3．速溶型阿霉素
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9页（15543字）
【中文释文】：
(多柔比星)
速溶型阿霉素(盐酸阿霉素)是一种蒽环类抗肿瘤抗生素，由Farmitalia Research Laboratories研究实验室从一种链霉菌(streptomyces peucetius var casesius)培养液中提炼而出。
速溶型阿霉素含10mg和50mg盐酸阿霉素，是一种灭菌，无热原，桔黄一红色含乳糖和羟基苯甲酸盐的冻干粉剂，溶于水和生理盐水。
〔生物活性〕
速溶型阿霉素的作用机理与该药可与DNA结合及抑制核酸合成有关。细胞培养研究表明：它具有迅速的细胞膜穿透力及抗生素在核周色质中有显着的聚积力。曾有报导，该药可迅速抑制核酸合成及有丝分裂，并致染色体异常。
动物实验表明，具细胞毒性药物的阿霉素对广谱的实验性肿瘤有免疫抑制作用，同时也造成各种毒性作用。如兔及鼠类的心脏毒性反应，鼠及狗类的睾丸萎缩，各类测试动物的骨髓抑制等。
〔临床药理学〕
药物动力学研究以核素标记阿霉素显示：静脉注射后的阿霉素，迅速降低到某一血浆浓度水平，不过，经胆道及泌尿系统排泄缓慢，可能是阿霉素与各组织结合所致。正如Flourimetric方法所确定，使用阿霉素5d后，经泌尿系统排泄的量，大约为摄入量的5%，经胆道排泄是最主要的排泄途径。使用阿霉素7d后，经胆道及大便排泄的量，约为摄入量的40%～50%。肝功能不全者，排泄会减慢，从而使该药蓄积于血和组织中。阿霉素不能通过血脑屏障。
〔适应证〕
阿霉素能成功地诱导多种肿瘤的缓解。包括乳腺癌、肺癌、甲状腺癌、卵巢癌，其它如骨肉瘤及软组织肉瘤、何杰金或非何杰金的淋巴瘤、神经母细胞瘤、Wilms瘤，急性淋巴细胞白血病及急性粒细胞白血病等。
〔禁忌证〕
阿霉素禁用于那些曾接受抗肿瘤药物化疗或放疗而致明显骨髓抑制的病人，亦禁用于那些已有累积剂量阿霉素或柔红霉素治疗的病人(见注意事项)。虽然资料总结没有显示阿霉素是诱导心脏毒性的危险因子，但对有心脏病病人，或有心脏病记录的病人，并不提倡用阿霉素。对膀胱癌并发尿道狭窄难于使用导管或膀胱癌并发泌尿道感染阻碍手术治疗的病人，不提倡行阿霉素局部膀胱灌注法治疗。
〔剂量-静脉注射〕
当以阿霉素作单一抗肿瘤药物治疗时，建议剂量为：成人每3周1次，应根据骨髓贮备情况，以体表面积60～75mg／m2，作静脉注射。对骨髓贮备不足的老年人，既往曾有用药史，肿瘤细胞骨髓浸润的病人建议用较低剂量(60mg／m2)。上述剂量可1次单剂量注射或连续3d分量给药。儿童给药建议连续3d以30mg／(m2·d)作静脉注射，疗程为每4周重复1次。
静脉注射阿霉素的累积剂量与剂型无关，不应超过550mg／m2(见注意事项)。阿霉素如与其它具骨髓抑制的药物联合化疗时，一般剂量为每3周或4周25～50mg／m2，如药物不具骨髓抑制性，则剂量为60～75mg／m2。
肝功能减退时，阿霉素剂量应当减少，以免增加其特有毒性。
通常，当中等程度的肝功能不良时(胆红素1．2～3mg%及磺溴酞钠潴留9%～15%)，剂量应减少50%，严重肝功能不良时，剂量应减少75%。
由于阿霉素在肾脏排泄量低，故中度肾功能不良时，亦无须减少剂量。
〔膀胱内灌注法〕
每次灌注建议剂量为30～50mg，重复时间可由1周至1个月。治疗作为预防性或疗效性时，应根据医生的意见，来决定使用次数及疗期长短。
当实行膀胱内灌注法治疗时，由于其间在循环系统的吸收度及运送量很低，故不会发生静脉注射阿霉素时所带来的问题。
〔注意事项〕
初用阿霉素治疗时，应密切注意观察病人情况，小心观察白细胞、红细胞及血小板的数量，以防严重骨髓抑制发生。白血病病人用正常剂量给药，通常有一过性的血细胞下降，用药后10～14d降到最低，通常21d可恢复至正常。在治疗开始及治疗期间，提倡用一般实验室的检验，如SGOT、SGPT、碱性磷酸酶，胆红素和BSP来评估病人的肝功能。须特别注意，阿霉素引起的心脏毒性。
累积剂量在550mg／m2以下时，发生心力衰竭的机率虽然很低(＜1%)，但超过限制剂量550mg／m2时，发生心力衰竭的机率就会增加，纵膈区既往行放疗的，最大蓄积量应在400mg／m2以下。阿霉素的使用总量应考虑到病人以前在接受放疗或联合治疗时，是否曾使用具有潜在心脏毒性的药物，如环磷酰胺及柔红霉素。心力衰竭有可能在完全缓解期或停用阿霉素治疗后几周内发生，而且一般常用的内科治疗并不能改善心力衰竭。每一治疗周期之前及后，都值得做基础心电图。心电图的改变，如T波低平或倒置，或S-T段下降，或心律失常发作，并不是停止用药的指征。现在认为QRS波低电压是阿霉素心脏毒性较为特异的表现。如果发生QRS波低电压，须慎重权衡继续用药治疗的益处，及发生不可逆心脏损害危险性两者间的利害关系。在累积总量很高时，心力衰竭可随时发生，而心电图预先无任何改变。阿霉素引起男性和女性不育，引起畸胎或对胎儿造成损害的可能性尚未得到足够评估。实验室资料显示，阿霉素可能引起胎儿生存能力下降，故孕妇应避免使用，阿霉素像其它抗肿瘤药物和免疫抑制药物一样对特定实验模型动物有潜在性致癌作用。注射阿霉素12d后，尿液可呈桔红色，如果皮肤意外接触到阿霉素，应立即彻底用肥皂及清水冲洗。在膀胱灌注时应特别小心，灌注期间及灌注后，应彻底清洗尿道周边区，并立即排除尿液。
〔副作用〕
骨髓抑制及心脏毒性是最重要的副作用(见注意事项)
脱发是常见副作用，发生率约85%，男性伴有胡子不长，不过停药后可恢复正常。口腔炎会在注射药物5～10d后出现，其特点是在舌两侧及舌下粘膜区域，连续3d给阿霉素药会导致严重性口腔炎。
可出现消化道症状如恶心、呕吐，腹泻也可发生。
如果注射阿霉素时发生药物外渗会导致严重的坏死。有报道，选用小静脉注射或1条静脉重复多次注射，可引起静脉硬化症(见注意事项)。
膀胱灌注法：可出现血尿，囊泡及尿道灼伤或刺痛，排尿困难，痛性尿淋沥及排尿频繁。
〔给药途径〕
速溶型阿霉素口服无效。须避免肌肉注射或鞘内注射。只能静脉注射给药。应先点滴生理盐水，以确保针头在静脉内，然后才在这一通畅的静脉输液管内注射速溶型阿霉素。这项技术可减少药物外渗的危险性及保证在注射完毕后可冲洗静脉。速溶型阿霉素切不可与肝素混合，因这类药物在化学性质上不相配伍，可产生沉淀物。
速溶型阿霉素可与其它化疗抗肿瘤药物联合应用，但切不可用同一瓶内来混合这些药物，在膀胱灌注治疗的案例中，速溶型阿霉素应在室温下溶于注射用水，建议的剂量浓度为1mg／ml。
〔包装规格〕
每瓶含10mg盐酸阿霉素，冻干粉剂。
每瓶50mg盐酸，阿霉素冻干粉剂需25mg生理食盐水配制溶液。
配制好的溶液在室温下可存放24h，在冰箱内(4～10℃)可存放48h，溶液必须避光。
〔生产厂家〕
意大利爱宝药厂
(附本品别名：Doxorubicin，14-羟基柔红霉素，亚法里亚霉素，阿得里亚霉素，羟基红比霉素，14-羟正定霉素，ADM，ADR，F．I-106，Adriacin，Adriblastina，14-hydroxydaunomycin，NSC-123127．)
【外文释文】：
doxorubicin
Presentation
Sterile pyrogen-free，orange-red，freeze-dried powder in vials containing 10 and 50 mg of doxorubicin hydrochioride with lactose and hydroxybenzoate．
Uses
Antimitotic and cytotoxic．Doxorubicin has been used successfully to produce regression in a wide range of neoplastic conditions including acute leukaemia，lymphomas，soft-tissue and osteogenic sarcomas，paediatric malignancies and adult solid tumours，in particular，breast and lung carcinomas．
