诱导促凋亡事件，抑制角质形成细胞增殖，减少粘附分子表达以及减少炎性浸润在银屑病斑块中而减少。

临床疗效和安全性

在一项中度至重度斑块状牛皮癣患者的一项双盲，3组，安慰剂和活性药物比较性对照III期研究（1102）中，对斯基拉伦斯的安全性和有效性进行了评估（研究1102）。 704名患者被随机分配以2：2：1的比例服用活性比较剂Skilarence（Fumaderm，一种具有相同含量的富马酸二甲酯加3种富马酸单乙酯盐的组合产品）和安慰剂。患者开始使用含有30 mg /天的富马酸二甲酯或安慰剂的片剂进行治疗，如第4.2节所述，在两个主动治疗组中的最高滴定度最高为720 mg / day。如果在达到最大剂量720 mg /天的富马酸二甲酯之前观察到治疗成功，则无需进一步增加剂量，并且应将剂量稳定地减少至单个维持剂量。如果在第4周到第16周个体无法忍受增加剂量的情况，则患者应恢复至第4周开始以来的最后耐受剂量，该剂量应维持到治疗期结束（第16周）。患者接受了长达16周的治疗，计划在停止治疗后长达12个月进行随访。

各治疗组之间的人口统计学特征和基线特征得到了很好的平衡。在699名患者中，大多数为白种人（99％）和男性（65％），平均年龄为44岁。大多数患者（91％）年龄＜65岁。根据基线时的牛皮癣面积和严重程度指数（PASI）和医师的整体评估（PGA）得分，大多数患者患有中度牛皮癣：基线时的平均PASI得分为16.35，而60％的患者在PGA中得分为中度。根据皮肤病生活质量指数（DLQI），大多数患者报告牛皮癣对其生活产生“很大”或“极大”影响，平均DLQI得分为11.5。

经过16周的治疗，根据活跃的比较者，PASI 75和PGA得分清楚或几乎清晰且不逊色（使用不逊色边际为-15％），发现Skilarence优于安慰剂（p ＜0.0001） （p ＜0.0003）基于PASI 75。

Fumaderm =活性比较剂，是具有相同含量的富马酸二甲酯和3种富马酸单乙酯氢盐的组合产品； n =有可用数据的患者人数； N ＝人口总数； PASI =牛皮癣区域严重程度指数； PGA =医师的全球评估； Skilarence与安慰剂的优势相比，PASI 75的差异为22.2％，PGA得分的差异为20.0％清晰或几乎清晰； Fumaderm与安慰剂的优势相比，PASI 75的差异为25.0％，PGA得分的差异为清晰或几乎24.4％明确; b Skilarence与Fumaderm的非劣效性，PASI 75得分为-2.8％，PGA得分为-4.4％，清晰或几乎清晰。

功效终点PASI得分与基线之间的平均变化百分比存在趋势，表明早在第3周（-11.8％）就开始出现对Skilarence的临床反应，与安慰剂相比在第8周时有统计学意义（-30.9％） 。到第16周，进一步改善（-50.8％）。

病人对生活质量的自我感觉得到改善，也证明了使用Skilarence治疗的好处。与安慰剂相比，用Skilarence治疗的患者在第16周的平均DLQI较低（5.4比8.8）。

停药2个月后评估反弹（定义为基线PASI值≥125％的恶化），并且显示富马酸酯对临床无影响，因为很少有患者被记录为有反弹（Skilarence 1.1％和活性比较剂2.2％，而安慰剂组为9.3％）。

目前尚无法获得Skilarence的长期功效数据，但是，在药代动力学和临床研究中，Skilarence的全身暴露，功效和安全性与含富马酸二甲酯的活性比较剂相当。因此，可以预期Skilarence的长期功效也可以与含富马酸二甲酯的产品相媲美。对于其他含富马酸二甲酯的产品，长期功效的维持已被充分描述，因此，在长期治疗至少24个月的患者中，预期可在Skilarence观察到16周的治疗益处。

小儿人口

欧洲药品管理局放弃了在这种适应症中对所有儿童人群的子项进行Skilarence研究的结果的提交义务（有关儿童使用的信息，请参阅第4.2节）。

5.2药代动力学性质

吸收性

口服后，在血浆中未检测到富马酸二甲酯，因为它被酯酶迅速水解成其活性代谢产物富马酸单甲酯。在健康受试者中口服单剂Skilarence 120 mg片剂后，在禁食或进食条件下，富马酸单甲酯的血浆峰值浓度分别达到约1325 ng / mL和1311 ng / mL。与食物一起食用斯基拉伦斯会使富马酸单甲酯的tmax从3.5小时推迟到9.0小时。

