多柔比星脂质体(楷莱)说明书如下:

【药品名称】
通用名：盐酸多柔比星脂质体注射液
商品名：楷莱【成份】
楷莱主要成份为盐酸多柔比星脂质体。

【 性状】
楷莱是一种脂质体制剂，系将盐酸多柔比星通过与甲氧基聚乙二醇的表面结合包封于脂质体中。这种工艺被称作为空间稳定或隐匿，可以保护脂质体免受单核巨噬细胞系统（MPS）识别，从而延长其在血液循环中的时间。
楷莱为无菌、半透明的红色混悬液，每瓶10 mL，含盐酸多柔比星2 mg/mL，是用于单剂量静脉滴注给药的浓缩液。楷莱的活性成分为盐酸多柔比星，是从一种波塞链霉菌表灰变种（strep tomyces peucetius var. caesius）培养液中提取得到的蒽环类细胞毒性抗生素。 【规格】
10ml:20mg【 药理作用】 
多柔比星抗肿瘤的确切机理尚不清楚。一般认为它具有抑制DNA、RNA和蛋白合成的细胞毒作用。这是由于这种蒽环类抗生素能嵌入DNA双螺旋的相邻碱基对之间，从而抑制其解链后再复制。
用楷莱对动物进行多剂量给药的研究中所显示的毒性与人体长期滴注盐酸多柔比星的结果相近。楷莱是将盐酸多柔比星包封并隐匿于脂质体中，因而其毒性反应的程度有所不同。
心脏毒性 ：兔的研究表明，合用楷莱的心脏毒性低于使用一般盐酸多柔比星制剂。
皮肤毒性 ：在大鼠和狗进行的重复给药试验中，用相当于临床应用的剂量可见严重的皮肤炎症和溃疡形成。在狗的研究中，降低给药剂量或者延长给药间隔可减少这些损伤的发生率和减轻严重程度。在长期静脉滴注用药的病人中也可见近似的皮肤损害，如手掌-足底红斑性感觉迟钝。
过敏反应 ：在狗的重复给药毒理研究中，给予脂质体（安慰剂）可见以下急性反应 ：低血压、粘膜苍白、流涎、呕吐和活动过多而后活动减少及嗜睡。狗使用楷莱和多柔比星可见相似但不很严重的反应，预给抗组胺药可以减轻低血压反应。然而这一反应并无生命危险，狗在停药后可迅速恢复正常。
局部毒性 ：皮下耐受性试验显示楷莱与盐酸多柔比星相比，在发生药液外渗下所产生的局部刺激或损害较轻。 

【药代动力学】 
楷莱是一种长循环周期的盐酸多柔比星脂质体，它在卡波氏肉瘤中的浓度比正常皮肤高。脂质体表面含有亲水聚合物甲氧基聚乙二醇（MPEG）。这些线性排列的MPEG基团从脂质体表面扩散形成一层保护膜，后者可减少脂类双分子层与血浆组分之间的相互作用。这可以延长楷莱脂质体在血循环中的时间，这些脂质体很小（平均直径大约100 nm），足以通过肿瘤的给养血管完整地渗透出来。在对C-26结肠癌肿瘤小鼠卡波氏肉瘤样损害的转基因小鼠实验中，有证据表明脂质体从血管中渗出并进入和蓄积在肿瘤中。这种脂质体具有低渗透性类脂基质与内部水性缓冲系统，两者协同保持盐酸多柔比星在血循环中处于包裹状态。
在对楷莱进行药代动力学评价中，给23例卡波氏肉瘤患者一次滴注20 mg/m2，历时30分钟。下表中列举了使用20 mg/m2楷莱（主要是脂质体包裹的盐酸多柔比星和少量的游离体）后得到的药动学参数(在滴注30分钟时测定)。
血浆峰浓度 ：8.34±0.49 mg/mL/h（平均值±标准差）。
血浆清除率 ：0.041±0.004 L/h/m2。
分布容积 ：2.72±0.120 L/m2。
AUC ：590.00±58.7 mg/mL/h。
λ1半衰期 ：5.2±1.4 小时。
λ2半衰期 ：55.0±4.8小时。
楷莱与文献报道的盐酸多柔比星常规制剂的人体药代动力学有显著差异。楷莱的药代动力学曲线呈线性，给药后呈二相分布，相时间较短（大约5小时），第二相时间较长（大约55小时），占曲线下面积（AUC）的大部分。盐酸多柔比星的组织分布广泛（分布容积700-1100 L/m2），消除速率快（24-73 L/m2）。相反，楷莱的药代动力学特征显示楷莱多半是在血液内，血中多柔比星的消除依靠脂质体载体。在脂质体外渗进入组织后，多柔比星才开始起效。
在相同剂量下，楷莱中占绝大多数的是以脂质体包裹形式存在的盐酸多柔比星（约占测得量的90-95%），楷莱的血药浓度和AUC值显著高于常规盐酸多柔比星制剂。在滴注给药后48-96小时，对卡波氏肉瘤和正常皮肤进行活组织检查：在接受20 mg/m2楷莱的治疗的病人中，给药48小时后卡波氏肉瘤中多柔比星总浓度（脂质体包裹和未包裹的）比正常皮肤平均高19倍（范围3-53）。 

