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

Javlor 25 mg / mL浓缩液，用于输液

2.定性和定量组成

一毫升浓缩物含有25毫克长春氟宁（酒石酸氢盐）。

一个2毫升的小瓶包含50毫克的长春氟宁（酒石酸氢盐）。

一个4毫升的小瓶中含有100毫克的长春氟宁（酒石酸氢盐）。

一个10毫升的小瓶包含250毫克的长春氟宁（酒石酸氢盐）。

有关赋形剂的完整列表，请参见第6.1节。

3.药物形式

浓缩用于输注的溶液（无菌浓缩液）。

透明，无色至浅黄色溶液。

4.临床特点

4.1治疗适应症

Javlor在单药治疗中被指定用于治疗先前的含铂治疗方案失败后患有晚期或转移性尿道上皮细胞癌的成年患者

对于工作状态≥2的患者，尚未研究长春氟宁的疗效和安全性。

4.2给药方式和方法

长春氟宁治疗应在有资格使用抗癌化学疗法的医师的协助下开始，并且仅限于专门用于细胞毒性化学疗法的单位。

在每个周期之前，应进行充分的全血细胞计数监测，以验证绝对中性粒细胞计数（ANC），血小板和血红蛋白，因为中性粒细胞减少，血小板减少和贫血是长春氟宁的常见不良反应。

剂量

推荐剂量为每3周静脉输注20分钟长春氟宁320 mg /m²。

如果WHO / ECOG的表现状态（PS）为1或PS为0，并且在接受骨盆照射之前，应以280 mg /m²的剂量开始治疗。在第一个周期中没有任何血液学毒性导致治疗延迟或剂量减少时，在随后的周期中，每3周剂量将增加至320 mg /m²。

推荐联合用药

为了预防便秘，建议在每次服用长春氟尼汀后的第1天至第5天或第7天服用泻药和饮食措施，包括口服水合作用（请参阅第4.4节）。

由于毒性导致剂量延迟或终止

因毒性而调整剂量

特殊人群

肝功能不全患者已完成对肝功能改变患者的药代动力学和耐受性I期研究（请参阅5.2节）。 在这些患者中，长春氟宁的药代动力学没有改变，但是根据长春氟宁给药后的肝生物学参数改变（γ-谷氨酰胺转移酶（GGT），转氨酶，胆红素），推荐剂量如下：

● 患者无需调整剂量：

  ○ 凝血酶原时间> 70％NV（正常值），并至少满足以下条件之一：[ULN（正常上限）<胆红素≤1.5×ULN和/或1.5xULN <转氨酶≤2.5×ULN和/ 或ULN

  ○ 转氨酶≤2.5xULN（仅在发生肝转移的情况下<5xULN）。

● 对于轻度肝功能不全（Child-Pugh A级）或凝血酶原时间≥60％NV且1.5×ULN <胆红素≤3×ULN的患者，长春氟宁的推荐剂量为每3周一次250 mg /m² 并提出以下至少一项标准：[转氨酶> ULN和/或GGT> 5×ULN]。

● 中度肝功能不全（Child-Pugh B级）或凝血酶原时间≥50％NV，胆红素> 3×ULN和转氨酶> ULN的患者，每3周一次给予长春氟宁的推荐剂量为200 mg /m² 和GGT> ULN。

未对严重肝功能不全（Child-Pugh C级）或凝血酶原时间<50％NV或胆红素> 5xULN或分离的转氨酶> 2.5xULN（仅在肝素情况下≥5xULN）的患者进行Vinflunine评估转移）或GGT> 15xULN。

肾功能不全的患者

在临床研究中，包括CrCl（肌酐清除率）> 60 mL / min的患者，并以推荐剂量治疗。

对于中度肾功能不全（40 mL / min≤CrCl≤60 mL / min）的患者，建议剂量为每3周280 mg /m²。

对于严重肾功能不全（20 mL / min≤CrCl <40 mL / min）的患者，推荐剂量为每3周250 mg /m²（请参阅5.2节）。

对于进一步的循环，如发生毒性，应调整剂量，如下表3所示。

老年患者（≥75岁）

小于75岁的患者无需调整与年龄相关的剂量（请参阅第5.2节）。至少75岁的患者建议的剂量如下：

● 对于至少75岁但小于80岁的患者，每3周给予长春氟宁剂量为280 mg /m²。

● 在80岁及以上的患者中，长春氟宁的剂量为每3周250 mg /m²。

对于进一步的循环，如发生毒性，应调整剂量，如下表3所示：

小儿人口

Javlor在儿科人群中没有相关用途

给药方法

在处理或服用Javlor药品之前，应采取预防措施，然后再稀释。 Javlor仅可单次使用。

有关给药前药物稀释的说明，请参阅第6.6节

Javlor只能静脉注射。

Javlor应通过20分钟静脉输注给药，而不应通过快速静脉推注给药。

外周线或中央导管均可用于长春氟宁给药。当通过周围静脉注射时，长春氟宁可引起静脉刺激（请参阅第4.4节）。如果是静脉小或硬化，淋巴水肿或同一静脉最近出现静脉穿刺，则最好使用中央导管。为避免外溢，在开始输注之前，请确保正确插入针头，这一点很重要。

为了冲洗静脉，应始终在稀释的Javlor给药后至少输注等体积的氯化钠9 mg / mL（0.9％）溶液或输注葡萄糖50 mg / mL（5％）溶液。

有关管理的详细说明，请参见第6.6节。

4.3禁忌症

对活性物质或其他长春花生物碱过敏。

最近（2周内）或当前严重感染。

首次给药的基线ANC <1,500 / mm3，后续给药的基线ANC <1,000 / mm3

主管部门（请参阅第4.4节）。

血小板<100,000 / mm3（请参阅第4.4节）。

母乳喂养（见4.6节）。

4.4特殊警告和使用注意事项

血液学毒性

中性粒细胞减少，白细胞减少，贫血和血小板减少是长春氟宁的常见不良反应。每次输注长春氟宁之前，应进行充分的全血细胞计数监测，以验证ANC，血小板和血红蛋白值（参见第4.3节）。

基线ANC <1,500 / mm3或血小板<100,000 / mm3的受试者禁忌长春氟宁的使用。对于随后的给药，在基线ANC <1,000 / mm3或血小板<100,000 / mm3的受试者中禁用长春氟宁。

具有血液学毒性的患者应减少推荐剂量（参见第4.2节）。

胃肠道疾病

接受治疗的患者中有15.3％发生≥3级便秘。 NCI CTC 3级便秘定义为需要人工排泄或灌肠的便秘，4级便秘则是阻塞或有毒的巨结肠。便秘是可逆的，可以通过特殊的饮食措施（例如口服水合和摄入纤维）以及在治疗周期的第1天至第5天或第7天服用缓泻剂（例如兴奋性泻药或粪便软化剂）来预防。便秘高风险患者（与阿片类药物，腹膜癌，腹部肿块，先前的大腹部手术同时治疗）应在早餐前每天的第1天至第7天服用渗透性泻药。