分配

富马酸单甲酯的血浆蛋白结合率约为50％。富马酸二甲酯对血清蛋白没有任何结合亲和力，可能进一步促进其从循环中的快速清除。

生物转化

富马酸二甲酯的生物转化不涉及细胞色素P450同工酶。体外研究表明，治疗剂量的富马酸单甲酯不抑制或诱导任何细胞色素P450酶，它不是P-糖蛋白的底物或抑制剂，也不是最常见的外排和摄取转运蛋白的抑制剂。体外研究表明，治疗剂量的富马酸二甲酯不抑制CYP3A4 / 5和BCRP，并且是一种弱P-糖蛋白抑制剂。

体外研究表明，富马酸二甲酯在pH 8（小肠中的pH）下迅速水解为富马酸单甲酯，而在pH 1（胃中的pH）下则迅速水解。富马酸二甲酯的一部分被酯酶和小肠的碱性环境水解，其余部分进入门静脉血液。进一步的研究表明，富马酸二甲酯（和较小程度的富马酸单甲酯）与还原型谷胱甘肽部分反应，形成谷胱甘肽加合物。在动物研究中，在大鼠肠粘膜中发现了这些加合物，并且在门静脉血中的含量较小。但是，口服后在动物或牛皮癣患者的血浆中未检出未结合的富马酸二甲酯。相比之下，血浆中可检测到未结合的富马酸单甲酯。通过三羧酸循环的氧化，进一步的代谢发生，形成二氧化碳和水。

消除

富马酸单甲酯代谢产生的CO2呼出是消除的主要途径。仅少量完整的富马酸单甲酯通过尿液或粪便排出体外。与谷胱甘肽反应而形成谷胱甘肽加合物的富马酸二甲酯部分被代谢为巯基酸，后者从尿液中排出。

富马酸单甲酯的表观末端消除半衰期约为2小时。

线性/非线性

尽管受试者之间存在较高的变异性，但以单剂量服用4 x 30 mg富马酸二甲酯（总剂量为120 mg）和2 x 120 mg富马酸二甲酯（总剂量）后，以AUC和Cmax衡量的暴露通常与剂量成比例。 240毫克）。

肾功能不全

没有针对肾功能不全患者的具体研究。但是，由于肾脏清除在血浆总清除中起着很小的作用，因此肾脏损害不太可能影响Skilarence的药代动力学特征（请参阅第4.2节）。

肝功能不全

对于肝功能不全的患者尚未进行任何具体研究。但是，由于富马酸二甲酯通过酯酶和小肠的碱性环境代谢而没有细胞色素P450的参与，因此预计肝功能损害不会影响其暴露（参见第4.2节）。

5.3临床前安全数据

非临床安全药理和遗传毒性数据显示对人类没有特殊危害。

毒理学

在非临床研究中，肾脏被确定为毒性的主要靶器官。狗的肾脏发现包括最小至中度的肾小管肥大，肾小管空泡的发生率和严重性增加以及最小至轻度的肾小管变性，这被认为在毒理学上相关。治疗3个月后未观察到的不良反应水平（NOAEL）为30 mg / kg /天，相当于最高建议剂量（720 mg /天）下人体全身暴露的2.9倍和9.5倍，分别为AUC和Cmax值。

生殖毒性

Skilarence尚未进行生育力或产前和产后发育研究。

在大鼠胚胎发育研究中，对胎儿体重或因母体给予富马酸二甲酯引起的畸形没有影响。但是，随着母体毒性剂量的增加，胎儿数量增加，“超额肝叶”和“异常骨排列”发生变化。孕产妇和胚胎毒性的NOAEL为40 mg / kg /天，相当于最高推荐剂量（720 mg /天）下人体全身暴露的0.2倍和2.0倍，分别为AUC和Cmax值。

