【商品名称】赛维健 Tomudex  

【通用名称】注射用雷替曲塞

【英文名】 Raltitrexed  for  Injection

【成份】本品活性成份为雷替曲塞。

辅料：甘露醇、磷酸氢二钠及氢氧化钠。

【性状】本品为白色或类白色疏松块状物或粉末。

【适应症】在患者无法接受联合化疗时，本品可单药用于治疗不适合5-Fu/亚叶酸钙的晚期结直肠癌患者。

【用法用量】

成人：推荐剂量为3毫克/平方米，用50-250毫升0.9%氯化钠注射液或5%葡萄糖注射液溶解稀释后静脉输注，给药时间15分钟，如果未出现毒性，可考虑按上述治疗每3周重复给药1次。本药应避免与其它药物混合输注。增加剂量会致使危及生命或致死性毒性反应的发生率升高，所以不推荐剂量大于3毫克/平方米。每次用药治疗前需检查全血细胞计数（包括白细胞分类计数和血小板计数）和肝、肾功能。治疗前应该白细胞计数﹥4.0×109/L、中性粒细胞计数﹥2.0×109/L和血小板计数﹥1.0×1011/L。出现毒性反应时，下一周期用药需延迟至不良反应消退；尤其是胃肠道毒性（腹泻或粘膜炎）及血液学毒性（中性粒细胞减少或血小板减少）需完全恢复才可进行后续治疗。出现胃肠道毒性者应至少每周检查一次全血细胞计数以监测血液学毒性。根据前一治疗周期观察到的最严重的胃肠道及血液学毒性等级，如果此类毒性已完全缓解，推荐按前一周期最严重的胃肠道、血液学毒性（以下毒性均按WHO标准分级）进行剂量调整： 剂量减少25%:血液学毒性（中性粒细胞减少或者血小板减少）3级或胃肠道毒性2级（腹泻或粘膜炎）；剂量减少50%:血液学毒性（中性粒细胞减少或者血小板减少）4级或胃肠道毒性3级（腹泻或粘膜炎）。一旦减量，后续治疗的剂量也须按减量后给药。出现4级胃肠道毒性（腹泻或粘膜炎），或3级胃肠道毒性伴4级血液学毒性时必须中止治疗；同时迅速给予标准支持治疗，包括静脉补水和造血功能支持。临床前研究提示可以使用亚叶酸治疗，按照临床经验需每6小时静脉注射25毫克/平方米亚叶酸直至症状缓解。对于此类患者建议停用本药。肾功能不全：血清肌酐异常者，每次用药治疗前应监测肌酐清除率。对于因年龄或体重下降等因素使血清肌酐可能与肌酐清除率相关性不好而血清肌酐正常的患者，应按相同程序操作。如果肌酐清除率<65毫升/min，作如下剂量调整：肝功能不全：对于轻到中度的肝功能损害患者不需调整剂量，但是因为部分药物经粪便排出（见药代动力学），且这些患者预后较差，故应慎用本药。本药未在重度肝功能损害患者中进行研究，因此对于显性黄疸或肝功能失代偿的患者不推荐使用。

【药理毒理】

药理作用

雷替曲塞为抗代谢类叶酸类似物，特异性地抑制胸苷酸合酶（TS）。与5-FU或氨甲喋呤相比，雷替曲塞是直接的和特异性的TS抑制剂。TS是胸腺嘧啶脱氧核苷三磷酸盐（TTP）合成过程的关键酶，而TTP又是DNA合成的必须核苷酸。抑制TS可导致DNA断裂和细胞凋亡。雷替曲塞经还原叶酸载体摄入细胞被叶酰聚谷氨酸合成酶转化成聚谷氨酸盐形式贮存细胞中，发挥更强TS抑制作用。雷替曲塞聚谷氨酸盐通过增强TS抑制能力、延长抑制时间而提高其抗肿瘤活性。但其在正常组织中的贮留可能会使毒性增加。

