95．威猛
出处：按学科分类—医药、卫生 军事医学科学出版社《临床常用进口药物手册》第527页（21374字）
【中文释文】：
(替尼泊苷)
替尼泊苷(VM．26)
50mg5ml／安瓿
〔性状〕
威猛(替尼泊苷，又名VM-26)为鬼臼毒素的半合成衍生物。用于治疗某些肿瘤的疾病。本品为中性亲脂性物质，几乎不溶水，必须溶于有机溶剂使用，威猛需用一种适当的注射剂赋形溶液稀释后，以静脉滴注给药。
每支安瓿剂含有5mg本品，溶于5ml非水性溶剂，含下列成分：氮二甲基乙酰胺300mg，苯甲醇150mg，聚氧乙基化蓖麻油2．5g，无水乙醇42．7%(W／W)，用马来酸调节pH至5左右。
〔临床药理〕
本品为周期特异性细胞毒药物，作用于细胞周期S2后期和G2期，通过阻止细胞进入有丝分裂而起作用。本品也引起DNA键的单链和双链断裂，其作用机理似为抑制Ⅱ型拓扑异构酶所致。
对实验性小鼠肿瘤，替尼泊苷在其体内具有广谱的抗肿瘤活性，包括多种血液系统肿瘤的各种实体瘤。体外和体内研究均显示对依托泊苷耐药细胞株与本品有完全交互耐药性，反之亦是如此，但偶见临床报告指出对两药可缺乏完全交叉耐药性。
〔药代动力学〕
在一定的剂量范围内，替尼泊苷的药代动力学参数呈线性。每日注射1次，连续用3d后，药物在体内不发生蓄积。已经证实成人和儿童体内对药物的代谢没有显着差异。
静脉输注后，药物从中央室快速清除，分布相半衰期约为1h，替尼泊苷在体内高蛋白结合率(＞99%)可能限制其在体内的分布。替尼泊苷在脑脊液中的浓度低于同时测定的血浆药物浓度。其在肾的清除率仅占总清除率的10%左右，替尼泊苷的清除相半衰期约为6～20h，尽管替尼泊苷的代谢途径尚未明确，但已证实诸如苯巴比妥和苯妥英这些对于肝代谢起诱导作用的药物可以增加替尼泊苷的清除(见“警告”，“药物的相互作用”)
〔适应证和用途〕
本品适用于治疗下列各种疾病通常与其他抗癌药物联合应用：
恶性淋巴瘤；
何杰金病；
急性淋巴细胞白血病，成人与儿童的高危病例；
颅内恶性肿瘤，即成胶质细胞癌，室管膜瘤，星形细胞瘤；
膀胱癌；
成神经细胞瘤和儿童的其它实体瘤。
〔禁忌证〕
对替尼泊苷或对本处方中任一组成分有过敏史者禁用。
严重白细胞减少或血小板减少病人禁用本品。
〔警告〕
本品只能供对肿瘤化疗药物有经验的医师使用，只有具备充分的医疗条件设施，方可进行替尼泊苷的治疗及处理并发症。可能严重的骨髓抑制会发展为感染或出血，应用本品时应定期进行血细胞计数及肝、肾功能检查，如发现骨髓受抑制或肝、肾功能异常应停止使用本品。
初次使用本品或重复使用后曾发生致死的严重过敏反应。
肝、肾功能严重损害的病人应谨慎使用。
〔妊娠期〕
妊娠妇女使用本品可造成胎儿损害，妊娠大鼠给予本品已发现胚胎毒性和致畸性，未曾在妊娠妇女组进行本品研究，如妊娠妇女应用本品或妇女在使用本品过程中怀孕，应告知病人，本品可对胎儿造成潜在性伤害，育龄期的妇女在使用本品时应告知避免受孕。
〔注意点〕
对肝、肾功能损害的病人或肿瘤已侵犯骨髓的病人，使用本品应谨慎小心。
用本品治疗时，应定期进行监测白细胞和血小板计数：如白细胞低于2000／mm3或血小板低于75000／mm3并非由恶性疾病本身引起的，应推迟使用，直至骨髓完全恢复正常。
在开始输入本品之前，应特别注意静脉留置导管是处于正确的位置，以保证输注本品进入静脉，因为输注于静脉血管外可产生组织坏死和(或)血栓性静脉炎。
曾有报道静脉输入本品时发生低血压的病例。所以，在输注本品开始30～60min内应仔细监测主要的体征。
〔药物的相互作用〕
由于苯巴比妥和苯妥英这样的抗惊厥药可以增加替尼泊苷的清除率，进而导致某一既定剂量的药物在体内作用时间缩短，对接受抗惊厥治疗的病人，可能需增加替尼泊苷的用量。
已经观察到甲苯磺丁脲，水杨酸钠和磺胺甲二唑在体外可以置换与血浆蛋白结合的替尼泊苷。由于替尼泊苷的蛋白结合率极高，少量降低与蛋白结合的药物就可以导致游离药物的显着增高，进而增强药物的作用和毒性。
〔致癌性，致突变性和生殖毒性〕
已经有报道威猛与其他抗肿瘤药物合用导致病人发生急性非淋巴细胞白血病。应考虑到对人类本身是一个潜在的致癌原。
在各种细菌和哺乳动物遗传毒性实验中发现替尼泊苷的诱变性，替尼泊苷可以引起小鼠细胞系的基因变异和人类细胞系的DNA损伤。有几种人类和小鼠组织培养物中已证实发生了染色体畸变。
〔哺乳妇女〕
本品能否排泄至人乳中尚不明了，因为许多药均可排泄至人乳中，也因为本品对哺乳期婴儿的潜在性严重不良反应，故应衡量使用本品对母体重要性的利弊而决定中断哺乳还是去中断本品治疗。
〔儿科〕
本品含有苯甲醇。所含有苯甲醇曾于新生儿发生毒性有关，曾报道，当使用含大量苯甲醇冲洗液洗低重早产儿时，发生以喘息性呼吸，核黄疸症，代谢性酸中毒，神经退行性变，血液异常为特征表现的综合征，以致于死亡。
在接受高于推荐剂量治疗的病人和先前曾用过止吐药的病人，可以发生急性中枢神经系统抑制和低血压。
〔不良反应〕
1．血液学反应 骨髓抑制常使剂量受限制，采用本品治疗7～14d后可发生白细胞减少与血小板减少症，通常2～3周内骨髓抑制可完全复原，白细胞减少较血小板减少更常见更为严重。也可以发生贫血和免疫溶血性贫血。
已经报道威猛与其他抗肿瘤药物合用可导致病人发生急性非淋巴细胞白血病。
2．胃肠道反应 恶心，呕吐是主要胃肠道毒性反应，但通常可采用止吐药物以控制这些症状。可以发生口炎／粘膜炎、厌食、腹泻、腹痛和肝功能异常。
秃发：本品的秃发发生率很高，特别见于接受多疗程的病人。
低血压：威猛快速静脉输注后可以发生暂时性低血压(见“制剂准备和用法”)已经有可能由于产生心律失常和低血压而致突然死亡的报道。
3．过敏反应 已有报道使用本品期间或用药后即刻可发生过敏性样的反应，主要表现为寒战，发热，心动过速，支气管痉挛，呼吸困难以及低血压，它们可能是由于溶剂中的聚氧乙基化蓖麻油组分或是由于替尼泊苷本身。这些反应可能在第一次用药时就发生，更常见于患脑肿瘤或神经细胞瘤的病人。
出现一种反应的危险性可能与重复给药及药物在体内的蓄积有关。停止输注本品及适时地使用升压药物、皮质激素、抗组胺药，或血容扩张剂，以上症状可立即减轻以致于消失。潮红、出汗、高血压、水肿等症状也有报道。
4．皮肤反应 伴有或不伴有瘙痒的荨麻疹也有报道。
5．神经病变 已经报道的神经毒性包括：由于硫酸长春新碱和威猛相互作用而导致病人出现严重的神经病变的病例，使用高于所推荐剂量的病人发生中枢神经系统的抑制。(见“过量”)
6．其它 下列反应也有报道：感染，肾功能不全，高血压，头痛，神情混乱和肌无力。
7．过量 在使用高于推荐剂量威猛的病人和先前用过止吐药的病人，已经观察到发生急性中枢神经系统抑制和低血压。
迄今尚无证明对本品过量有效的解毒剂。用量过大出现并发症的先兆继发于药物对骨髓的抑制。
〔剂量和用法〕
对个别适应证的特定剂量和治疗方案应参考近期的文献。
〔单药治疗〕
每个疗程总剂量在300mg／m2，在3～5d期间给予，每3周或待骨髓恢复后可重复一个疗程。
〔联合治疗〕
本品可与其它几种已批准化疗药物联合使用，当与其它骨髓抑制药联合应用时，应适当降低本品的剂量，应定期监测外周血像计数，需要时应定期进行骨髓检查。