富马酸二甲酯已被证明可在大鼠中穿过胎盘膜进入胎儿血液。

致癌性

未对Skilarence进行致癌性研究。根据现有数据表明富马酸酯可能会激活与肾脏肿瘤发展相关的细胞途径，不能排除外源性富马酸二甲酯在肾脏上的潜在致瘤活性。

6.药物特性

6.1辅料清单

Skilarence 30毫克和Skilarence 120毫克

核心：

一水乳糖

纤维素微晶

交联羧甲基纤维素钠

胶体无水二氧化硅

硬脂酸镁

斯基伦仑30毫克

涂层：

甲基丙烯酸-丙烯酸乙酯共聚物（1：1）

滑石

柠檬酸三乙酯

二氧化钛（E171）

二甲硅油

盗贼120毫克

涂层：

甲基丙烯酸-丙烯酸乙酯共聚物（1：1）

滑石

柠檬酸三乙酯

二氧化钛（E171）

二甲硅油

靛蓝胭脂红（E132）

氢氧化钠

6.2不兼容

不适用。

6.3保质期

3年。

6.4特殊的储存注意事项

该药品不需要任何特殊的存储条件。

6.5容器的性质和内容

Skilarence 30毫克

采用PVC / PVDC-铝泡罩包装的42、70和210耐胃药片剂。

Skilarence 120毫克

PVC / PVDC-铝泡罩包装中的40、70、90、100、120、180、200、240、300、360和400耐胃液片剂。

并非所有包装尺寸都可以销售。

6.6特殊处置注意事项

对处置无特殊要求。

7.营销授权持有人

Almirall，S.A.

龙达·米特将军（151）

08022巴塞罗那

西班牙

8.营销授权号

EU/1/17/1201/001

EU/1/17/1201/002

EU/1/17/1201/003

EU/1/17/1201/004

EU/1/17/1201/005

EU/1/17/1201/006

EU/1/17/1201/007

EU/1/17/1201/008

EU/1/17/1201/009

EU/1/17/1201/010

EU/1/17/1201/011

EU/1/17/1201/012

EU/1/17/1201/013

EU/1/17/1201/014

9.首次授权日期/授权更新

首次授权日期：2017年6月23日

10.文本的修订日期

有关该药品的详细信息，请访问欧洲药品管理局的网站http://www.ema.europa.eu。

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。

本说明书来源于：欧盟药品管理局EMA

https://www.ema.europa.eu/en/documents/product-information/skilarence-epar-product-information_en.pdf

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②本说明书仅供参考，最新的说明书详见药品附带的说明书。

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT 

Skilarence 30 mg gastro-resistant tablets 

Skilarence 120 mg gastro-resistant tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Skilarence 30 mg 

Each gastro-resistant tablet contains 30 mg dimethyl fumarate. 

Skilarence 120 mg 

Each gastro-resistant tablet contains 120 mg dimethyl fumarate.

Excipient with known effect 

Skilarence 30 mg 

Each gastro-resistant tablet contains 34.2 mg lactose (as monohydrate). 

Skilarence 120 mg 

Each gastro-resistant tablet contains 136.8 mg lactose (as monohydrate). 

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 

Gastro-resistant tablet. 

Skilarence 30 mg 

White, film-coated, round, biconvex tablet with a diameter of approximately 6.8 mm. 

Skilarence 120 mg 

Blue, film-coated, round, biconvex tablet with a diameter of approximately 11.6 mm.

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

Skilarence is indicated for the treatment of moderate to severe plaque psoriasis in adults in need of systemic medicinal therapy.

4.2 Posology and method of administration

Skilarence is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis. 

Posology

To improve tolerability, it is recommended to begin treatment with a low initial dose with subsequent gradual increases. In the first week, Skilarence 30 mg is taken once daily (1 tablet in the evening). In the second week, Skilarence 30 mg is taken twice daily (1 tablet in the morning and 1 in the evening). In the third week, Skilarence 30 mg is taken three times daily (1 tablet in the morning, 1 at midday, and 1 in the evening). From the fourth week, treatment is switched to only 1 tablet of Skilarence 120 mg in the evening. This dose is then increased by 1 Skilarence 120 mg tablet per week at different times of day for the subsequent 5 weeks, as shown in the table below. The maximum daily dose allowed is 720 mg (3 x 2 tablets of Skilarence 120 mg).

If a particular dose increase is not tolerated, it may be temporarily reduced to the last tolerated dose.

If treatment success is observed before the maximum dose is reached, no further increase of dose is necessary. After clinically relevant improvement of the skin lesions has been achieved, consideration should be given to gradual reduction of the daily dose of Skilarence to the maintenance dose required by the individual.

Dosage modifications may also be necessary if abnormalities in laboratory parameters are observed (see section 4.4).

Elderly patients

Clinical studies of Skilarence did not include sufficient numbers of patients aged 65 years and above to determine whether they respond differently compared to patients under 65 years (see section 5.2). Based on the pharmacology of dimethyl fumarate, a need for dose adjustment in the elderly is not expected.

Renal impairment 

No dose adjustment is needed in patients with mild to moderate renal impairment (see section 5.2). Skilarence has not been studied in patients with severe renal impairment, and use of Skilarence is contraindicated in these patients (see section 4.3).

Hepatic impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment (see section 5.2). Skilarence has not been studied in patients with severe hepatic impairment, and use of Skilarence is contraindicated in these patients (see section 4.3).

Paediatric population

The safety and efficacy of Skilarence in paediatric patients below the age of 18 years have not been established. There are no data available with Skilarence in paediatric patients.