【毒理研究 】 
致突变性和致癌性 ：虽然楷莱尚未进行该方面研究，但楷莱的药理活性成份盐酸多柔比星具有致突变作用和致癌作用。脂质体（安慰剂）无致突变作用和致癌作用。
生殖毒性 ：小鼠给予楷莱单剂量（36 mg/kg）导致轻至中度的卵巢或睾丸萎缩。大鼠重复给药（≥ (greater than or equal to) 0.25 mg/kg天）会导致睾丸重量下降和精子减少。狗重复给药（1 mg/kg/天）后观察到曲细精管弥散性变性和精子显著减少。 

【适应症】 
楷莱可用于低CD4（<200 CD4淋巴细胞/mm3）及有广泛皮肤粘膜内脏疾病的与艾滋病相关的卡波氏肉瘤（AIDS-KS）病人。
楷莱可用作全身化疗药物，或者用作治疗病情有进展的AIDS-KS病人的二线化疗药物，也可用于不能耐受下述两种以上药物联合化疗的病人 ：长春新碱、博莱霉素和多柔比星（或其他蒽环类抗生素）。 

【用法用量】 
楷莱应为每2-3周静脉内给药20 mg/m2，给药间隔不宜少于10天，因为不能排除药物蓄积和毒性增强的可能。病人应持续治疗2-3个月以产生疗效。为保持一定的疗效，在需要时继续给药。楷莱用250毫升5%葡萄糖注射液稀释，静脉滴注30分钟以上。禁止大剂量注射或给用未经稀释的药液。建议楷莱滴注管与5%葡萄糖滴注管相连接以进一步稀释并限度地减少血栓形成和外渗危险。
楷莱禁用于肌肉和皮下注射。
肝功能不全病人 ：对少数肝功能不全病人（胆红素值达4 mg/dl）给予20 mg/ m2楷莱，血浆清除率和清除半衰期未见变化。然而在取得进一步的经验之前，根据以往盐酸多柔比星的使用经验，对于肝功能不全的病人楷莱的给药量要减少。建议当胆红素高于以下数值时考虑减少用量 ：血清胆红素1.2-3.0 mg/dl，用常用量的1/2 ；大于3 mg/dl时用常用量的1/4。
肾功能不全病人 ：由于多柔比星由肝脏代谢和经胆汁排泄，故使用楷莱时剂量不需作调整。
脾切除病人 ：目前尚无楷莱用于脾切除病人的经验，故不推荐使用。 