如果2级便秘（定义为需要泻药）持续5天或更长时间或≥3级，应调整长春氟宁的剂量（请参阅第4.2节）。

如果出现任何≥3级的胃肠道毒性（呕吐或恶心除外）或粘膜炎（≥2级，持续5天或以上或任何持续时间≥3级），则需要调整剂量。等级2被定义为“中等”，等级3被定义为“严重”，等级4被定义为“威胁生命”（请参阅​​第4.2节中的表2）。

心脏疾病

长春氟宁给药后几乎没有观察到QT间隔延长。尽管长春氟宁未观察到室性心律失常，但这种作用可能导致室性心律不齐的风险增加。但是，对于心律失常风险增加的患者（例如充血性心力衰竭，已知的QT间隔延长病史，低钾血症），应谨慎使用长春氟宁（参见4.8节）。不建议同时使用两种或更多种延长QT / QTc间隔时间的物质（请参阅第4.5节）。

当对有心肌梗塞/局部缺血或心绞痛史的患者服用长春氟宁时，建议特别注意（见4.8节）。可能会发生缺血性心脏事件，尤其是在患有基础性心脏病的患者中。因此，应由医生对接受Javlor的患者进行心脏事件的监视。有心脏病史的患者应格外小心，并应定期仔细评估获益/风险评估。发生心脏缺血的患者应考虑停用长春氟宁。

后可逆性脑病综合征（PRES）

长春氟宁给药后观察到PRES病例。

典型的临床症状具有不同程度：神经系统（头痛，意识模糊，癫痫发作，视觉障碍），全身性（高血压）和胃肠道（恶心，呕吐）。

放射学症状是大脑后部的白质异常。出现PRES症状的患者应控制血压。为了确定诊断，建议进行脑成像。

临床和放射学特征通常在治疗中断后迅速消失而没有后遗症。

出现PRES神经征象的患者应考虑停用长春氟宁（参见4.8节）。

低钠血症

使用长春氟宁可观察到严重的低钠血症，包括由于抗利尿激素分泌异常综合征（SIADH）引起的病例（参见第4.8节）。因此，在用长春氟宁治疗期间，建议定期监测血清钠水平。

肝功能不全

肝功能不全的患者应减少推荐剂量（参见第4.2节）。

肾功能不全

中度或重度肾功能不全患者应减少推荐剂量（见第4.2节）。

老年患者（≥75岁）

75岁及以上的患者应降低推荐剂量（请参阅第4.2节）。

相互作用

应避免将CYP3A4的强效抑制剂或强效诱导剂与长春氟宁同时使用（参见第4.5节）。

管理

鞘内注射Javlor可能致命。

当通过外周静脉注射时，长春氟宁可诱导1级（22％的患者，14.1％的周期），2级（11.0％的患者，6.8％的周期）或3级（0.8％的患者） ，0.2％的周期）静脉刺激。 所有病例均迅速消退，没有中断治疗。

应按照第6.6节中的说明进行管理。

避孕

具有生殖潜力的男人和女人在治疗期间以及最后一次长春氟宁给药后3个月内必须使用有效的避孕方法（请参见4.6节）。

4.5与其他药品的相互作用以及其他形式的相互作用

体外研究显示长春氟宁对CYP1A2，CYP2B6或CYP3A4活性均无诱导作用，对CYP1A2，CYP2B6，CYP2C8，CYP2C9，CYP2C19，CYP2D6和CYP3A4均无抑制作用。

体外研究表明，长春氟宁与其他长春花生物碱一样，是一种Pgp底物，但亲和力较低。因此，具有临床意义的相互作用的风险应该很小。

当长春氟宁与顺铂，卡铂，卡培他滨或吉西他滨合用时，未观察到药物动力学相互作用。

当长春氟宁与阿霉素合用时，未观察到药代动力学相互作用。但是，这种组合与血液学毒性特别高的风险有关。

一期研究评估酮康唑治疗（一种强效CYP3A4抑制剂）对长春氟宁的药代动力学的影响表明，酮康唑（400 mg口服，每天一次，共8天）的共同给药导致长春氟宁的血液暴露增加30％和50％及其代谢物4Odeacetyl-vinflunine（DVFL）。

因此应避免同时使用长春氟宁和强效CYP3A4抑制剂（如ritonavir，酮康唑，伊曲康唑和葡萄柚汁）或诱导剂（如利福平和贯叶连翘（St John's wort）），因为它们可能会增加或降低长春氟宁和DVFL的浓度（请参阅第4.4和5.2节）。

应避免将长春氟尼与其他延长QT / QTc间隔的药物同时使用（请参阅第4.4节）。

观察到长春氟宁与聚乙二醇化/脂质体阿霉素之间的药代动力学相互作用，导致长春氟宁暴露量明显增加了15％至30％，而阿霉素AUC的表观减少了2至3倍，而对于阿霉素而言，代谢产物的浓度却没有受到影响。根据一项体外研究，这种变化可能与长春氟宁在脂质体上的吸附以及两种化合物血液分布的改变有关。因此，使用这种类型的组合时应格外小心。

一项体外研究（轻微抑制长春氟尼新陈代谢）已提示可能与紫杉醇和多西紫杉醇（CYP3底物）发生相互作用。尚未对长春氟宁与这些化合物合用的具体临床研究。

与阿片类药物同时使用可能会增加便秘的风险。

4.6生育，怀孕和哺乳

男性和女性避孕

男女患者都应在停止治疗后三个月内采取适当的避孕措施。

怀孕

目前尚无孕妇使用长春氟宁的数据。动物研究表明，胚胎毒性和致畸性（参见第5.3节）。根据动物研究的结果和该药物的药理作用，存在胚胎和胎儿异常的潜在风险。

因此，除非绝对必要，否则在怀孕期间不应使用长春氟宁。如果在治疗过程中发生怀孕，应告知患者未出生婴儿的风险，并进行认真监测。应该考虑遗传咨询的可能性。还建议对希望在治疗后生孩子的患者进行遗传咨询。

哺乳

未知长春氟宁或其代谢产物是否会从人乳中排出。由于可能会对婴儿造成非常有害的影响，因此禁止在用长春氟宁治疗期间母乳喂养（请参阅第4.3节）。

生育能力

由于使用长春氟宁治疗可能会导致不可逆转的不育，因此在治疗前应寻求有关精子保存的建议。

4.7对驾驶和使用机器的能力的影响

Javlor可能会引起不良反应，例如疲劳（非常常见）和头晕（常见），可能会对驾驶和使用机器的能力造成轻微或中度的影响。建议患者不要驾驶或使用机器不利反应，可能会对开展这些活动的能力产生影响（请参阅第4.8节）。