Method of administration 

Skilarence is for oral use. Skilarence tablets must be swallowed whole with fluid during or immediately after a meal. The coating of the gastro-resistant tablets is designed to prevent gastric irritation. Therefore, the tablets should not be crushed, divided, dissolved or chewed.

4.3 Contraindications

‒ Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

‒ Severe gastrointestinal disorders.

‒ Severe hepatic or renal impairment.

‒ Pregnancy and breast-feeding. 

4.4 Special warnings and precautions for use

Haematology

Skilarence may decrease leukocyte and lymphocyte counts (see section 4.8). It has not been studied in patients with pre-existing low leukocyte or lymphocyte counts. 

Before treatment 

Prior to initiating treatment with Skilarence, a current complete blood count (including differential blood count and platelet count) should be available. Treatment should not be initiated if leukopenia below 3.0x109 /L, lymphopenia below 1.0x109 /L or other pathological results are identified.

During treatment

During treatment a complete blood count with differential should be performed every 3 months. Action is needed in the following circumstances:

Leukopenia: If a marked decrease in the total number of white blood cells is found, the situation should be monitored carefully and treatment with Skilarence should be discontinued at levels below 3.0x109 /L.

Lymphopenia: If the lymphocyte count falls below 1.0x109 /L but is ≥0.7 x109 /L, blood monitoring should be performed monthly until levels return to 1.0x109 /L or higher for two consecutive blood tests at which point monitoring can again be performed every 3 months. If the lymphocyte count falls below 0.7x109 /L, the blood test must be repeated and if the levels are confirmed to be below 0.7x109 /L, then treatment must be stopped immediately. Patients developing lymphopenia should be monitored after stopping treatment until their lymphocyte count has returned to the normal range (see section 4.8).

Other haematological disorders

Therapy should be discontinued and caution is advised if other pathological results occur. In any case blood counts should be monitored until values have returned to the normal range.

Infections

Skilarence is an immunomodulator and may affect the way the immune system responds to infection. For patients with pre-existing infections of clinical relevance, the physician should decide if treatment with Skilarence should only be initiated once the infection has resolved. If a patient develops an infection during treatment with Skilarence, suspension of treatment should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Skilarence should be instructed to report symptoms of infection to a physician.

Opportunistic infections/progressive multifocal leukoencephalopathy (PML)

Cases of opportunistic infections, particularly of progressive multifocal leukoencephalopathy (PML) have been reported with other dimethyl fumarate-containing products (see section 4.8). PML is an opportunistic infection caused by the John-Cunningham virus (JCV) that can be fatal or cause severe disabilities. PML is probably caused by a combination of factors.

A previous infection with JCV is considered a prerequisite for the development of PML. Risk factors can include previous immunosuppressive treatment and the existence of certain concomitant disorders (such as some autoimmune disorders or malignant haematological conditions). A modified or weakened immune system as well as genetic or environmental factors can also constitute risk factors.

Persistent moderate or severe lymphopenia during treatment with dimethyl fumarate is also considered a risk factor for PML. Patients who develop lymphopenia should be monitored for signs and symptoms of opportunistic infections, particularly for symptoms indicative of PML. Typical symptoms associated with PML are diverse, become worse over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision and changes in thinking, memory and orientation leading to confusion and personality changes. If PML is suspected, treatment with Skilarence should be stopped immediately and further appropriate neurological and radiological examinations performed.

Prior and concomitant treatment with immunosuppressive or immunomodulating therapies 

Limited data are available on the efficacy and safety of Skilarence in patients who have been previously treated with other immunosuppressive or immunomodulating therapies. When switching patients from such therapies to Skilarence, the half-life and mode of action of the other therapy should be considered in order to avoid additive effects on the immune system.

No data are available on the efficacy and safety of Skilarence when taken concomitantly with other immunosuppressive or immunomodulating therapies (see section 4.5).

Pre-existing gastrointestinal disease

Skilarence has not been studied in patients with pre-existing gastrointestinal disease. Skilarence is contraindicated in patients with severe gastrointestinal disease (see sections 4.3). Gastrointestinal tolerability can be improved by following the dose titration schedule on initiating Skilarence treatment and by taking Skilarence with food (see sections 4.2 and 4.8).

Renal function

Since renal elimination plays a minor role in the clearance of Skilarence from plasma, it is unlikely that renal impairment would affect the pharmacokinetic characteristics, and so a need for dose adjustment in patients with mild to moderate renal impairment is not expected (see sections 4.2 and 5.2).