Doxorubicin is frequently used in combination chemotherapy regimens involving other cytotoxic drugs．Doxorubicin cannot be used as an antibacterial agent．
Dosage and administration
For reconstitution the contents of the 10 mg vial may be dissolved in 5 ml Water for Injections or Sodium Chloride Injection and those of the 50 mg vial in 25 ml of the same solvents．
After adding the diluent，the vial contents will dissolve with gentle shaking，without inversion，with in 30 seconds．The approximate displacement value of the contents of a 50 mg vial，after 25 ml of solvent have been added is 0．15 ml．
Adults and children
Intravenous administration：This is the most frequently used route of administration．The reconstituted solution is given via the tubing of a freely-running intravenous infusion，taking 2-3 minutes over the injection．This technique minimizes the risk of thrombosis or perivenous extravasation which can lead to severe cellulitis and vesication．Commonly used acceptable solutions are Sodium Chloride Injection，Dextrose Injection 5% or Sodium Chloride and Dextrose Injection．
Dosage is usually calculated on the basis of body surface area．On this basis，60-75 mg／m2 may be given every three weeks when doxorubicin is used alone．If it is used in combination with other antitumour agents having over lapping toxicity，the dosage of doxorubicin may need to be reduced to 30-40 mg／m2 every three weeks．If dosage is to be calculated on the basis of body weight，1．2-2．4 mg／kg should be given as a single dose every three weeks．It has already been shown that giving doxorubicin as a single dose every three weeks greatly reduces the distressing toxic effect，mucositis；however there are still some who believe that dividing the dose over three successive days(0．4-0．8 mg／kg or 20-25 mg／m2 on each day)gives greater effectiveness even though at the cost of higher toxicity．
Administration of doxorubicin in weekly regimen has been shown to be as effective as the 3-weekly regimen．The recommended dosage is 20 mg／m2 weekly although objective responses have been seen at 6-12 mg／m2．
Weekly administration leads to a reduction in cardiotoxicitv．
Dosage may need to be reduced for patients who have had prior treatment with other cytotoxic agents．Dosage may also need to be reduced in children and the elderly．
If hepatic or renal function is impaired，doxorubicin dosage should be reduced according to the following table．
Serum Bilirubin BSP Retention Recommended Dose
Levels
1．2-3．0 mg／100 ml 9%-15% 50%nomal dose
＞3．0 mg／100 ml ＞15% 25%normal dose
Intra-arterial administration：Intra-arterial injection has been used in attempts to produce intense local activity while keeping the total dose low and therefore reducing general toxicity．It should be emphasized that this technique is potentially extremely hazardous and can lead to widespread necrosis of the perfused tissue unless due precautions are taken．
Intra-arterial injection should only be attempted by those fully conversant with this technique．