4.8不良影响

安全概要摘要

在二期和一期三期试验中，尿路上皮移行细胞癌患者（450例长春氟宁治疗的患者）中与治疗相关的最常见不良反应是血液学疾病，主要是中性粒细胞减少和贫血。胃肠道疾病，尤其是便秘，厌食，恶心，口腔炎/粘膜炎，呕吐，腹痛和腹泻，以及一般性疾病，如乏力/疲劳。

不良反应列表

不良反应按系统器官分类，严重程度的频率和等级在下面列出（NCI CTC 2.0版）。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）;非常罕见（<1 / 10,000）;未知（无法从可用数据中估算）。在每个频率组中，不良反应的严重程度从高到低依次为。

表4在用长春氟宁治疗的尿路上皮移行细胞癌患者中观察到的不良反应

a  售后经验报告的不良反应

b  根据非TCCU临床试验计算出的频率

所有迹象的不良反应

以下描述了在尿路上皮移行细胞癌患者和其他疾病患者中出现的不良反应以及长春花生物碱类效应的潜在严重或不良反应：

血液和淋巴系统疾病

在43.8％的患者中观察到3/4级中性粒细胞减少。严重贫血和血小板减少症较少见（分别为8.8％和3.1％）。在5.2％的患者中观察到发热性嗜中性白血球减少症定义为ANC <1,000 / mm3，发烧≥38.5°C，来源不明，无临床微生物学记录的感染（NCI CTC 2.0版）。在2.8％的患者中观察到3/4级中性粒细胞减少症的感染。

共有8名患者（占治疗人群的0.6％）死于感染，是中性粒细胞减少症的并发症。

胃肠道疾病

便秘是长春花生物碱的一种分类作用：11.8％的患者在用长春氟宁治疗期间经历了严重的便秘。报告的3/4级肠梗阻在进行医疗护理时可逆，占1.9％。便秘由医疗护理（请参阅第4.4节）。

神经系统疾病

感觉周围神经病是长春花生物碱的一类作用。 0.6％的患者经历过3级。在研究过程中全部解决。

后部可逆性脑病综合征的罕见病例已有报道（见4.4节）。

心血管疾病

心脏效应是长春花生物碱的已知类别效应。 0.5％的患者经历过心肌梗塞或局部缺血，其中大多数患者已患有心血管疾病或危险因素。一名患者死于心肌梗塞，另一名患者死于心肺骤停。

长春氟宁给药后几乎没有观察到QT间隔延长。

呼吸，胸和纵隔疾病

呼吸困难发生在3.2％的患者中，但很少严重（3/4级：1.2％）。

据报道，在一名用长春氟宁治疗的患者中，支气管痉挛的症状与适应症不同。

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

因过量服用长春氟宁引起的主要毒性作用是抑制骨髓，有引起严重感染的危险。

目前尚无用于长春氟宁过量的解毒剂。 如果用药过量，应将患者关在专门的病房，并严密监测生命机能。 还应采取其他适当措施，例如输血，施用抗生素和生长因子。

5.药理特性

5.1药效学性质

药物治疗组：抗肿瘤药，长春花生物碱和类似物，ATC代码：L01CA05

作用机理

长春氟宁在长春花结合位点处或附近与微管蛋白结合，从而抑制其聚合成微管，从而导致跑步机抑制，微管动力学破坏，有丝分裂停滞和凋亡。在体内，长春氟宁在存活延长和肿瘤生长抑制方面均对小鼠中的多种人类异种移植物显示出显着的抗肿瘤活性。

临床疗效和安全性

一项III期和两项II期试验支持在先前的含铂治疗方案失败后，使用Javlor治疗晚期或转移性尿路上皮癌，作为二线治疗。

在两项多中心，开放标签，单组II期临床试验中，总共有202名患者接受了长春氟宁治疗。

在一项多中心，开放标签的对照III期临床试验中，将253例患者随机分配接受长春氟宁+ BSC（最佳支持治疗）治疗，将117例患者随机分配到BSC治疗组。

中位总生存期为6.9个月（长春氟宁+ BSC）与4.6个月（BSC），但差异未达到统计学意义。危险比0.88（95％CI 0.69，1.12）。但是，对无进展生存期有统计学意义的影响。 PFS中位数为3.0个月（长春氟宁+ BSC）对1.5个月（BSC）（p = 0.0012）。

此外，对ITT人群进行的预先指定的多变量分析表明，如果考虑到预后因素（PS，内脏受累，碱性磷酸酶，血红蛋白，骨盆照射），长春氟宁对总体生存具有统计学显着的治疗效果（p = 0.036）考虑;危险比0.77（95％CI 0.61，0.98）。在合格人群中也观察到总体生存率的统计学显着性差异（p = 0.040）（该人群排除了在基线时有临床显着违反协议的13例不符合治疗条件的患者）；危险比0.78（95％CI 0.61，0.99）。这被认为是与功效分析最相关的人群，因为它最紧密地反映了要治疗的人群。因过量服用长春氟宁引起的主要毒性作用是抑制骨髓，有引起严重感染的危险。

目前尚无用于长春氟宁过量的解毒剂。 如果用药过量，应将患者关在专门的病房，并严密监测生命机能。 还应采取其他适当措施，例如输血，施用抗生素和生长因子。

在有或没有使用顺铂的患者中均证明了疗效。

在符合条件的人群中，根据先前的顺铂使用与BSC进行的总生存率（OS）的亚组分析显示，HR（95％CI）= [0.64（0.40 – 1.03）； p = 0.0821]，而无先前的顺铂，HR（95％CI）= [0.80（0.60 – 1.06）； p = 0.1263]，在先前的顺铂存在下。调整预后因素后，无或有顺铂患者亚组的OS分析显示，HR（95％CI）= [0.53（0.32 – 0.88）； p = 0.0143]，HR（95％CI）= [0.70（0.53 – 0.94）； p = 0.0174]。

在先前使用顺铂与BSC进行无进展生存期（PFS）的亚组分析中，结果为：HR（95％CI）= [0.55（0.34 – 0.89）； p = 0.0129]，而无先前的顺铂，HR（95％CI）= [0.64（0.48 – 0.85）； [p = 0.0040]在先前的顺铂存在下。调整预后因素后，无或有顺铂患者亚组的PFS分析显示HR（95％CI）= [0.51（0.31 – 0.86）； p = 0.0111]和HR（95％CI）= [0.63（0.48 – 0.84）； p = 0.0016]。