注意：患唐氏综合征的病人对骨髓抑制性化学疗法的反应特别敏感，因此，对这些病人应考虑减少用量。
〔制剂准备和用法〕
注意：已经有报道用(由亚烯丙基腈，丁二烯和苯乙烯组成的聚合物)制成的硬塑料器具接触到N，N-二甲基乙酰胺(威猛处方中的一个溶剂)时使其发生分解。在威猛和威猛的稀释溶液中尚未见有这种后果的报道。
为了避免本品从聚氯乙烯容器中抽提出增塑剂(二[2-乙基己基]邻苯二甲酸盐)，应使用不含增塑剂的大容量灭菌容器如玻璃或聚烯容器制备威猛溶液。同样，给病人输注威猛药液时亦应使用不含增塑剂的器具。
使用前即刻将5ml本品50mg安瓿剂用50ml，125ml，250ml或500ml5%葡萄糖或0．9%氯化钠注射剂稀释，这样稀释后的药液所提供替尼泊苷的终浓度分别为1．0，0．4，0．2和0．1mg／ml，然后将已稀释的溶液进行静脉输注。输注时间不少于30min，为减少低血压反应的可能性，本品不应静脉推注或静脉快速输注，输注本品的过程中必须密切注意保证输注导管的尖端保留在静脉腔内，以避免输注液的外溢和可能发生的组织刺激作用。
如按上述方法稀释，置于所推荐的大容量玻璃容器或聚烯灭菌容器内含鬼臼噻吩苷0．1，0．2，或0．4mg／ml的溶液置于普通日光灯下24h可保持稳定。无需冷藏。含威猛终浓度为1mg／ml的药液，贮存于室温和普通日光灯下稳定性稍差，因此需在制备后4h以内使用以减少发生沉淀的可能性。
注意：如果不按照上述方法操作，而用其它任何方法稀释本品，无论用其它的何种稀释剂或其它的任何浓度，均有可能产生沉淀。一旦发生沉淀，就不能给病人使用。同样，通过各种输液器具，长时间输注替尼泊苷(24h)时也发生了沉淀反应。因此在给病人输入药液时，需时常注意检查药液及整个输液系统。肝素溶液会引起替尼泊苷发生沉淀，因此在给病人输药之前或之后，必须用5%葡萄糖或0．9%氯化钠注射液彻底冲洗输药用的注射针／管等用具。配制威猛溶液时应尽可能轻地搅动威猛稀释液，因为剧烈搅动可以引起沉淀。本品药液中不应混入其它药物。
〔抗癌药物配制和处理的程序〕
应小心地处理和配备威猛药液。如果药液溅上皮肤，应立即用水和肥皂彻底清洗。如果粘膜沾上药液，用水彻底冲洗。
应考虑正确的配制和处理抗癌药物的程序问题，已公布了有关本问题的几种程序指南，对于指南中介绍各程序的必要性和准确性尚未取得一致意见。
稳定性：本品装于铅玻璃安瓿中，室温(25℃)贮存，在包装上指明的有效期内保持稳定。
安瓿剂，每支5ml，内含50mg本品，每盒10支。
〔生产厂家〕
美国百布里斯尼-迈耶-施贵宝公司
(附本品别名：鬼臼噻吩苷，Vehem)
【外文释文】：
Teniposide(VM-26)
Description
Vumon(teniposide；also known as VM-26)is a semisynthetic derivative of podophyllo toxin used in the treatment of certain neoplastic diseases．It is a neutral lipophilic compound practically insoluble in water．It must be prepared in organic solvents．Vumon is administered after dilution with a suitable parenteral vehicle，by intravenous infusion．
Each ampoule contains 50 mg of teniposide dissolved in 5 ml of a nonaqueous solution containing the following：N，N-dimethyl-acetamide 300 mg，benzyl alcohol 150 mg，polyoxyethylated castor oil(Cremophor EL*)2．5g，dehydrated ethanol 42．7%(v／v)，and maleic acid to adjust pH to approximately 5．
*Cremophor EL is the registered trademark of BASF Aktiengesellschaft．
Clinical pharmacology
Vumon is a phase-specific cytotoxic drug，acting in the late S2 or G2 phase of the cell cycle preventing cells from entering mitosis．Vumon also produces single and double strand breaks in DNA．The mechanism of action appears to be due to inhibition of type ll topoisomerases．
Teniposide has a broad spectrum of in vivo antitumour activity against murine tumours，including haematologic malignancies and various solid tumours．Cells resistant to etoposide may be fully cross resistant to teniposide and vice versa in both in vivo and in vitro studies，although there have been occasional clinical reports suggesting a lack of complete cross-resistance．
Pharmacokinetics
The pharmacokinetics of teniposide appear to be linear over a range of doses．Drug accumulation does not occur after daily administration for 3 days．No major differences in the disposition of the drug in adults and children have been identified．