Intravesical administration：Doxorubicin is being increasingly used by intravesical administration for the treatment of transitional cell carcinoma，papillary bladder tumours and carcinoma-in-situ．It should not be employed in this way for the treatment of invasive tumours which have penetrated the bladder wall．It has also been found useful to instil doxorubicin into the bladder at intervals after transurethral resection of a tumour in order to reduce the probability of recurrence．While at present many regimens are in use，making interpretation difficult，thefollowing may be helpful guides：The concentration of doxorubicicn in the bladder should be 50 mg per 50 ml．To avoid undue dilution with urine，the patient should be instructed not to drink any fluid in the 12 hours prior to instillation．This should limit urine production to approximately 50 ml per hour．The patient should be rotated a quarter turnevery 15 minutes while the drug is in situ．
Exposure to the drug solution for one hour is generally adequate and the patient should be instructed to void at the end of this time．
Contraindications，warnings，etc
Doxorubicin Rapid Dissolution is intended for use under the direction of those experienced in cytotoxic therapy．
Hypersensitivity to hydroxybenzoates is a contra-indication．
Dosage should not be repeated in the presence of bone-marrow depression or buccal ulcerations．The latter may be preceded by premonitory buccal burning sensations and repetition in the presence of this symptom is not advised．Haematological monitoring should be undertaken regularly in both haematological and non-haematological conditions，because of the possibility of bone-marrow depression which may become evident around ten days from the time of administration．
Cardiotoxicity may be manifested in tachycardia，including superventricular tachycardia and ECG changes．
Routine ECG monitoring is recommended and caution should be exercised in patients with impaired cardiac function．A cumulative dose of 450-550 mg／m2 should only be exceeded with extreme caution．Above this level the risk of irreversible congestive cardiac failure increases greatly．The total dose of doxorubicin administered to the individual patient should also take account of any previous or concomitant therapy with other potentially cardiotoxic agents such as high-dose i．v．cyclophosphamide，mediastinal irradiation or related anthracyclic compounds such as daunorubicin．
Administration of doxorubicin weekly has been shown to be associated with reduced cardiotoxicity compared with a 3-weekly schedule allowing patients to be treated to a higher cumulative dose．It should be noted that cardiac failure may occur several weeks after administration and may not respond to treatment．
Baseline and follow-up ECGs during and immediately after drug administration are advisable．Transient ECG changes，such as T-wave flattening，S-T segment depression and arrhythmias，are not considered indications for the suspension of doxorubicin therapy．A reduction of the QRS wave is considered more indicative of cardiac toxicity．If this change occurs，the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage．
Severe cardiac failure may occur suddenly without premonitory ECG changes．
Doxorubicin rapid dissolution may impart a red colour to the urine，particularly to the first specimen passed after the injection，and patients should be advised that this is no cause for alarm．
Alopecia occurs frequently，including the interruption of beard-growth，but all hair growth normally resumes after treatment is stopped．
Nausea，vomiting and diarrhoea may also occur．