【楷莱不良反应 】 
对AIDS-KS病人的临床开放和对照研究显示，与楷莱相关的常见的不良反应是骨髓抑制，几乎近一半病人发生。
白细胞减少是病人常见的不良反应，也可见贫血和血小板减少。这些反应一般在治疗早期便可见，而且是暂时的。临床试验中很少因骨髓抑制而停药。出现血液学毒性反应可能需要减少用量或暂停及推迟治疗。当中性粒细胞计数<1000/mm3，或血小板计数<5万/mm3时应暂停使用楷莱。当中性粒细胞计数<1000/mm3时，可同时使用G-CSF或GM-CSF来维持血液细胞数目。
在临床研究中使用楷莱常见有临床意义的实验室检查异常（≥ (greater than or equal to) 5%）包括碱性磷酸酶增加以及门冬酰胺转移酶和胆红素增加，这些反应被认为与基础疾病有关而与楷莱无关。根据报道，血红蛋白和血小板减少的发生率较低（<5%），白细胞减少导致的脓毒病更为少见（<1%）。以上某些异常的产生可能与HI感染有关，而非楷莱造成。
其他发生率较高（≥ (greater than or equal to) 5%）的不良反应有 ：恶心，无力，脱发，发热，腹泻，与滴注有关的急性反应和口腔炎。
滴注反应主要有潮红，气短，面部水肿，头痛，寒战，背痛，胸部和喉部收窄感，低血压。在多数情况下，不良反应发生在个疗程。采用某种对症处理，暂停滴注或减缓滴注速率后经过几个小时即可消除这些反应。
据报道，连续滴注常规盐酸多柔比星的病人可见口腔炎，接受楷莱的病人亦时有报道。这并不影响病人完成治疗，一般无需调整剂量，除非口腔炎影响病人的饮食能力，此时可延长给药间期或减量。
楷莱临床研究中常发生呼吸系统不良反应（≥ (greater than or equal to) 5%），这可能与AIDS病人的机会性感染有关。KS病人使用楷莱后可见机会性感染，在HIV引起的免疫缺陷病人中常见发生。在临床研究中，常见的机会性感染是念珠菌病，巨细胞病毒感染，单纯疱疹，卡氏肺囊虫肺炎及单纯鸟分支杆菌感染。
其他不很常见的不良反应（<5%）有手掌-足底红斑性感觉迟钝，口腔念珠菌病，恶心，呕吐，体重下降，皮疹，口腔溃疡，呼吸困难，腹痛，过敏反应包括过敏症，血管扩张，头晕，厌食，舌炎，便秘，感觉异常，视网膜炎和意识模糊。
手掌-足底红斑性感觉迟钝是一种有痛感的红色斑症。一般病人在治疗6周或更多时间后会出现这种反应。该反应似乎与剂量和用法有关，通过延长给药间期1-2周或减量后得以缓解。多数病人1-2周后便会消除，可使用皮质激素。这种反应在一些病人身上显得严重并使人十分衰弱，因而可能需要停药。
用常规多柔比星制剂治疗时充血性心衰的发生率高。虽然对10例接受楷莱累积用量>460 mg/m2的AIDS-KS病人作心肌内膜活组织检查时，9例并未显示蒽环类药物性心肌病，但进一步的证实，使用楷莱发生心肌病变的风险与多柔比星相近。建议AIDS-KS病人的用药剂量为每2或3周20 mg/m2。当累积剂量>400 mg/m2时要注意心脏毒性，这要经过20个疗程，历时约40-60周。
虽然至今尚见由于楷莱外渗而造成局部坏死的报道，但楷莱仍被认为是一种刺激性药物。动物研究显示，盐酸多柔比星以脂质体形式给药减少了外渗伤害的可能。如果发生任何外渗的迹象（如刺痛，红斑）都应立即中止滴注，而从另一静脉重新开始。用冰敷外渗部位30分钟有助于减轻局部反应。楷莱不可用于肌肉和皮下注射。
由于先前的放疗而产生的皮肤不良反应在使用楷莱时偶见复发。 

【楷莱禁忌】 
楷莱禁用于对楷莱活性成份或其他成份过敏的病人。也不能用于孕妇和哺乳期妇女。对于使用α干扰素进行局部或全身治疗有效的AIDS-KS病人，禁用楷莱。 

【注意事项 】 
心脏损害 ：所有接受楷莱治疗的病人均须经常进行心电图监测。发生一过性心电图改变如T波平坦，S-T段压低和心律失常等时不必立即中止楷莱治疗。然而，QRS复合波减小则是心脏毒性的重要指征。当出现这一改变时，应考虑采用检测蒽环类药物心脏损害可靠的方法进行检查，如心肌内膜活检。
与心电图相比，考察和监测心脏功能更为特异的方法是通过超声心动描记术或多孔动脉造影术（MUGA）测定左室射血分数。在使用楷莱前应常规采用这些方法检测，在治疗期间应定期复查。当楷莱累积剂量超过450 mg/m2时必须在每次用药前考虑评定左室。
每当怀疑出现心脏病变时，如左室射血分数低于治疗前和（或）低于预后相应值（<45%），均应进行心肌内膜活检，必须对继续治疗的益处与产生不可逆性心脏损害的危险进行认真评价。
由于心肌病变而产生的充血性心衰可能会突然发生，事先未见心电图改变，亦可在停药后数周才出现。
在用蒽环类药物治疗期间，上述各种监测心脏功能的评定试验和方法应按以下次序使用 ：心电图监测，左室射血分数，心肌内膜活检。当测定结果显示心脏损害与使用楷莱有关时，应认真权衡继续治疗的益处与心脏损伤的利害关系。
对于有心血管病史的病人，只有当利大于弊时才能接受楷莱治疗。
心功能不全病人接受楷莱治疗时要谨慎。
对已经用过其他蒽环类药物的病人，应注意观察。盐酸多柔比星总剂量的确定亦应考虑先前（或同时）使用的心脏毒性药物，如其他蒽环类/蒽醌类药物诸如氟尿嘧啶。
骨髓抑制 ：许多使用楷莱治疗的AIDS-KS病人均有艾滋病或许多合用药物等引起的基础骨髓抑制。对于这类病人，骨髓抑制看来是剂量限制性不良反应。由于可能发生骨髓抑制。故在用药期间应经常检查血细胞计数，至少在每次用药前作检查。
持续性骨髓抑制可导致重复感染和出血。
糖尿病人 ：应注意楷莱每瓶内含蔗糖，而且滴注时用5%葡萄糖注射液稀释。
对驾车和操作机器的影响 ：虽然至今的研究中楷莱并不影响驾驶能力，但使用楷莱偶尔出现（<5%）头晕和嗜睡。所以有上述反应的病人应避免驾车和操作机器。 