Following intravenous infusion，initial clearance from the central compartment is rapid with a distribution half-life of approximately 1 hour．Teniposide is highly protein bound，＞99%，which may limit its distribution within the body，levels of teniposide in CSF are low relative to simultaneously measured plasma levels．Mean terminal half-life has ranged from approximately 6-20 hours with renal clearance accounting for only about 10%of total clearance．While metabolic pathways for teniposide have not been characterized，agents such as phenobarbital and phenytoin that induce hepatic metabolism，have been shown to increase the clearance of teniposide．(see Precautions-Drug Interactions．)
Indications and usage
Vumon is indicated in the treatment of the following，usually in combination with other anticancer agents：
Malignant lymphomas
Hodgkin’s disease
Acute lymphoblastic leukaemia，high risk，in adults and children
Urinary bladder carcinoma
Neuroblastoma and other solid tumours in children
Contraindications
Vumon should not be given to individuals who have demonstrated a previous hypersensitivity to teniposide or to any component of the formulation．
Vumon is contraindicated in patients who have severe leucopenia．thrombocytopenia．
Warnings
Vumon should be only by physicians experienced with cancer chemotherapeutic drugs．Management of therapy and complications is possible only when adequate treatment facilities are readily available．Severe myelosuppression with resultant infection or bleeding may occur．Blood counts as renal and hepatic function tests must be done regularly．Discontinue the drug if abnormal depression of bone marrow or abnormal renal or hepatic function is seen．
Life threatening anapylactic reactions have occurred following initial teniposide administration or after repeated exposure．
Use with caution in patients with severe hepatic and／or renal impairment．
Pregnancy
Vumon may cause fetal harm when administered to a pregnant woman．Embryotoxic and teratogenic effects have been seen in pregnant rats given teniposide．No studies in pregnant women have been conducted．If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug，the patient should be apprised of the potential hazard to the foetus．Women of child-bearing potential should be advised to avoid becoming pregnant．
Precautions
Vumon(teniposide)should be administered with care to patients with marrow involvement by tumour and to patients with impaired renal or hepatic function．
Regular monitoring of white blood cell and platelet counts should be performed during treatment with Vumon．If the white blood cell count is below 2000 cells／mm3 or the platelet count is below 75 000 cells／mm3，unless caused by malignant disease，treatment should be postponed until bone marrow recovery is complete．
Care should be taken to ensure that Vumon infusions are given through an intravenous catheter in proper position prior to infusion．Extravasation，necrosis and／or thrombophlebitis may result with improper administration．
Instances of hypotension have been reported during Vumon infusion．Therefore，vital signs should be monitored carefully during the first 30-60 minutes after the start of the infusion．
Drug Interactions