小儿人口

欧洲药物管理局放弃了在输尿管和膀胱癌以及乳腺癌的治疗中，在所有小儿科人群中使用Javlor提交研究结果的义务（有关小儿科使用的信息，请参见第4.2节）。

5.2药代动力学性质

Vinflunine的药代动力学在癌症患者的给药剂量范围内（从30 mg /m²到400 mg / m2）是线性的。

血液接触长春氟宁（AUC）与白细胞减少症，中性粒细胞减少和疲劳的严重程度显着相关。

分配

长春氟宁与人血浆蛋白适度结合（67.2±1.1％），血浆与全血浓度之比为0.80±0.12。蛋白结合主要涉及高密度脂蛋白和血清白蛋白，并且在患者中观察到的长春氟宁浓度范围内是不饱和的。与α-1酸性糖蛋白和血小板的结合是微不足道的（<5％）。分布的最终体积很大，为2422±676升（约35 l / kg），表明广泛分布到组织中。

生物转化

除4-O-去乙酰基长春花碱（DVFL）是血液中由多种酯酶形成的唯一活性代谢物和主要代谢物外，所有鉴定出的代谢物均由细胞色素CYP3A4同工酶形成。

消除

在多指数浓度衰减后消除了长春氟宁，最终半衰期（t1 / 2）接近40小时。与长春氟宁相比，DVFL形成缓慢且消除速度较慢（约120小时的t1 / 2）。

长春氟宁及其代谢产物通过粪便（2/3）和尿液（1/3）排泄。

在372例患者的群体药代动力学分析中（656种药代动力学特征），总血液清除率为40 l / h，个体间和个体内变异性较低（分别表示为25％和8％，以变异系数表示）。

特殊人群的药代动力学

肝功能不全

与具有正常肝功能的患者相比，在表现出不同程度肝功能不全的25例患者中未观察到长春氟宁和DVFL药代动力学的改变。人群药代动力学分析进一步证实了这一点（长春氟宁清除率与肝功能不全生物学指标之间没有相关性）。但是，对于肝功能不全的患者，建议调整剂量（请参阅第4.2节）。

肾功能不全

根据计算的肌酐清除率（CrCl）值对2例肾功能不全的患者进行了药代动力学I期研究：第1组（n = 13例）中度损伤（40 mL / min≤CrCl≤60 mL / min ）和第2组（n = 20例）严重受损（20 mL / min≤CrCl <40 mL / min）。 这项研究的药代动力学结果表明，当CrCl降低时，长春氟宁清除率降低。 人群药代动力学分析进一步证实了这一点（56名CrCl患者在20 mL / min至60 mL / min之间），表明长春氟宁的清除率受肌酐清除率值的影响（Cockcroft和Gault公式）。 对于中度和重度肾功能不全的患者，建议调整剂量（请参阅第4.2节）。

老年人（≥75岁）

在老年患者中进行了长春氟宁的药代动力学I期研究（n = 46）。 长春氟宁的剂量根据3个年龄段进行了调整，如下所示：

与70岁以下的年轻对照组相比，≥80岁的患者中的Vinflunine清除率显着降低。

70≤年龄<75岁和75≤年龄<80岁的患者未改变长春氟宁的药代动力学。

根据PK和安全性数据，建议在老年人组中降低剂量：

75≤年龄<80岁； 年龄≥80岁。

对于进一步的循环，应在有毒性的情况下调整剂量（参见第4.2节）。

其他

根据人群的药代动力学分析，性别和工作状态（ECOG评分）均对长春氟宁清除率没有影响，长春氟宁清除率与体表面积成正比。

5.3临床前安全数据

放射性长春氟宁对大鼠的影像学分布研究表明，肺，肾，肝，唾液和内分泌腺以及胃肠道中的化合物水平迅速高于血液中的化合物水平。

临床前数据显示，在所有测试的物种中，中度至重度中性粒细胞减少和轻度贫血，对狗和大鼠具有肝毒性（其特点是剂量升高的肝转氨酶和高剂量的肝坏死/肝细胞改变）。这些毒性作用与剂量有关，并且在1个月的恢复期后完全或部分可逆。长春氟宁没有引起动物周围神经病变。

在大鼠体内微核试验中，长春氟宁已被证明具有致分裂性（诱导染色体断裂），并且在小鼠淋巴瘤试验中（无代谢激活作用），其具有致突变性和致分裂性。

尚未研究长春氟宁的致癌潜力。

在生殖研究中，长春氟宁似乎具有致死性和致畸性，对兔子有致畸作用。在大鼠的产前和产后发育研究中，长春氟宁诱导2位雌性的子宫和阴道畸形，对交配和/或胚珠着床产生不利影响，并显着降低了受精数量。

6.药物特性

6.1辅料清单

注射用水

6.2不兼容

除第6.6节中提及的药物外，不得将此药物与其他药物混合。

6.3保质期

未打开的小瓶

3年。

稀释溶液

稀释药品的化学和物理使用稳定性已证明如下：

• 在聚乙烯或聚氯乙烯输液袋中避光：在冰箱（2°C-8°C）中长达6天，或在25°C下长达24小时；

从微生物学的角度来看，稀释后应立即使用该产品。如果不立即使用，则用户应负责使用前的使用时间和使用条件，并且在2°C至8°C的温度下通常不会超过24小时，除非在受控且经过验证的无菌条件下进行了稀释。

6.4特殊的储存注意事项

存放在冰箱（2°C-8°C）中。

存放在原始包装中以防光照。

有关药品稀释后的储存条件，请参阅第6.3节。

6.5容器的性质和内容

透明的I型玻璃小瓶，用灰色丁基或黑色氯丁基橡胶塞封闭，上面盖有压接的铝环和盖。每个小瓶包含2毫升（50毫克长春氟宁），4毫升（100毫克长春氟宁）或10毫升（250毫克长春氟宁）浓缩液用于输注。

包装大小为1和10小瓶。

并非所有包装尺寸都可以销售。

6.6处置和其他处置的特殊预防措施

准备和给药的一般注意事项。

长春氟宁是一种具有细胞毒性的抗癌药物，与其他潜在的有毒化合物一样，在处理Javlor时应谨慎行事。应考虑正确处理和处置抗癌药物的程序。所有转移程序都需要严格遵守无菌技术，最好采用垂直层流安全罩。 Javlor输液应仅由经过细胞毒剂处理培训的人员准备和使用。怀孕的工作人员不应该处理Javlor。建议使用手套，护目镜和防护服。

如果溶液与皮肤接触，应立即用肥皂和水彻底清洗。如果接触到粘膜，则应用水彻底冲洗。

浓缩液稀释

应将与计算出的长春氟宁剂量相对应的Javlor（浓缩液）体积混入100 mL袋装的9 mg / mL（0.9％）氯化钠溶液中进行输注。也可以使用葡萄糖50 mg / mL（5％）溶液进行输注。稀释后的溶液应避免光照直至给药（参见第6.3节）。