During the Phase III placebo-controlled clinical trial, renal function was not seen to deteriorate during therapy across treatment groups. However, Skilarence has not been studied in patients with severe renal impairment, and some cases of renal toxicity have been reported during post-marketing surveillance with fumaric acid esters. Hence, Skilarence is contraindicated in patients with severe renal impairment (see section 4.3).

Renal function (e.g. creatinine, blood urea nitrogen and urinalysis) should be checked prior to initiation of treatment and every 3 months thereafter. In the event of a clinically relevant change in renal function, particularly in the absence of alternative explanations, consideration should be given to dosage reduction or treatment discontinuation.

Fanconi syndrome

Early diagnosis of Fanconi syndrome and discontinuation of Skilarence treatment are important to prevent the onset of renal impairment and osteomalacia, as the syndrome is usually reversible. The most important signs are: proteinuria, glucosuria (with normal blood sugar levels), hyperaminoaciduria and phosphaturia (possibly concurrent with hypophosphatemia). Progression might involve symptoms such as polyuria, polydipsia and proximal muscle weakness. In rare cases hypophosphataemic osteomalacia with non-localised bone pain, elevated alkaline phosphatase in serum and stress fractures may occur. Importantly, Fanconi syndrome can occur without elevated creatinine levels or low glomerular filtration rate. In case of unclear symptoms Fanconi syndrome should be considered and appropriate examinations should be performed.

Hepatic function

Skilarence has not been studied in patients with severe hepatic impairment and is contraindicated in these patients (see section 4.3).

It is recommended to monitor hepatic function (SGOT, SGPT, gamma-GT, AP) prior to initiation of treatment and every 3 months thereafter, since elevation of hepatic enzymes has been observed in some patients in the Phase III study. In the event of a clinically relevant change in hepatic parameters, particularly in the absence of alternative explanations, consideration should be given to dose reduction or treatment discontinuation.

Flushing

Patients should be made aware that they are likely to experience flushing in the first few weeks of taking Skilarence (see section 4.8).

Lactose

Skilarence contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Skilarence should be used cautiously in combination with other systemic antipsoriatic therapy (e.g. methotrexate, retinoids, psoralens, ciclosporin, immunosuppressants or cytostatics) (see section 4.4). During treatment with Skilarence, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided.

Concurrent therapy with nephrotoxic substances (e.g. methotrexate, ciclosporin, aminoglycosides, diuretics, NSAIDs or lithium) may increase the potential for renal adverse reactions (e.g. proteinuria) in patients taking Skilarence.

In cases of severe or prolonged diarrhoea during treatment with Skilarence, absorption of other medicinal products may be affected. Caution should be exercised when prescribing medicinal products with a narrow therapeutic index that require absorption in the intestinal tract. The efficacy of oral contraceptives may be reduced and the use of an alternative barrier contraceptive method is recommended to prevent possible failure of contraception (see the prescribing information of the oral contraceptive).

Consumption of large quantities of strong alcoholic drinks (more than 30% alcohol by volume) should be avoided because it may lead to increased dissolution rates of Skilarence and, therefore, may increase the frequency of gastrointestinal adverse reactions.

Vaccination during treatment with Skilarence has not been studied. Immunosuppression is a risk factor for the use of live vaccines. The risk of vaccination should be weighed against the benefit.

There is no evidence for Skilarence interaction with cytochrome P450 and the most common efflux and uptake transporters, thus no interactions are expected with medicinal products metabolised or transported by these systems (see section 5.2).

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

Skilarence is not recommended in women of child-bearing potential not using appropriate contraception. In patients experiencing diarrhoea during Skilarence treatment, the effect of oral contraceptives may be reduced and additional barrier methods of contraception may be necessary (see section 4.5).

Pregnancy

There are limited data from the use of dimethyl fumarate in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Skilarence is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to newborns or infants cannot be excluded. Therefore, Skilarence is contraindicated during breastfeeding (see section 4.3).

Fertility

There are no human or animal data on the effects of Skilarence on fertility.

4.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been conducted. Skilarence may have a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of Skilarence (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions observed with Skilarence in the Phase III clinical study (1102) in psoriasis patients were gastrointestinal events (62.7%), flushing (20.8%) and lymphopenia (10.0%). Most adverse reactions were considered mild and did not lead to discontinuation of study treatment. The only adverse reactions that led to discontinuation of treatment in >5% of patients were gastrointestinal reactions. For monitoring recommendations and clinical management of adverse reactions, see section 4.4.

Tabulated list of adverse reactions

The following is a list of adverse reactions experienced by patients treated with Skilarence during the clinical study and with Fumaderm, a related medicinal product containing dimethyl fumarate along with other fumaric acid esters.

The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to＜1/10); uncommon (≥1/1,000 to＜1/100); rare (≥1/10,000 to＜1/1,000); very rare (<1/10,000);>＜1/10,000); and not known (cannot be estimated from available data).