Anticonvulsants such as phenobarbital and phenytoin increase the clearance rate of teniposide resulting in lower systemic exposure for a given teniposide dose．Increased doses may be required in patients receiving anticonvulsant therapy．
Tolbutamide，sodium salicylate and sulfamethizole have been shown in vitro to displace teniposide from plasma protein．Because of extremely high binding of teniposide to proteins，small decreases in binding could result in substantial increases in free drug with associated increased drug effect and toxicity．
Carcinogenesis，Mutagenesis，Impairment of Fertility
The occurrence of acute nonlymphocytic leukaemia has been reported in patients treated with Vumon in association with other antineoplastic agents．
Teniposide should be considered a potential carcinogen in humans．
Teniposide has been shown to be mutagenic in various bacterial and mammalian genetic toxicity tests．Teniposide has caused gene mutations in murine cell lines and DNA damage in human cell lines．Chromosome aberrations have been demonstrated in several human and murine tissue cultures．
Teniposide has caused reduced spermatogenesis in monkeys and dogs，and reduced testicular and ovarian weights in dogs．
Nursing Mothers
It is not known whether this drug is excreted in human milk，because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Vumon，a decision should be made whether to discontinue nursing or to discontinue the drug，taking into account the importance of the drug to the mother．
Paediatrics
Vumon contains benzyl alcohol．Benzyl alcohol has been associated with toxicity in newborns．A syndrome characterized by gasping respirations，kernicterus，metabolic acidosis，neurologic deterioration，haematologic abnormalities and death have been reported to occur following administration of benzyl alcohol containing flush solutions to low birth weight，preterm infants．
Acute central nervous system depression and hypotension have been observed in patients who were receiving higher than recommended doses of Vumon，and who were also pre-treated with antiemetic drugs．
Adverse reactions
Haematologie
Myelosuppression is often dose-limiting，with leucopenia and thrombocytopenia occurring ／-14 days after Vumon treatment．Bone marrow recovery is usually complete within 2-3 weeks．Leucopenia is more frequent and more severe than thrombocytopenia．Anaemia also occurs and immune haemolytic anaemia has been reported．
The occurrence of acute nonlymphocytic leukaemia has been reported in patients treated with Vumon in association with other antineoplastic agents．(whitlock，1991，Hawkins，1992)
Gastrointestinal
Nausea and vomiting are the major gastrointestinal toxicities．The nausea and vomiting can usually be controlled by antiemetic therapy．Stomatitis／mucositis，anorexia，diarrhoea，abdominal pain and hepatic disfunction may occur．
Alopecia
A high incidence of alopecia has been reported，especially in patients receiving multiple courses of therapy．
Hypotension
Transient hypotension may occur following rapid intravenous administration of Vumon(see Preparation and Administration)．Sudden death due to probable arrhythmia and hypotension has been reported．