给药方法

Javlor仅可用于静脉内使用。

Javlor仅可单次使用。

稀释Javlor浓缩物后，将按以下方式管理输液：

● 应在大静脉上最好在大静脉上建立500毫升氯化钠9 mg / mL（0.9％）注射溶液或葡萄糖50 mg / mL（5％）溶液输注静脉通道。 前臂或使用中央静脉线。 应当避免手背的静脉和靠近关节的静脉。

● 静脉输注应以500毫升袋装的氯化钠9 mg / mL（0.9％）溶液的一半或葡萄糖50 mg / mL（5％）溶液（即250 mL）的一半自由流动开始 率冲洗静脉。

● 用于输注的Javlor溶液应背负于最靠近500 mL袋的侧面注射端口，以在给药期间进一步稀释Javlor。

●  Javlor输液应在20分钟内输注。

● 应经常评估通畅性，并在整个输注过程中保持外渗预防措施。

● 输液完成后，应以300 mL的流速运行氯化钠9 mg / mL（0.9％）溶液或葡萄糖50 mg / mL（5％）溶液的剩余250 mL输注袋 /H。 为了冲洗静脉，应始终在注射Javlor溶液后再输注等体积的氯化钠9 mg / mL（0.9％）溶液或葡萄糖50 mg / mL（5％）溶液。 输液。

任何未使用的药品或废料应按照当地对细胞毒性药品的要求进行处理。

7.营销授权持有人

皮埃尔·法布尔（Pierre Fabre）

45，Abel Gance地点

F-92100布洛涅

法国

8.营销授权号

欧盟/ 1/09/550 / 001-012

9.首次授权日期/授权更新

首次授权日期：2009年9月21日

最新续订日期：2014年5月16日

10.文本的修订日期

XX月YYYY

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

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

温馨提醒：

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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

Javlor 25 mg/mL concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One mL of concentrate contains 25 mg of vinflunine (as ditartrate).

One 2 mL vial contains 50 mg of vinflunine (as ditartrate).

One 4 mL vial contains 100 mg of vinflunine (as ditartrate).

One 10 mL vial contains 250 mg of vinflunine (as ditartrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate). 

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Javlor is indicated in monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen

Efficacy and safety of vinflunine have not been studied in patients with performance status ≥ 2.

4.2 Posology and method of administration

Vinflunine treatment should be initiated under the responsibility of a physician qualified in the use of anticancer chemotherapy and is confined to units specialised in the administration of cytotoxic chemotherapy.

Before each cycle, adequate monitoring of complete blood counts should be conducted to verify the absolute neutrophil count (ANC), platelets and haemoglobin as neutropenia, thrombocytopenia and anaemia are frequent adverse reactions of vinflunine.

Posology

The recommended dose is 320 mg/m² vinflunine as a 20 minute intravenous infusion every 3 weeks.

In case of WHO/ECOG performance status (PS) of 1 or PS of 0 and prior pelvic irradiation, the treatment should be started at the dose of 280 mg/m². In the absence of any haematological toxicity during the first cycle causing treatment delay or dose reduction, the dose will be increased to 320 mg/m² every 3 weeks for the subsequent cycles.

Recommended co-medication

In order to prevent constipation, laxatives and dietary measures including oral hydration are recommended from day 1 to day 5 or 7 after each vinflunine administration (see section 4.4).

Dose delay or discontinuation due to toxicity

Dose adjustments due to toxicity

Special populations

Patients with hepatic impairment A pharmacokinetic and tolerability phase I study in patients with altered liver functions test has been completed (see section 5.2). Vinflunine pharmacokinetics was not modified in those patients, however based on hepatic biologic parameter modifications following vinflunine administration (gamma glutamyl transferases (GGT), transaminases, bilirubin), the dose recommendations are as follows:

●  No dose adjustment is necessary in patients:

with a prothrombin time > 70% NV (Normal Value) and presenting at least one of the following criteria: [ ULN (Upper Limit of Normal) < bilirubin ≤ 1.5×ULN and/or 1.5xULN < transaminases ≤ 2.5×ULN and/or ULN < GGT ≤ 5×ULN ]

with transaminases ≤ 2.5xULN ( < 5xULN only in case of liver metastases).

●  The recommended dose of vinflunine is 250 mg/m² given once every 3 weeks in patients with mild liver impairment (Child-Pugh grade A) or in patients with a prothrombin time ≥ 60% NV and 1.5×ULN < bilirubin ≤ 3×ULN and presenting at least one of the following criteria: [ transaminases > ULN and/or GGT > 5×ULN ].

●  The recommended dose of vinflunine is 200 mg/m² given once every 3 weeks in patients with moderate liver impairment (Child-Pugh grade B) or in patients with a prothrombin time ≥ 50% NV and bilirubin > 3×ULN and transaminases > ULN and GGT > ULN.

Vinflunine has not been evaluated in patients with severe hepatic impairment (Child-Pugh grade C), or in patients with a prothrombin time < 50%NV or with bilirubin > 5xULN or with isolated transaminases > 2.5xULN ( ≥ 5xULN only in case of liver metastases) or with GGT > 15xULN.

Patients with renal impairment

In clinical studies, patients with CrCl (creatinine clearance) > 60 mL/min were included and treated at the recommended dose. 

In patients with moderate renal impairment (40 mL/min ≤ CrCl ≤ 60 mL/min), the recommended dose is 280 mg/m² given once every 3 weeks. 

In patients with severe renal impairment (20 mL/min ≤ CrCl < 40 mL/min) the recommended dose is 250 mg/m² every 3 weeks (see section 5.2).

For further cycles, the dose should be adjusted in the event of toxicities, as shown in table 3 below.

Elderly patients (≥ 75 years)

No age-related dose modification is required in patients less than 75 years old (see section 5.2). The doses recommended in patients of at least 75 years old are as follows:

●  in patients of at least 75 years old but less than 80 years, the dose of vinflunine to be given is 280 mg/m² every 3 weeks.

●  in patients 80 years old and above, the dose of vinflunine to be given is 250 mg/m² every 3 weeks.

For further cycles, the dose should be adjusted in the event of toxicities, as shown in table 3 below:

Paediatric population

There is no relevant use of Javlor in the paediatric population

Method of administration

Precautions to be taken before handling or administering the medicinal product Javlor must be diluted prior to administration. Javlor is for single use only.

For instructions on dilution of the medicinal product before administration, see section 6.6

Javlor MUST ONLY be administered intravenously.

Javlor should be administered by a 20-minute intravenous infusion and NOT be given by rapid intravenous bolus.