Description of selected adverse reactions

Gastrointestinal disturbances

Data from the Phase III clinical study as well as from the literature show that gastrointestinal disorders with dimethyl fumarate-containing products are most likely to occur during the first 2 to 3 months after starting treatment. No apparent dose relationship and no risk factors for the occurrence of these adverse reactions could be identified. Diarrhoea was a common adverse reaction (36.9%) among patients taking Skilarence, leading to medicinal product withdrawal in about 10% of patients. More than 90% of these diarrhoea events were of mild to moderate severity (see section 4.4).

Flushing

Based on observations in the Phase III clinical study as well as on literature data, flushing is most likely to occur during the early weeks of treatment and tends to lessen with time. In the clinical study a total of 20.8% of patients receiving Skilarence experienced flushing, which was mild in the majority of cases (see section 4.4). Published clinical experience with dimethyl fumarate-containing products shows that individual episodes of flushing usually begin shortly after taking the tablets and resolve within a few hours.

Haematological changes

Data from the Phase III clinical study as well as from the literature show that changes in haematological parameters are most likely to occur during the first 3 months after starting treatment with dimethyl fumarate. In particular, in the clinical study there was a slight decrease in mean lymphocyte counts starting between weeks 3 and 5 and reaching a maximum in week 12 where approximately one third of patients had lymphocyte values below 1.0x109 /L. The mean and median values of lymphocytes remained within the normal range during the clinical study. At week 16 (end of treatment), there was no further decline in lymphocyte counts. At week 16 of treatment, 13/175 (7.4%) of patients were noted to have lymphocyte levels＜0.7x 109 /L. Blood sampling for safety clinical laboratory tests at follow-up visits was only performed in case of abnormalities at the preceeding visit. During the treatment free follow up, lymphocyte levels of＜0.7x 109 /L were observed in 1/29 (3.5%) patient at 6 months and 0/28 (0%) at 12 months after stopping treatment. At 12 months after stopping treatment 3/28 (10.7%) of patients had lymphocyte values below 1.0x109 /L, which would represent 3/279 (1.1%) of the patients started on Skilarence.

For the total leukocyte count, a decline became apparent at week 12 of treatment; it slowly increased again at week 16 (end of treatment); and 12 months after stopping treatment all patients had values above 3.0x109 /L.

A transient increase in mean values of eosinophils was noted as early as week 3, reached a maximum at week 5 and 8, and had returned to baseline values at week 16.

For monitoring recommendations and clinical management of haematological adverse reactions, see section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Symptomatic treatment is indicated in the case of an overdose. No specific antidote is known.

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

Pharmacotherapeutic group: Other immunosuppressants, ATC code: L04AX07

Mechanism of action

The anti-inflammatory and immunomodulating effects of dimethyl fumarate and its metabolite monomethyl fumarate are not fully elucidated but are thought to be mainly due to the interaction with the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. This interaction with glutathione leads to the inhibition of translocation into the nucleus and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).

The main activity of dimethyl fumarate and monomethyl fumarate is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype. The inflammatory cytokine production is reduced with induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules, and diminished inflammatory infiltrate within psoriatic plaques.

Clinical efficacy and safety

The safety and efficacy of Skilarence was assessed in one double-blind, 3-arm, placebo- and active comparator-controlled Phase III study (1102) in patients with moderate to severe plaque psoriasis (Study 1102). 704 patients were randomised to receive Skilarence, an active comparator (Fumaderm, a combination product with the same content of dimethyl fumarate plus 3 monoethyl fumarate salts) and placebo in a ratio of 2:2:1. Patients began treatment with tablets containing 30 mg/day dimethyl fumarate or placebo, titrating up to a maximum of 720 mg/day in both active treatment arms as described in section 4.2. If treatment success was observed before the maximum dose of 720 mg/day of dimethyl fumarate was reached, no further increase of dosage was necessary and the dosage was to be steadily reduced to an individual maintenance dose. In case of individual intolerability of the increased dosage during weeks 4 to 16, the patient was to return to the last tolerated dose taken since the start of week 4, which was to be maintained until end of the treatment period (week 16). Patients received treatment for up to 16 weeks and follow-up visits were planned for up to 12 months after treatment was stopped.

The demographic and baseline characteristics were well balanced between the treatment groups. Of the 699 patients, most were Caucasian (99%) and male (65%), and the mean age was 44 years. Most patients (91%) were＜65 years of age. Most patients had moderate psoriasis based on Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA) scores at baseline: the mean PASI score at baseline was 16.35 and 60% of patients scored as moderate on the PGA. The majority of patients reported a “very large” or “extremely large” effect of psoriasis on their life based on the Dermatology Life Quality Index (DLQI), with a mean DLQI score of 11.5.