毒理研究

急性毒性：小鼠和大鼠的LD50分别为＞500mg/kg和875-1249mg/kg。小鼠在≥750mg/kg剂量时可导致中毒死亡。 重复给药毒性：大鼠连续1个月及6个月间隔给药研究发现其毒性完全与药物的细胞毒作用有关。主要靶器官为胃肠道、骨髓和睾丸。在犬中进行了相同的试验研究，犬的靶器官与大鼠相同，但出现毒性反应的血浆药物水平明显低于预期临床水平。剂量蓄积现象与临床使用相似，仅诱发药理作用相关的组织增生。此外，在犬30天重复给药实验中观察到了心血管变化（心动过缓），该反应机制尚不清楚。

遗传毒性：在细菌回复突变试验（Ames）、E.coli或中国仓鼠卵巢细胞基因突变试验中，雷替曲塞无诱导突变作用，在体外人淋巴细胞试验中，雷替曲塞引起染色体受损增加，在体外的人结肠（HCT-8）癌细胞试验中可引起单链DNA断裂增加。经加入胸腺嘧啶脱氧核苷可得到改善，说明雷替曲塞为抗代谢药物。大鼠体内微核试验显示雷替曲塞在细胞毒剂量水平可引起骨髓的染色体损伤。

生殖毒性：试验显示雷替曲塞可损害雄性大鼠生殖力，停药3个月后恢复。雷替曲塞可引起孕鼠出现死胎和胚胎畸形。

致癌性：雷替曲塞的致癌性尚未进行评价。

【药代动力学】

国外临床研究资料显示，患者注射3mg/m2雷替曲塞，药物浓度与时间呈三室模型。注射结束时浓度达最高峰，然后迅速下降，之后进入慢消除相。静脉注射3mg/m2雷替曲塞主要药代动力学参数如下，根据27名肿瘤患者静脉输注雷替曲塞15分钟进行计算： 最初分布相(α)的t1/2α约为10分钟，反映雷替曲塞在体内的分布变化非常迅速，由于时间短，这项测定结果的可靠性不如t1/2β和t1/2γ，消除相半衰期t1/2γ也即最长半衰期代表了药物从体内清除的速率。虽然患者间存在一些差异，雷替曲塞的平均最大浓度在1.6-3mg/m2剂量范围内成比例地增加。在临床剂量范围内雷替曲塞的Cmax与用药剂量呈线性关系。肾功能正常者3周间期连续用药血浆中无明显药物蓄积。除在细胞内被聚谷氨酸化外，雷替曲塞不被代谢，主要以原形经尿排出（40%-50%）。10天约15%雷提曲塞经粪便排泄。观察期间碳-14标识的雷替曲塞约一半没有回收到，即部分（以聚谷氨酸盐的形式）贮留于组织中。29天红血球中检测到微量放射标记。性别、年龄对雷替曲塞药代动力学参数无影响，儿童药代动力学尚无研究。初步研究显示肝损伤患者用药雷替曲塞的清除率降低，但降低程度尚未明确。轻到中度的肝功能不全患者血浆清除率下降低于25%。轻到中度的肾功能不全(Cr：25-65ml/min)者血浆清除率明显下降（约50%）。