Either peripheral lines or a central catheter can be used for vinflunine administration. When infused through a peripheral vein, vinflunine can induce venous irritation (see section 4.4). In case of small or sclerosed veins, lymphoedema or recent venipuncture of the same vein, the use of a central catheter may be preferred. To avoid extravasations it is important to be sure that the needle is correctly introduced before starting the infusion.

In order to flush the vein, administration of diluted Javlor should always be followed by at least an equal volume of sodium chloride 9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion.

For detailed instructions on administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or other vinca alkaloids.

Recent (within 2 weeks) or current severe infection.

Baseline ANC < 1,500/mm3 for the first administration, baseline ANC < 1,000/mm3 for subsequent

administrations (see section 4.4).

Platelets < 100,000/mm3 (see section 4.4).

Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Hematological toxicity

Neutropenia, leucopenia, anaemia and thrombocytopenia are frequent adverse reactions of vinflunine. Adequate monitoring of complete blood counts should be conducted to verify the ANC, platelet and haemoglobin values before each vinflunine infusion (see section 4.3).

Initiation of vinflunine is contraindicated in subjects with baseline ANC < 1,500/mm3 or platelets < 100,000/mm3 . For subsequent administrations, vinflunine is contraindicated in subjects with baseline ANC < 1,000/mm3 or platelets < 100,000/mm3 .

The recommended dose should be reduced in patients with haematological toxicity (see section 4.2).

Gastrointestinal disorders

Grade ≥ 3 constipation occurred in 15.3% of treated patients. NCI CTC Grade 3 constipation is defined as an obstipation requiring manual evacuation or enema, Grade 4 constipation as an obstruction or toxic megacolon. Constipation is reversible and can be prevented by special dietary measures such as oral hydration and fibre intake, and by administration of laxatives such as stimulant laxatives or faecal softners from day 1 to day 5 or 7 of the treatment cycle. Patients at high risk of constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal masses, prior major abdominal surgery) should be medicated with an osmotic laxative from day 1 to day 7 administered once a day in the morning before breakfast.

In case of Grade 2 constipation, defined as requiring laxatives, for 5 days or more or Grade ≥ 3 of any duration, the dose of vinflunine should be adjusted (see section 4.2).

In case of any Grade ≥ 3 gastrointestinal toxicity (except vomiting or nausea) or of mucositis (Grade 2 for 5 days or more or Grade ≥ 3 of any duration) dose adjustment is required. Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening” (see Table 2 in section 4.2).

Cardiac disorders

Few QT interval prolongations have been observed after the administration of vinflunine. This effect may lead to an increased risk of ventricular arrhythmias although no ventricular arrhythmias were observed with vinflunine. Nevertheless, vinflunine should be used with caution in patients with increase of the proarrhythmic risk (e.g. congestive heart failure, known history of QT interval prolongation, hypokalaemia) (see section 4.8). The concomittant use of two or more QT/QTc interval prolonging substances is not recommended (see section 4.5).

Special attention is recommended when vinflunine is administered to patients with prior history of myocardial infarction/ischaemia or angina pectoris (see section 4.8). Ischaemic cardiac events may occur, especially in patients who have underlying cardiac disease. Thus, patients receiving Javlor should be vigilantly monitored by physicians for the occurrence of cardiac events. Caution should be exercised in patients with a history of cardiac disease and the benefit / risk assessment should be carefully evaluated regularly. Discontinuation of vinflunine should be considered in patients who develop cardiac ischaemia.

Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have been observed after administration of vinflunine.

The typical clinical symptoms are, with various degrees: neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and gastrointestinal (nausea, vomiting).

Radiological signs are white matter abnormalities in the posterior regions of the brain. Blood pressure should be controlled in patients developing symptoms of PRES. To confirm the diagnosis, brain imaging is recommended.

Clinical and radiological features usually resolved rapidly without sequelae after treatment discontinuation. 

Discontinuation of vinflunine should be considered in patients who develop neurological signs of PRES (see section 4.8).

Hyponatraemia

Severe hyponatraemia, including cases due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), has been observed with the use of vinflunine (see section 4.8). Therefore, regular monitoring of serum sodium levels is recommended during treatment with vinflunine.

Hepatic impairment

The recommended dose should be reduced in patients with hepatic impairment (see section 4.2).

Renal impairment

The recommended dose should be reduced in patients with moderate or severe renal impairment (see section 4.2).

Elderly patients (≥ 75 years)

The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2).

Interactions

The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be avoided (see section 4.5).

Administration

Intrathecal administration of Javlor may be fatal.

When infused through a peripheral vein, vinflunine can induce Grade 1 (22% of the patients, 14.1% of the cycles), Grade 2 (11.0% of the patients, 6.8% of the cycles) or Grade 3 (0.8% of the patients, 0.2% of the cycles) venous irritation. All cases resolved rapidly without treatment discontinuation.

Instructions for administration should be followed as described in section 6.6.

Contraception

Men and women with reproductive potential must use an effective method of contraception during the treatment and up to 3 months after the last vinflunine administration (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

In vitro studies showed that vinflunine had neither inducing effects on CYP1A2, CYP2B6 or CYP3A4 activity nor inhibition effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

In vitro studies showed that vinflunine is a Pgp-substrate like other vinca alkaloids, but with a lower affinity. Therefore, risks of clinically significant interactions should be unlikely.

No pharmacokinetic interaction was observed in patients when vinflunine was combined with either cisplatin, carboplatin, capecitabine or gemcitabine.

No pharmacokinetic interaction was observed in patients when vinflunine was combined with doxorubicin. However, this combination was associated with a particularly high risk of haematological toxicity.

A phase I study evaluating the effect of ketoconazole treatment (a potent CYP3A4 inhibitor) on vinflunine pharmacokinetics indicated that co-administration of ketoconazole (400 mg orally once daily for 8 days) resulted in a 30% and 50% increase in blood exposures to vinflunine and its metabolite 4Odeacetyl-vinflunine (DVFL), respectively.

Therefore the concomitant use of vinflunine and potent CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole and grapefruit juice) or inducers (such as rifampicin and Hypericum perforatum (St John’s wort)) should be avoided since they may increase or decrease vinflunine and DVFL concentrations (see section 4.4 and 5.2).

The concomitant use of vinflunine with others QT/QTc interval prolonging medicinal products should be avoided (see section 4.4).

A pharmacokinetic interaction between vinflunine and pegylated/liposomal doxorubicin was observed, resulting in a 15% to 30% apparent increase in vinflunine exposure and a 2 to 3-fold apparent decrease of doxorubicin AUC, whereas for doxorubicinol, the concentrations of the metabolite were not affected. According to an in vitro study, such changes could be related to adsorption of vinflunine on the liposomes and a modified blood distribution of both compounds. Therefore, caution should be excercised when this type of combination is used.