After 16 weeks of treatment, Skilarence was found to be superior to placebo (p<0.0001) based on>＜0.0001) based on PASI 75 and PGA score clear or almost clear and non-inferior (using a non-inferiority margin of -15%) to the active comparator (p<0.0003) based on PASI 75. >＜0.0003) based on PASI 75.

Fumaderm = Active comparator, a combination product with the same content of dimethyl fumarate plus 3 monoethyl hydrogen fumarate salts; n=number of patients with available data; N=number of patients in population; PASI=Psoriasis Area Severity Index; PGA=Physician’s Global Assessment; a Superiority of Skilarence vs. Placebo with a difference of 22.2% for PASI 75 and 20.0% for PGA score clear or almost clear, superiority of Fumaderm vs Placebo with a difference of 25.0% for PASI 75 and 24.4% for PGA score clear or almost clear; b Non-inferiority of Skilarence vs. Fumaderm with a difference of -2.8% for PASI 75 and -4.4% for PGA score clear or almost clear.

There was a trend in the efficacy endpoint PASI score mean % change from baseline, indicating the onset of a clinical response to Skilarence as early as week 3 (-11.8%) which became statistically significant compared to placebo by week 8 (-30.9%). Further improvement was seen by week 16 (-50.8%).

The benefits of treatment with Skilarence were also supported by patient self-perceived improvements in their quality of life. At week 16, patients treated with Skilarence had a lower mean DLQI compared to placebo (5.4 vs 8.8).

Rebound (defined as worsening of ≥125% of baseline PASI value) was assessed after 2 months off treatment and was shown not to be a clinical concern with fumaric acid esters, as it was documented in very few patients (Skilarence 1.1% and active comparator 2.2%, compared to 9.3% in the placebo group).

Long-term efficacy data are currently not available for Skilarence, however, in the pharmacokinetic and clinical studies the systemic exposure, efficacy and safety of Skilarence were shown to be comparable to the active comparator containing dimethyl fumarate. Hence it is reasonable to expect the long-term efficacy of Skilarence to also be comparable to dimethyl fumarate-containing products. Maintenance of long term efficacy has been well described for other dimethyl fumarate-containing products, and therefore the treatment benefits seen with Skilarence at 16 weeks can be expected to be maintained in patients treated over the long term for at least 24 months.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Skilarence in all subsets of the paediatric population in this indication (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

After oral administration, dimethyl fumarate is not detected in plasma because it is rapidly hydrolysed by esterases to its active metabolite monomethyl fumarate. After oral administration of a single Skilarence 120 mg tablet in healthy subjects, monomethyl fumarate reached plasma peak concentrations of around 1325 ng/mL and 1311 ng/mL under fasted or fed conditions, respectively. Taking Skilarence with food delayed the tmax of monomethyl fumarate from 3.5 to 9.0 hours.

Distribution

The plasma protein binding of monomethyl fumarate is around 50%. Dimethyl fumarate does not show any binding affinity to serum proteins which may further contribute to its rapid elimination from the circulation.

Biotransformation

The biotransformation of dimethyl fumarate does not involve cytochrome P450 isoenzymes. In vitro studies have shown that monomethyl fumarate at the therapeutic dose does not inhibit or induce any of the cytochrome P450 enzymes, it is not a substrate or inhibitor of P-glycoprotein and is not an inhibitor of the most common efflux and uptake transporters. In vitro studies have shown that dimethyl fumarate at a therapeutic dose does not inhibit CYP3A4/5 and BCRP and is a weak P-glycoprotein inhibitor.

In vitro studies have shown that hydrolysis of dimethyl fumarate to monomethyl fumarate occurs rapidly at pH 8 (pH in the small intestine), but not at pH 1 (pH in the stomach). A part of the total dimethyl fumarate is hydrolysed by esterases and the alkaline milieu of the small intestine, while the remainder enters the portal vein blood. Further studies have shown that dimethyl fumarate (and to a lesser extent monomethyl fumarate) reacts partially with reduced glutathione forming a glutathioneadduct. These adducts were detected in animal studies in the intestinal mucosa of rats and to a smaller extent in portal vein blood. Unconjugated dimethyl fumarate, however, cannot be detected in the plasma of animals or psoriatic patients following oral administration. By contrast, unconjugated monomethyl fumarate is detectable in plasma. Further metabolism occurs through oxidation via the tricarboxylic acid cycle forming carbon dioxide and water.