【不良反应】国外临床试验信息与其他细胞毒性药物相似，雷替曲塞的主要不良反应包括对胃肠道、血液系统及肝酶的可逆性影响。胃肠道系统最常见的不良反应为恶心(58%)、呕吐(37%)、腹泻(38%)和食欲不振(28%)。较少见的不良反应包括粘膜炎、口炎（包括口腔溃疡）、消化不良和便秘，有报道胃肠道出血可能与粘膜炎和/或血小板减少有关。腹泻通常为轻或中度（WH01/2级），可发生于雷骛曲塞给药后任何时间，也有可能发生重度腹泻（WHO3/4级），且可能与并发的骨髓毒性尤其是白细胞减少（特别是中性粒细胞减少）有关。可停止给药或根据毒性反应的等级降低剂量（见用法用量）。恶心和呕吐通常为轻度（WHO1/2级），常于用药一周内发生，可用止吐药治疗。造血系统可能与药物有关的不良反应为白细胞减少（特别是中性粒细胞减少）、贫血和血小板减少（发生率分别为22%、18%和5%），可单独发生或同时发生，这些反应通常为轻到中度(WHO1/2)，于用药后第1或2周内发生，第3周前恢复。也有可能发生重度（WHO3/4级，白细胞减少（特别是中性粒细胞减少）和WHO4级的血小板减少，可能会危及生命或致命，尤其与胃肠道毒性反应同时发生时。肝脏常见AST和ALT的可逆性升高（发生率分别为16%和14%），当这些变化与潜在的恶性肿瘤的进展无关时，通常表现为无症状和自限性。其他较少见的不良反应包括体重下降、脱水、外周性水肿、高胆红素血症和碱性磷酸酶升高。心血管系统据报道，在治疗晚期结直肠癌临床试验中一些患者出现心律和心功能异常，包括窦性心动过速、室上性心动过速到房颤和充血性心衰。使用雷替曲塞治疗的患者心律及心功能异常的发生率分别为2.8%和1.8%，而对照组患者的发生率分别为1.9%和1.4%。由于多数异常与潜在的情状如败血症及脱水同时发生，且治疗前超过三分之一的患者已发生心血管异常，故不能确定与给药间的因果关系。肌肉骨骼和神经系统小于2%的患者可发生关节痛和张力过强（通常为肌痉挛）等不良反应。皮肤、附件和特殊感官皮疹较为常见（发生率14%），有时伴有瘙痒，其他较少见的反应有脱皮、脱发、出汗、味觉异常和结膜炎。全身乏力最为常见（发生率49% ）和发热（发生率22%），通常为轻到中度，在用药一周内发生，且可逆。有可能发生重度乏力并伴有身体不适和流感样症状，其他较少见的反应为腹痛、疼痛、头痛、蜂窝织炎和败血症。以下为临床试验中结直肠癌患者使用雷替曲塞治疗时发生率为2%或以上可能与药物有关的不良反应。 下表列出在4项结直肠癌临床试验中报道的严重不良事件数量，包括将住院治疗作为严重不良事件的标准。参加这些临床试验的患者中总计有37%的患者经历过1次包括住院治疗的严重不良事件。国内临床试验信息在国内进行了一项多中心，随机盲法、阳性药物平行对照的临床研究，评价注射用雷替曲塞（3mg/m2）联合奥沙利铂(130mg/m2)（21天重复）与5-FU/CF(375mg/m2/200mg/m2)联合奥沙利铂(130mg/m2)（21天重复）比较治疗局部晚期或转移性结盲肠癌患者的疗效和安全性。本试验入组患者216例，试验组113例。分析安全集(SS)214例，试验组112例。国内临床试验显示本品联合奥沙利铂的不良反应主要包括恶心、呕吐、乏力、腹泻、中性粒细胞减少、贫血、血小板减少、转氨酶升高等。试验组粒细胞减少的发生率高于对照组，但两组因粒细胞缺乏所致的剂量调整无明显差别，两组使用升白药物患者的比例相当，未发生与粒细胞减少相关的严重不良事件。转氨酶升高多为I/II度，无症状且可逆。与对照组相比III/IV度转氨酶升高的发生率两组间无明显差别。试验组与对照组相比，恶心（57.1%/75.5%，P=0.006）、呕吐（37.5%/60.8%，P=O.O01）的发生率明显降低。国内临床试验中本品联合奥沙利铂用药所产生的不良事件及发生率见下表。

【注意事项】

本品须由掌握肿瘤化疗并能熟练处理化疗相关的毒性反应的临床医师给药或在其指导下使用。接受治疗的患者应配合监护，以便及时发现可能的不良反应（尤其是腹泻）并处理。 与其他细胞毒性药物一样，造血功能低下、一般状况差、既往经放疗者慎用。 老年患者更易出现毒性反应，尤其是胃肠道毒性（腹泻或粘膜炎），应严格监护。 本药部分经由粪便排泄（见药代动力学），因此轻度到中度的肝功能损害者应慎用，而重度肝功能损害者不推荐使用。 夫妻任何一方接受本药治疗期间以及停药后至少6个月内应避孕。 无药液外渗的临床经验，但动物试验时药液外渗无明显刺激性反应。 雷替曲塞系细胞毒性药物，药物配制及操作按同类药物常规进行。 此前使用5-氟尿嘧啶治疗方案疾病仍然进展患者可能会对雷替曲塞产生耐药。 