Hypersensitivity
Anaphylactic-like reactions characterized by chills，fever，tachycardia，bronchospasm，dyspnoea and hypotension have been reported to occur during or immediately after Vumon administration．They may be due to the Cremophor EL component of the vehicle or to teniposide itself．These reactions may occur on the first dose and may occur more commonly in patients with brain tumours or in patients with neuroblastoma．The risk of having a reaction may be related to repeated exposure and cumulative dose．These reactions have usually responded promptly to cessation of the infusion and administration of pressor agents，corticosteroids，antihistamines or volume expanders as appropriate．Flushing，sweating，hypertension and oedema have also been reported．
Dermatologic
Urticaria with or without pruritus has been reported．
Neurotoxicity
Neurotoxicity has been reported，including severe cases of neuropathy in patients due to an interaction of vincristine sulfate and Vumon．Central nervous system depression has been observed in patients receiving higher than recommended doses(see Overdosage)．
Other
The following reactions also have been reported：infection，renal disfunction，hypertension，headache，confusion and asthenia．
Overdosage
Acute central nervous system depression and hypotension have been observed in patients who were receiving higher than recommended doses of Vumon，and who were also pre-treated with antiemetic drugs．
No proven antidotes have been established for Vumon overdosage．The anticipated complications of overdosage are secondary to bone marrow suppression．
Dosage and administration
The current literature should be consulted for specific doses and regimens for particular indications．
Monotherapy
Total dose per course is 300 mg／m2，given over a 3-5 day period．Cycles may be repeated every 3 weeks or upon recovery of bone marrow．
Dosage should be adjusted according to individual patient variability and toxicity，when employed as a single agent or in combination with other antineoplastic agents．
Combination Therapy
Vumon has been used in combination with several other approved chemotherapeutic agents．When it is used in combination with other myelosuppressive drugs，the dose should be appropriately reduced．Peripheral blood counts should be monitored and，if necessary，marrow evaluations performed regularly．
Note：patients with Downs syndrome may be especially sensitive to myelosuppressive chemotherapy，therefore，dose modification may need to be considered in these patients．
Preparation and Administration
Note：hard plastic devices made of ABS(a polymer composed of acronitrile，butadiene and styrene)have been reported to decompose when exposed to N，N-dimethylacetamide，oneof the solvents present in the Vumon formulation．This effect has not been reported for Vumon itself，or for diluted solutions of Vumon．
In order to prevent extraction of the plasticizer DEHP〔di(2-ethylhexyl)phthalate〕from polyvinyl chloride(PVC)containers，solutions of Vumon should be prepared in nonDEHP containing large volume parenteral containers such as glass or polyolefin containers．Vumon solutions should be administered with non-DEHP containing administration sets．