The risk of thrombophlebitis at the injection site may be minimized by following the procedure for administration recommended above．A stinging or burning sensation at the site of administration signifies a small degree of extravasation and the infusion should be stopped and re-started in another vein．
Pregnancy and lactation：There is no conclusive information as to whether doxorubicin may adversely affect human fertility of cause teratogenesis．Experimental data，however，suggest that doxorubicin may harm the foetus and should，therefore，not be administered to pregnant women or to mothers who are breast-feeding．
Overdosage Single doses of 250 mg and 500 mg of doxorubicin have proved fatal．Such doses may cause acute myocardial degeneration within 24 hours and severe myelosuppression，the effects of which are greatest between 10-15 days after administration．Treatment should aim to support the patient during this period and should utilise such measures as blood transfusions and reverse barrier nursing．Delayed cardiac failure may occur up to six months after the overdose．Patients should be observed carefully and should signs of cardiac failure arise be treated along conventional lines．
Pharmaceutical precautions
The vial contents are under a negative pressure to minimize aerosol for mation during reconstitution，particular care should be taken when the needle is inserted．Inhalation of any aerosol produced during reconstitution must be avoided．
The following protective recommendations are given due to the toxic nature of this subatance：
Personnel should be trained in good technique for reconstitution and handling．Pregnant staff should be excluded from working with this drug．
Personnel handling Doxorubicin rapid dissolution should wear protective clothing，goggles，gowns and disposable gloves and masks．
A designated area should be defined for reconstitution(preferably under a laminar flow system)．The work surface should be protected by disposable，plastic-backed，absorbent paper．
All items used for reconstitution，administration or cleaning，including gloves，should be placed in high-risk．
Waste-disposal bags for high temperature incineration should be incinerated．
The reconstituted solution is stable when stored for up to 48 hours at room temperature in normal artificial light．however，in line with good pharmaceutical practice it is recommended that it should normally be stored at 2°-8℃，protected from light and used within 24 hours．The reconstituted solution is chemically stable for at least 24 hours at room temperature in strong sunlight．
The reconstituted solution contains 0．02% hydroxybenzoate．This is not a preservative solution．
Discard any unused solution．
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug．
Doxorubicin Rapid Dissolution should not be mixed with heparin as a precipitate may form and it is not rcommended that Doxorubicin Rapid Dissolution be mixed with other drugs．
Accidental contact with the skin or eyes should be treated immediately by copious lavage with water or soap and water or sodium bicarbonate solution medical attention should be sought．
Spillage or leakage should be treated with dilute sodium hypochlorite(1%available chlorine)solution，preferably soaking overnight and then water．All cleaning materials should be disposed of as indicated previously．
Package quantities
10 mg and 50 mg vials supplied in individual cartons．
Manufacturer
Erba Ltd．Italy