【禁忌】孕妇、治疗期间妊娠或哺乳期妇女禁用。在使用本药之前，应排除妊娠可能。（见孕妇哺乳期妇女用药）重度肾功能损害者禁用。

【孕妇与妊娠用药】夫妻任何一方接受本药治疗期间以及停药后至少6个月内应避孕。孕妇、哺乳期妇女或治疗期间妊娠者禁用。用药前需排除妊娠。生殖试验显示雷替曲塞可损害雄性大鼠生殖力，停药3个月后恢复。雷替曲塞可致孕鼠出现死胎和胚胎畸形。

【儿童用药】本药在儿童中使用的安全性和有效性尚未确立，暂不推荐。

【老年用药】参照成人的用法用量，但同其他细胞毒药物一样，本药应慎用。老年患者更容易出现毒性反应。应对不良反应尤其是胃肠道毒性（腹泻或粘膜炎）进行严格监护。

【药物相互作用】

临床尚未发现特殊的药物相互作用，与叶酸、亚叶酸及包含这些成分的维生素制剂合用会降低药物作用。所以在使用本药前和使用本药期间禁用此类药物。雷替曲塞的蛋白结合率为93％，有可能与其他蛋白结合率高的药物发生相互作用。但体外试验未发现与华法令有相互作用。研究显示，肾小管主动分泌能促进雷替曲塞经肾排泄，提示本药有可能与其他主动分泌的药物如非甾体抗炎药（NSAIDS）发生相互作用。但目前临床安全性试验未发现接受雷替曲塞治疗并伴随使用NSAIDS、华法令及其他常用药物时出现明显相互作用。

【药物过量】目前尚无确切有效解毒剂。一旦超量使用可考虑使用亚叶酸治疗。根据经验，每6小时静脉注射25mg/m2亚叶酸，越晚使用亚叶酸效果越差。超量用药预期不良反应容易扩大。应仔细监测有关胃肠道和血液学的毒性征兆并有针对性采取措施治疗。

【包装规格】玻璃管制注射剂瓶装，1瓶/盒。

【贮藏】密闭，在凉暗处（避光且不超过20℃）保存。

【有效期】24个月

1. Name of the medicinal product

Tomudex 2 mg powder for solution for infusion.

2. Qualitative and quantitative composition

One vial contains 2 mg raltitrexed.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for solution for infusion.

White to cream coloured powder.

4. Clinical particulars

4.1 Therapeutic indications

The palliative treatment of advanced colorectal cancer where 5-fluorouracil and folinic acid based regimens are either not tolerated or inappropriate.

4.2 Posology and method of administration

Posology

Adults

The dose of raltitrexed is calculated on the basis of the body surface area. The recommended dose is 3 mg/m2 given intravenously, as a single short, intravenous infusion in 50 to 250 ml of either 0.9% sodium chloride solution or 5% dextrose (glucose) solution. It is recommended that the infusion is given over a 15 minute period. Other drugs should not be mixed with raltitrexed in the same infusion container. In the absence of toxicity, treatment may be repeated every 3 weeks.

Dose escalation above 3 mg/m2 is not recommended, since higher doses have been associated with an increased incidence of life-threatening or fatal toxicity.

Prior to the initiation of treatment and before each subsequent treatment a full blood count (including a differential count and platelets), liver transaminases, serum bilirubin and serum creatinine measurements should be performed.

The total white cell count should be greater than 4,000/mm3, the neutrophil count greater than 2,000/mm3 and the platelet count greater than 100,000/mm3 prior to treatment. In the event of toxicity the next scheduled dose should be withheld until signs of toxic effects regress. In particular, signs of gastrointestinal toxicity (diarrhoea or mucositis) and haematological toxicity (neutropenia or thrombocytopenia) should have completely resolved before subsequent treatment is allowed. Patients who develop signs of gastrointestinal toxicity should have their full blood counts monitored at least weekly for signs of haematological toxicity.