Elimination

Exhalation of CO2 resulting from the metabolism of monomethyl fumarate is the primary route of elimination; only small amounts of intact monomethyl fumarate are excreted through urine or faeces. The portion of dimethyl fumarate that reacts with glutathione, forming a glutathione-adduct, is metabolised further to its mercapturic acid, which is excreted in the urine.

The apparent terminal elimination half-life of monomethyl fumarate is about 2 hours.

Linearity/non-linearity

Despite the high inter-subject variability, the exposure measured as AUC and Cmax was generally dose-proportional after single dose administration of 4 x 30 mg dimethyl fumarate tablets (total dose of 120 mg) and 2 x 120 mg dimethyl fumarate tablets (total dose of 240 mg).

Renal impairment

No specific studies have been performed in patients with renal impairment. However, because renal elimination plays a minor role in the total clearance from plasma, it is unlikely that renal impairment may affect the pharmacokinetic characteristics of Skilarence (see section 4.2).

Hepatic impairment

No specific studies have been performed in patients with hepatic impairment. However, as dimethyl fumarate is metabolised by esterases and the alkaline milieu of the small intestine without the involvement of cytochrome P450, hepatic impairment is not expected to influence exposure (see section 4.2).

5.3 Preclinical safety data

Non-clinical safety pharmacology and genotoxicity data reveal no special hazard for humans.

Toxicology

The kidney was identified as a major target organ of toxicity in non-clinical studies. Renal findings in dogs included minimal to moderate tubular hypertrophy, increased incidence and severity of tubular vacuolation and minimal to slight tubular degeneration, which were considered toxicologically relevant. The no-observed adverse-effect-level (NOAEL) after 3 months of treatment was 30 mg/kg/day, which corresponds to 2.9-fold and 9.5-fold the human systemic exposure at the highest recommended dose (720 mg/day), as AUC and Cmax values, respectively.

Reproduction toxicity

No fertility or pre- and post-natal development studies have been conducted with Skilarence.

There were no effects on foetal body weights or malformations attributed to maternal administration of dimethyl fumarate during the embryo-foetal development study in rats. However, there was an increased number of foetuses with the variations “supernumerary liver lobe” and “abnormal iliac alignment” at maternally toxic doses. The NOAEL for maternal and embryo-foetal toxicity was 40 mg/kg/day, corresponding to 0.2-fold and 2.0-fold the human systemic exposure at the highest recommended dose (720 mg/day), as AUC and Cmax values, respectively.

Dimethyl fumarate has been shown to cross the placental membrane into foetal blood in rats.

Carcinogenicity

No carcinogenicity studies have been performed for Skilarence. Based on available data suggesting that fumaric acid esters may activate cellular pathways related to the development of renal tumours, a potential tumorigenic activity of exogenously administered dimethyl fumarate on the kidneys cannot be excluded.

6. PHARMACEUTICAL PARTICULARS 

6.1 List of excipients

Skilarence 30 mg and Skilarence 120 mg

Core: 

Lactose monohydrate 

Cellulose microcrystalline 

Croscarmellose sodium 

Colloidal anhydrous silica 

Magnesium stearate

Skilarence 30 mg 

Coating: 

Methacrylic acid-ethyl acrylate copolymer (1:1) 

Talc 

Triethyl citrate 

Titanium dioxide (E171) 

Simethicone

Skilarence 120 mg 

Coating:

Methacrylic acid-ethyl acrylate copolymer (1:1) 

Talc 

Triethyl citrate 

Titanium dioxide (E171) 

Simethicone 

Indigo carmine (E132) 

Sodium hydroxide

6.2 Incompatibilities 

Not applicable. 

6.3 Shelf life 

3 years. 

6.4 Special precautions for storage 

This medicinal product does not require any special storage conditions. 

6.5 Nature and contents of container

Skilarence 30 mg 

42, 70 and 210 gastro-resistant tablets in PVC/PVDC-aluminium blister packs. 

Skilarence 120 mg 

40, 70, 90, 100, 120, 180, 200, 240, 300, 360 and 400 gastro-resistant tablets in PVC/PVDC-aluminium blister packs. 

Not all pack sizes may be marketed.

6.6 Special precautions for disposal 

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER 

Almirall, S.A. 

Ronda General Mitre, 151 

08022 Barcelona 

Spain

8. MARKETING AUTHORISATION NUMBERS

EU/1/17/1201/001

EU/1/17/1201/002

EU/1/17/1201/003

EU/1/17/1201/004

EU/1/17/1201/005

EU/1/17/1201/006

EU/1/17/1201/007

EU/1/17/1201/008

EU/1/17/1201/009

EU/1/17/1201/010

EU/1/17/1201/011

EU/1/17/1201/012

EU/1/17/1201/013

EU/1/17/1201/014

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23 june 2017

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。