A possible interaction with paclitaxel and docetaxel (CYP3 substrates) has been suggested from an in vitro study (slight inhibition of vinflunine metabolism). No specific clinical studies of vinflunine in combination with these compounds have been carried out yet.

The concomitant use of opioids could enhance the risk of constipation.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Both male and female patients should take adequate contraceptive measures up to three months after the discontinuation of the therapy.

Pregnancy

There are no data available on the use of vinflunine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities.

Vinflunine should therefore not be used during pregnancy, unless it is strictly necessary. If pregnancy occurs during treatment, the patient should be informed about the risk for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy.

Breast-feeding

It is unknown whether vinflunine or its metabolites are excreted in human milk. Due to the possible very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated (see section 4.3).

Fertility

Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.

4.7 Effects on ability to drive and use machines

Javlor may cause adverse reactions such as fatigue (very common) and dizziness (common) which may lead to a minor or moderate influence on the ability to drive and use machines..Patients should be advised not to drive or use machines if they experience any adverse reaction with a potential impact on the ability to perform these activities (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The most frequent treatment-related adverse reactions reported in the two phase II and one phase III trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with vinflunine) were haematological disorders, mainly neutropenia and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain and diarrhoea, and general disorders such as asthenia/fatigue.

Tabulated list of adverse reactions

Adverse reactions are listed below by System Organ Class, frequency and grade of severity (NCI CTC version 2.0). 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); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine

a adverse reactions reported from post-marketing experience 

b frequency calculated on the basis of non-TCCU clinical trial

Adverse reactions in all indications

Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in patients with other disease than this indication and potentially severe or adverse reactions that are a class effect of the vinca alkaloids are described below:

Blood and lymphatic system disorders

Grade 3/4 neutropenia was observed in 43.8% of patients. Severe anaemia and thrombocytopenia were less common (respectively 8.8 and 3.1 %). Febrile neutropenia defined as ANC < 1,000/mm3 and fever ≥ 38.5°C of unknown origin without clinically microbiologically documented infection (NCI CTC version 2.0) was observed in 5.2% of patients. Infection with Grade 3/4 neutropenia was observed in 2.8 % of patients.

Overall 8 patients (0.6% of the treated population) died from infection as a complication occurring during neutropenia.

Gastrointestinal disorders

Constipation is a class effect of the vinca alkaloids: 11.8% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 1.9% of patients was reversible when managed by medical care. Constipation is managed by medical care (see section 4.4).

Nervous system disorders

Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.6% patients. All resolved during the study.

Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4).

Cardiovascular disorders

Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.5% of the patients and most of them had a pre-existing cardiovascular disease or risk factors. One patient died after myocardial infarction and another one due to a cardiopulmonary arrest.

Few QT interval prolongations have been observed after the administration of vinflunine.

Respiratory, thoracic and mediastinal disorders

Dyspnoea occurred in 3.2% of the patients but was rarely severe (Grade 3/4: 1.2%).

Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication.

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

The main toxic effect due to an overdose with vinflunine is bone marrow suppression with a risk of severe infection.

There is no known antidote for vinflunine overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions should be closely monitored. Other appropriate measures should be taken, such as blood transfusions, administration of antibiotics and growth factors.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplasic agents, vinca alkaloids and analogues, ATC code: L01CA05

Mechanism of action

Vinflunine binds to tubulin at or near to the vinca binding sites inhibiting its polymerisation into microtubules, which results in treadmilling suppression, disruption of microtubule dynamic, mitotic arrest and apoptosis. In vivo, vinflunine displays significant antitumor activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition.

Clinical efficacy and safety

One phase III and two phase II trials support the use of Javlor for treatment of advanced or metastatic transitional cell carcinoma of the urothelium as second-line therapy after failure of a prior platinumcontaining regimen.

In the two multi-centre open-label, single-arm phase II clinical trials a total of 202 patients were treated with vinflunine.

In the multi-centre, open-label controlled phase III clinical trial, 253 patients were randomised to treatment with vinflunine + BSC (best supportive care) and 117 patients to the BSC arm.

The median overall survival was 6.9 months (vinflunine + BSC) vs. 4.6 months (BSC), but the difference did not reach statistical significance; hazard ratio 0.88 (95% CI 0.69, 1.12). However a statistically significant effect was seen on progression-free survival. Median PFS was 3.0 months (vinflunine + BSC) vs 1.5 months (BSC) (p=0.0012).

In addition a pre-specified multivariate analysis performed on the ITT population demonstrated that vinflunine had a statistically significant treatment effect (p=0.036) on overall survival when prognostic factors (PS, visceral involvement, alkaline phosphatases, haemoglobin, pelvic irradiation) were taken into consideration; hazard ratio 0.77 (95% CI 0.61, 0.98). A statistically significant difference on overall survival (p=0.040) was also seen in the eligible population (which excluded 13 patients with clinically significant protocol violations at baseline who were not eligible for treatment); hazard ratio 0.78 (95% CI 0.61, 0.99). This is considered the most relevant population for the efficacy analysis, as it most closely reflects the population intended for treatment.

Efficacy was demonstrated in both patients with or without prior cisplatin use.

In the eligible population, the subgroup analyses according to the prior cisplatin use versus BSC on overall survival (OS) showed a HR (95% CI) = [0.64 (0.40 – 1.03); p=0.0821] in the absence of prior cisplatin, and a HR (95% CI) = [0.80 (0.60 – 1.06); p=0.1263] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of OS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.53 (0.32 – 0.88); p=0.0143] and a HR (95% CI) = [0.70 (0.53 – 0.94); p=0.0174], respectively.

In the subgroup analyses of prior cisplatin use versus BSC for progression free survival (PFS), the results were: HR (95% CI) = [0.55 (0.34 – 0.89); p=0.0129] in the absence of prior cisplatin, and a HR (95% CI) = [0.64 (0.48 – 0.85); p=0.0040] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of PFS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.51(0.31 – 0.86); p=0.0111] and a HR (95% CI) = [0.63(0.48 – 0.84); p=0.0016], respectively.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Javlor in all subsets of the paediatric population in the treatment of ureter and bladder carcinoma and the treatment of breast carcinoma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Vinflunine pharmacokinetics is linear in the range of administered doses (from 30 mg/m² to 400 mg/m2 ) in cancer patients.

Blood exposure to vinflunine (AUC), significantly correlated with severity of leucopenia, neutropenia and fatigue.

Distribution

Vinflunine is moderately bound to human plasma proteins (67.2±1.1%) with a ratio between plasma and whole blood concentrations of 0.80±0.12. Protein binding mainly involves high density lipoproteins and serum albumin and is non-saturable on the range of vinflunine concentrations observed in patients. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%). The terminal volume of distribution is large, 2422±676 litres (about 35 l/kg) suggesting extensive distribution into tissues.