Immediately before administration，each 5 ml ampoule of Vumon containing 50 mg of teniposide must be diluted with 50 ml，125 ml，250 ml or 500 ml of either 5 percent dextrose injection or 0．9 percent sodium chloride injection．Such dilution provides final teniposide concentrations of 1 mg／ml，0．4 mg／ml，0．2 mg／ml and 0．1 mg／ml，respectively．The diluted solution should then be administered by intravenous infusion over a minimum of thirty minutes．To reduce the possibility of hypotensive reactions，Vumon should not be administered by bolus injection or rapid infusion．Greatest care should be taken to ensure that the catheter tip remains in the vein during administration，to avoid extravasation and possible tissue irritation．
When diluted as recommended above，solutions that contain teniposide 0．1mg，0．2 mg，or 0．4 mg／ml，are stable under normal fluorescent lighting for 24 hours in the recommended large volume glass or polyolefin parenteral containers．Refrigeration is not recommended．Vumon solutions prepared at a final teniposide concentration of 1 mg／ml，and stored at room temperature under normal fluorescent lighting are less stable，and should be administered within 4 hours of preparation to reduce the potential for precipitation．
Note：this product may precipitate when diluted in any manner，with any diluent or to any concentration other than those described above．If evidence of precipitation does appear，the solution should not be administered．Likewise，precipitation has occurred when prolonged infusions of teniposide(24 hours)were administered through a variety of infusion devices．These infusions，and their delivery systems，should be inspected frequently during administration．Heparin solution can cause precipitation of teniposide，therefore，administration sets／tubing，etc．，should be flushed thoroughly with 5%dextrose injection or 0．9%sodium chloride injection，before and after administration of Vumon．Diluted Vumon solutions should be subjected to as little agitation as is necessary to prepare the solution，since excessive agitation can result in precipitation．No other drugs should be mixed with Vumon infusion．
Procedure for handling and disposal of anti-cancer drugs
Caution should be exercised in handling and preparing solution of Vumon．If Vumon contacts the skin，immediately wash thoroughly with soap and water．If Vumon contacts mucous membranes，flush thoroughly with water．
Procedures for proper handling and disposal of anti-cancer drugs should be considered．Several guidelines on this subject have been published．There is no generalagreement that all of the procedures recommended in these guidelines are necessary or appropriate．
Stability
When stored at room temperature(25℃)，Vumon packaged in flint glass ampoules will remain stable until expiration date indicated on package．
How supplied
Ampoules：50 mg／5 ml in packs of 10
Manufacturer
Bristol-Myers Squibb Company USA