Based on the worst grade of gastrointestinal and haematological toxicity observed on the previous treatment and provided that such toxicity has completely resolved, the following dose reductions are recommended for subsequent treatment:

● 25% dose reduction: in patients with WHO grade 3 haematological toxicity (neutropenia or thrombocytopenia) or WHO grade 2 gastrointestinal toxicity (diarrhoea or mucositis).

● 50% dose reduction: in patients with WHO grade 4 haematological toxicity (neutropenia or thrombocytopenia) or WHO grade 3 gastrointestinal toxicity (diarrhoea or mucositis).

Once a dose reduction has been made, all subsequent doses should be given at the reduced dose.

Treatment should be discontinued in the event of any WHO grade 4 gastrointestinal toxicity (diarrhoea or mucositis) or in the event of a WHO grade 3 gastrointestinal toxicity associated with WHO grade 4 haematological toxicity. Patients with such toxicity should be managed promptly with standard supportive care measures including i.v. hydration and bone marrow support. In addition, preclinical data suggest that consideration should be given to the administration of leucovorin (folinic acid). From clinical experience with other antifolates, leucovorin may be given at a dose of 25 mg/m2 i.v. every 6 hours until the resolution of symptoms. Further use of raltitrexed in such patients is not recommended.

It is essential that the dose reduction scheme should be adhered to since the potential for life threatening and fatal toxicity increases if the dose is not reduced or treatment not stopped as appropriate.

Elderly population

Dosage and administration as for adults. However, raltitrexed should be used with caution in elderly patients (see section 4.4).

Paediatric population

Raltitrexed is not recommended for use in children as safety and efficacy have not been established in this group of patients.

Renal impairment

For patients with abnormal serum creatinine, before the first or any subsequent treatment, a creatinine clearance should be performed or calculated.

For patients with a normal serum creatinine when the serum creatinine may not correlate well with the creatinine clearance due to factors such as age or weight loss, the same procedure should be followed. If creatinine clearance is ≤65 ml/min, the following dose modifications are recommended:

Dose modification in the presence of renal impairment

See section 4.3 for use in patients with severe renal impairment

Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment. However, given that a proportion of the drug is excreted via the faecal route, (see section 5.2) and that these patients usually form a poor prognosis group, patients with mild to moderate hepatic impairment need to be treated with caution (see section 4.4). Raltitrexed has not been studied in patients with severe hepatic impairment, clinical jaundice or decompensated liver disease and its use in such patients is not recommended.

Method of administration

Each vial, containing 2mg of raltitrexed, should be reconstituted with 4ml of sterile water for injections to produce a 0.5 mg/ml solution.

The appropriate dose of solution is diluted in 50 - 250 ml of either 0.9% sodium chloride or 5% glucose (dextrose) injection and administered by a short intravenous infusion over a period of 15 minutes.

4.3 Contraindications

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

Raltitrexed should not be used in pregnant women, in women who may become pregnant during treatment or women who are breast feeding. Pregnancy should be excluded before treatment with raltitrexed is commenced. (see section 4.6).

Raltitrexed is contraindicated in patients with severe renal impairment (creatinine clearance < 25ml/min).

Administration of leucovorin (folinic acid), folic acid or vitamin preparations containing these agents with raltitrexed is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Raltitrexed must only given by or under the supervision of a physician who is experienced in cancer chemotherapy, and in the management of chemotherapy-related toxicity. Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions (particularly diarrhoea) may be detected and treated promptly (see section 4.2).

In common with other cytotoxic agents of this type, caution is necessary in patients with depressed bone marrow function, poor general condition, or prior radiotherapy.

Patients whose disease progressed on previous treatment for advanced disease with 5-fluorouracil based regimens may also be resistant to the effects of raltitrexed.

Elderly patients are more vulnerable to the toxic effects of raltitrexed. Since renal function tends to decline with age and the plasma clearance of raltitrexed is reduced with renal function impairment, there is a potential for accumulation of raltitrexed in elderly patients. Extreme care should be taken to ensure adequate monitoring of adverse reactions especially signs of gastrointestinal toxicity (diarrhoea or mucositis) and myelosuppression (neutropenia, thrombocytopenia, infection) and dose should be reduced and /or delayed as appropriate. A proportion of the raltitrexed is excreted via the faecal route (see section 5.2), therefore patients with mild to moderate hepatic impairment should be treated with caution.