Biotransformation

All metabolites identified are formed by the cytochrome CYP3A4 isoenzyme, except for 4-O-deacetylvinflunine (DVFL), the only active metabolite and main metabolite in blood which is formed by multiple esterases.

Elimination

Vinflunine is eliminated following a multi-exponential concentration decay, with a terminal half-life (t1/2) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t1/2 of approximately 120 h).

The excretion of vinflunine and its metabolites occurs through faeces (2/3) and urine (1/3).

In a population pharmacokinetic analysis in 372 patients (656 pharmacokinetic profiles), the total blood clearance was 40 l/h with low inter and intra-individual variability (25% and 8%, respectively, expressed as coefficient of variation).

Pharmacokinetics in special populations

Hepatic impairment

No modification of vinflunine and DVFL pharmacokinetics was observed in 25 patients presenting varying degrees of hepatic impairment, compared to patients with normal hepatic function. This was further confirmed by the population pharmacokinetic analysis (absence of relationship between vinflunine clearance and biology markers of hepatic impairment). However, dose adjustments are recommended in patients with liver impairment (see section 4.2).

Renal impairment

A pharmacokinetic phase I study was performed in 2 groups of patients with renal impairment classified according to the calculated creatinine clearance (CrCl) values: group 1 (n=13 patients) with moderate impairment (40 mL/min ≤ CrCl ≤ 60 mL/min) and group 2 (n=20 patients) with severe impairment (20 mL/min ≤ CrCl < 40 mL/min). The pharmacokinetic results of this study indicated a reduction of vinflunine clearance when CrCl is decreased. This is further confirmed by the population pharmacokinetic analysis (56 patients with CrCl between 20 mL/min and 60 mL/min), showing that vinflunine clearance is influenced by the creatinine clearance value (Cockcroft and Gault formula). Dose adjustments are recommended in patients with moderate and severe renal impairment (see section 4.2).

Elderly (≥ 75 years)

A pharmacokinetic phase I study of vinflunine was performed in elderly patients (n=46). Vinflunine doses were adjusted according to 3 age groups as shown below:

Vinflunine clearance was significantly decreased in patients ≥ 80 years old as compared to a control group of younger patients < 70 years.

Pharmacokinetics of vinflunine was not modified for patients 70 ≤ age < 75 years and 75 ≤ age < 80 years.

Based on both PK and safety data, dose reductions are recommended in the elder groups:

75 ≤ age < 80 years; and age ≥ 80 years.

For further cycles the dose should be adjusted in the event of toxicities (see section 4.2).

Others

According to the population pharmacokinetic analysis, neither gender nor performance status (ECOG score) had an impact on vinflunine clearance which is directly proportional to body surface area.

5.3 Preclinical safety data

Imaging distribution studies following radioactive vinflunine in rats, illustrated that the compound levels in lungs, kidneys, liver, salivary and endocrine glands, and gastrointestinal tract were rapidly higher than those in blood.

Preclinical data revealed moderate to severe neutropenia and mild anaemia, in all species tested, with liver toxicity in dogs and rats (characterized by dose-dependent increases in liver transaminases and hepatic necrosis/hepatocellular alterations at high doses). These toxic effects were dose-related and fully or-partially reversible following a 1-month recovery period. Vinflunine did not induce peripheral neuropathy in animals.

Vinflunine has shown to be clastogenic (induces chromosome breakage) in the in vivo micronucleus test in rat as well as mutagenic and clastogenic in a mouse lymphoma assay (without metabolic activation).

The carcinogenic potential of vinflunine has not been studied.

In the reproduction studies, vinflunine appeared to be embryolethal and teratogenic in rabbits and teratogenic in rats. During the pre- and post-natal development study in rat, vinflunine induced malformations of the uterus and vagina in 2 females, and adversely affected mating and/or ovule implantation and markedly lowered the number of concepti.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

3 years.

Diluted solution

Chemical and physical in-use stability has been demonstrated for the diluted medicinal product as follows:

●    protected from light in polyethylene or polyvinylchloride infusion bag: for up to 6 days in a refrigerator (2°C-8°C) or for up to 24 hours at 25°C;

●   exposed to light in polyethylene or polyvinylchloride infusion set for up to 1 hour at 25°C.

From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C-8°C).

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Clear type I glass vials closed by a grey butyl or black chlorobutyl rubber stopper covered with a crimped-on aluminium ring and a cap. Each vial contains either 2 mL (50 mg vinflunine), 4 mL (100 mg vinflunine) or 10 mL (250 mg vinflunine) of concentrate for solution for infusion.

Pack size of 1 and 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

General precautions for preparation and administration.

Vinflunine is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, caution should be exercised in handling Javlor. Procedure for proper handling and disposal of anticancer medicinal products should be considered. All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood. Javlor solution for infusion should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant staff should not handle Javlor. The use of gloves, goggles and protective clothing is recommended.

If the solution comes into contact with the skin, this should be washed immediately and thoroughly with soap and water. If it comes into contact with mucous membranes, the membranes should be flushed thoroughly with water.

Dilution of the concentrate

The volume of Javlor (concentrate) corresponding to the calculated dose of vinflunine should be mixed in a 100 mL bag of sodium chloride 9 mg/mL (0.9%) solution for infusion. Glucose 50 mg/mL (5%) solution for infusion may also be used. The diluted solution should be protected from light until administration (see section 6.3).

Method of administration

Javlor is for intravenous use ONLY.

Javlor is for single use only.

After dilution of the Javlor concentrate, the solution for infusion will be administered as follows:

●  A venous access should be established for a 500 mL bag of sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for infusion, on a large vein preferably in the upper part of the forearm or using a central venous line. The veins of the hand dorsum and those close to joints should be avoided.

●  The intravenous infusion should be started with half of the 500 mL bag of sodium chloride 9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion, i.e. 250 mL, at a free flowing rate to flush the vein.

●  The Javlor solution for infusion should be piggy-backed to the side injection port closest to the 500 mL bag to further dilute Javlor during administration.

●  The Javlor solution for infusion should be infused over 20 minutes.

●  The patency should be assessed frequently and extravasation precautions should be maintained throughout the infusion.

●  After the infusion is completed, the remaining 250 mL from the sodium chloride 9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion bag should be run at a flowing rate of 300 mL/h. In order to flush the vein, administration of Javlor solution for infusion should always be followed by at least an equal volume of sodium chloride 9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.

7. MARKETING AUTHORISATION HOLDER

Pierre Fabre Médicament

45, place Abel Gance

F-92100 Boulogne

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/550/001-012

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 September 2009

Date of the latest renewal: 16 May 2014

10. DATE OF REVISION OF THE TEXT

XX month YYYY

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。