Treatment with raltitrexed in patients with severe hepatic impairment is not recommended.

It is recommended that pregnancy should be avoided during treatment and for at least 6 months after cessation of treatment if either partner is receiving raltitrexed (see section 4.6).

There is no clinical experience with extravasation. However, perivascular tolerance studies in animals did not reveal any significant irritant reaction.

Raltitrexed is a cytotoxic agent and should be handled according to normal procedures adopted for such agents (see section 6.6).

4.5 Interaction with other medicinal products and other forms of interaction

No specific clinical drug - drug interaction studies have been conducted in man.

Leucovorin (folinic acid), folic acid or vitamin preparations containing these agents must not be given immediately prior to or during administration of raltitrexed, since they may interfere with its action.

Clinical trials evaluating the use of raltitrexed in combination with other antitumour therapies are currently ongoing.

Raltitrexed is 93% protein bound and while it has the potential to interact with similarly highly protein bound drugs, no displacement interaction with warfarin has been observed in vitro. Data suggest that active tubular secretion may contribute to the renal excretion of raltitrexed, indicating a potential interaction with other actively secreted drugs such as non-steroidal anti-inflammatory drugs (NSAIDS). However, a review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with raltitrexed who also received concomitant NSAIDS, warfarin and other commonly prescribed drugs.

4.6 Fertility, pregnancy and lactation

Pregnancy

Pregnancy should be avoided if either partner is receiving raltitrexed. It is also recommended that conception should be avoided for at least 6 months after cessation of treatment.

Raltitrexed should not be used during pregnancy or in women who may become pregnant during treatment (see section 5.3). Pregnancy should be excluded before treatment with raltitrexed is started.

Breast-feeding

Raltitrexed should not be given to women who are breast-feeding.

Fertility

Fertility studies in the rat indicate that raltitrexed can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased. Raltitrexed caused embryo lethality and foetal abnormalities in pregnant rats.

4.7 Effects on ability to drive and use machines

Raltitrexed may cause malaise or asthenia following infusion and the ability to drive/use machinery could be impaired whilst such symptoms continue.

4.8 Undesirable effects

As with other cytotoxic drugs, raltitrexed may be associated with certain adverse drug reactions. These mainly include reversible effects on the haemopoietic system, liver enzymes and gastrointestinal tract. Table 1 presents the possible adverse drug reactions occurring with Tomudex treatment.

In this section undesirable effects are defined as follows: 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 the available data).

Table 1: Adverse drug reactions in patients treated with Tomudex for advanced colorectal carcinoma divided by System Organ Class and frequency

a Leukopenia (neutropenia in particular), anaemia and thrombocytopenia, alone or in combination, are usually mild to moderate and occur in the first or second week after treatment and recover by the third week.

b Severe (WHO grade 3 and 4) leukopenia (neutropenia in particular) and thrombocytopenia of WHO grade 4 can occur and may be life-threatening or fatal especially if associated with signs of gastrointestinal toxicity.

c Nausea and Vomiting are usually mild (WHO grade 1 and 2), occur usually in the first week following the administration of Tomudex, and are responsive to antiemetics.

d Diarrhoea is usually mild or moderate (WHO grade 1 and 2) and can occur at any time following the administration of Tomudex. However, severe diarrhoea (WHO grade 3 and 4) can occur and may be associated with concurrent haematological suppression especially leukopenia (neutropenia in particular). Subsequent treatment may need to be discontinued or dose reduced according to the grade of toxicity (see Section 4.2).

e Diarrhoea and vomiting may be severe and if untreated may proceed to dehydration, hypovolaemia and renal impairment

f from spontaneous reporting

g Gastrointestinal bleeding may be associated with mucositis and/or thrombocytopenia.

h Asthenia and fever were usually mild to moderate following the first week of administration of Tomudex and reversible. Severe asthenia can occur and may be associated with malaise and a flu-like syndrome.

i Increases in AST and ALT have usually been asymptomatic and self-limiting when not associated with progression of the underlying malignancy.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no clinically proven antidote available. In the case of inadvertent or accidental administration of an overdose, preclinical data suggest that consideration should be given to the administration of leucovorin. From clinical experience with other antifolates leucovorin may be given at a dose of 25mg/m2 i.v. every 6 hours. As the time interval between raltitrexed administration and leucovorin rescue increases, its effectiveness in counteracting toxicity may diminish.

The expected manifestations of overdose are likely to be an exaggerated form of the adverse drug reactions anticipated with the administration of the drug. Patients should, therefore, be carefully monitored for signs of gastrointestinal and haematological toxicity. Symptomatic treatment and standard supportive care measures for the management of this toxicity should be applied.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, ATC code: L01BA03.

Raltitrexed is a folate analogue belonging to the family of anti-metabolites and has potent inhibitory activity against the enzyme thymidylate synthase (TS). Compared to other antimetabolites such as 5-fluorouracil or methotrexate, raltitrexed acts as a direct and specific TS inhibitor. TS is a key enzyme in the de novo synthesis of thymidine triphosphate (TTP), a nucleotide required exclusively for deoxyribonucleic acid (DNA) synthesis. Inhibition of TS leads to DNA fragmentation and cell death. Raltitrexed is transported into cells via a reduced folate carrier (RFC) and is then extensively polyglutamated by the enzyme folyl polyglutamate synthetase (FPGS) to polyglutamate forms that are retained in cells and are even more potent inhibitors of TS. Raltitrexed polyglutamation enhances TS inhibitory potency and increases the duration of TS inhibition in cells which may improve antitumour activity. Polyglutamation could also contribute to increased toxicity due to drug retention in normal tissues.

In clinical trials, raltitrexed at the dose of 3mg/m2 i.v. every 3 weeks has demonstrated clinical antitumour activity with an acceptable toxicity profile in patients with advanced colorectal cancer.

Four large clinical trials have been conducted with raltitrexed in advanced colorectal cancer. Of the three comparative trials, two showed no statistical difference between raltitrexed and the combination of 5-fluorouracil plus folinic acid for survival while one trial showed a statistically significant difference in favour of the combination of 5-fluorouracil plus folinic acid. Raltitrexed as a single agent was as effective as the combination of 5-fluorouracil and folinic acid in terms of objective response rate in all trials.

5.2 Pharmacokinetic properties

Following intravenous administration at 3.0 mg/m2, the concentration-time profile in patients was triphasic: Peak concentrations, found at the end of the infusion, were followed by a rapid initial decline in concentration. This was followed by a slow elimination phase. The key pharmacokinetic parameters are presented below:

Summary of mean pharmacokinetic parameters in patients administered 3.0 mg/m2 Raltitrexed by intravenous infusion

The maximum concentrations of raltitrexed increased linearly with dose over the clinical dose range tested.

During repeated administration at three week intervals, there was no clinically significant plasma accumulation of raltitrexed in patients with normal renal function.

Apart from the expected intracellular polyglutamation, raltitrexed was not metabolised and was excreted unchanged, mainly in the urine, 40 - 50%. Raltitrexed was also excreted in the faeces with approximately 15% of the radioactive dose being eliminated over a 10 day period. In the [14C] - raltitrexed trial approximately half of the radiolabel was not recovered during the study period. This suggests that a proportion of the raltitrexed dose is retained within tissues, perhaps as raltitrexed polyglutamates, beyond the end of the measurement period (29 days). Trace levels of radiolabel were detected in red blood cells on Day 29.

Raltitrexed pharmacokinetics are independent of age and gender. Pharmacokinetics have not been evaluated in children.

Mild to moderate hepatic impairment led to a small reduction in plasma clearance of less than 25%.

Mild to moderate renal impairment (creatinine clearance of 25 to 65 ml/min) led to a significant reduction (approximately 50%) in raltitrexed plasma clearance.

5.3 Preclinical safety data

Perivascular tolerance in studies in animals did not reveal any significant irritant reaction.

Acute toxicity

The approximate LD50 values for the mouse and rat are 875-1249 mg/kg and >500 mg/kg respectively. In the mouse, levels of 750 mg/kg and above caused death by general intoxication.

Chronic toxicity

In one month continuous and six month intermittent dosing studies in the rat, toxicity was related entirely to the cytotoxic nature of the drug. Principal target organs were the gastrointestinal tract, bone marrow and the testes. In similar studies in the dog, cumulative dose levels similar to that used clinically, elicited only pharmacologically-related changes to proliferating tissue. Target organs in the dog were therefore similar to the rat.

Mutagenicity

Raltitrexed was not mutagenic in the Ames test or in supplementary tests using E. coli or Chinese hamster ovary cells. Raltitrexed caused increased levels of chromosome damage in an in vitro assay of human lymphocytes. This effect was ameliorated by the addition of thymidine, thus confirming it to be due to the anti-metabolic nature of the drug. An in vivo micronucleus study in the rat indicated that at cytotoxic dose levels, raltitrexed is capable of causing chromosome damage in the bone marrow.

Reproductive toxicology

Fertility studies in the rat indicate that raltitrexed can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased. Raltitrexed caused embryo lethality and foetal abnormalities in pregnant rats.

Carcinogenicity

The carcinogenic potential of raltitrexed has not been evaluated.

6. Pharmaceutical particulars

6.1 List of excipients

Mannitol

Dibasic sodium phosphate (heptahydrate or dodecahydrate)

Sodium hydroxide

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

6.3 Shelf life

Unopened Vial - 3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C.

From a microbiological point of view, the product should be used immediately. 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 to 8°C, unless reconstitution/ dilution (etc) has taken place in controlled and validated aseptic conditions.

Once reconstituted, Tomudex is chemically stable for 24 hours at 25°C exposed to ambient light. For storage recommendation, see sections 6.4 and 6.6.

6.4 Special precautions for storage

Unopened vial - Do not store above 25°C. Keep container in the outer carton to protect from light.

For storage conditions after reconstitution of the medical product, see section 6.3.

6.5 Nature and contents of container

5 ml clear neutral type I glass vials, with a bromobutyl rubber closure and aluminium crimp seal with a plastic flip-off cover.

The vials are packed in individual cartons to protect the product from light.

6.6 Special precautions for disposal and other handling

There is no preservative or bacteriostatic agent present in Tomudex or the materials specified for reconstitution or dilution. Tomudex must therefore be reconstituted and diluted under aseptic conditions and it is recommended that solutions of Tomudex should be used as soon as possible. Reconstituted Tomudex solution is for single use only.

In accordance with established guidelines, when diluted in 0.9% sodium chloride or 5% glucose (dextrose) solution, it is recommended that administration of the admixed solution should commence as soon as possible after admixing. The admixed solution must be completely used or discarded within 24 hours of reconstitution of Tomudex intravenous injection.

Reconstituted and diluted solutions do not need to be protected from light.

Do not store partially used vials or admixed solutions for future patient use.

Any unused injection or reconstituted solution should be discarded in a suitable manner for cytotoxics.

Tomudex should be reconstituted for injection by trained personnel in a designated area for the reconstitution of cytotoxic agents. Cytotoxic preparations such as Tomudex should not be handled by pregnant women.

Reconstitution should normally be carried out in a partial containment facility with extraction e.g. a laminar air flow cabinet, and work surfaces should be covered with disposable plastic-backed absorbent paper.

Appropriate protective clothing, including normal surgical disposable gloves and goggles, should be worn. In case of contact with skin, immediately wash thoroughly with water. For splashes in the eyes irrigate with clean water, holding the eyelids apart, for at least 10 minutes. Seek medical attention.

Any spillages should be cleared up using standard procedures.

Waste material should be disposed of by incineration in a manner consistent with the handling of cytotoxic agents.

7. Marketing authorisation holder

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

United Kingdom

8. Marketing authorisation number(s)

PL 04515/0225

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 25 June 2000

10. Date of revision of the text

03/2019

Ref: gxTM 4_2