【孕妇及哺乳期妇女用药】 
楷莱对大鼠有胚胎毒性，对家兔有胚胎毒性和堕胎作用。不能排除致畸作用。目前尚无孕妇使用楷莱的经验。因此楷莱禁用于孕妇。建议育龄妇女或其配偶在用楷莱治疗期间及停药后6个月内避孕。
目前尚不清楚乳汁中是否分泌楷莱，鉴于授乳婴儿可能因楷莱而致严重不良反应，因而母亲在接受楷莱前应停止哺乳。 

【楷莱儿童用药 】 
关于18岁以下病人使用楷莱的安全性和有效性尚未确定。 

【楷莱老年用药】 
60岁以上病人使用楷莱的安全性和有效性尚未确定。 

【楷莱药物相互作用 】 
未对楷莱正式进行相互作用研究。但对于已知与多柔比星可产生相互作用的药物，在合用时就注意。虽无正式的研究报告，但楷莱与其他盐酸多柔比星制剂一样，会增强其他抗癌治疗的毒性。已有报道合用盐酸多柔比星会加重环磷酰胺导致的出血性膀胱炎，增强巯嘌呤的肝细胞毒性。所以同时合用其他细胞毒性药物，特别是骨髓毒性药物时需谨慎。 

【楷莱 药物过量 】 
盐酸多柔比星急性过量可加重粘膜炎，白细胞减少和血小板减少等毒性反应。严重骨髓抑制患者出现急性用药过量的治疗措施为住院、抗生素疗法、输注血小板和粒细胞，对症治疗粘膜炎。 

【楷莱用药须知】 
禁止使用有沉淀物或其他杂质的器材。
根据推荐剂量和病人的体表面积确定楷莱的剂量。
用灭菌注射器吸取适量楷莱。
由于楷莱中未加防腐剂或抑菌剂，故必须严格遵守无菌操作。
在给药前须取出所需量用250毫升5%葡萄糖注射液稀释。
除5%葡萄糖注射液外的其他稀释剂或任何抑菌剂都可能使楷莱产生沉淀。
建议将楷莱滴注管与5%葡萄糖静脉滴注管相连通。
使用楷莱溶液时要谨慎，需戴手套。如果药液与皮肤或粘膜发生接触，应立即用肥皂水清洗。楷莱的运送和处理的方法与其 他抗癌药物相同。

【楷莱禁忌】
不得与其他药物混合使用。 

【贮藏】 
未开封的药瓶应保存在2-8°C环境下，避免冷冻。
楷莱用5%葡萄糖注射液稀释后供静脉滴注的药液应立即使用。稀释液不立即使用时应保存在2-8°C环境下，不超过24小时。
药液未用完的药瓶应丢弃。

【有效期】
18个月。 

Caelyx

Active Substance: doxorubicin hydrochloride 
Common Name: doxorubicin 
ATC Code: L01DB
Marketing Authorisation Holder: Janssen-Cilag International N.V.
Active Substance: doxorubicin hydrochloride 
Status: Authorised
Authorisation Date: 1996-06-21
Therapeutic Area: Multiple Myeloma Ovarian Neoplasms Breast Neoplasms Sarcoma, Kaposi
Pharmacotherapeutic Group: Antineoplastic agents

Therapeutic Indication

Caelyx is indicated:

· as monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk;

· for treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen;

· in combination with bortezomib for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant;

· for treatment of AIDS-related Kaposi’s sarcoma (KS) in patients with low CD4 counts (<200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease. Caelyx may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and standarddoxorubicin (or other anthracycline).

What is Caelyx?

Caelyx is concentrate to be made up into a solution for infusion (drip into a vein). It contains the active substance doxorubicin hydrochloride (2 mg/ml).

What is Caelyx used for?

Caelyx is used to treat the following types of cancer in adults:

· metastatic breast cancer in patients at risk of heart problems. ‘Metastatic’ means the cancer has spread to other parts of the body. Caelyx is used on its own for this disease;

· advanced ovarian cancer (cancer of the ovary) in women whose previous treatment including a platinum-based anticancer medicine has stopped working;

· Kaposi’s sarcoma (a cancer of the blood vessels) in patients with acquired immune deficiency syndrome (AIDS) who have very damaged immune systems and extensive sarcoma on the skin, the moist body surfaces or the internal organs;

· multiple myeloma (a cancer of the cells in the bone marrow), in patients with progressive disease who have received at least one other treatment in the past and have already undergone or are unsuitable for a bone-marrow transplant. Caelyx is used in combination with bortezomib (another anticancer medicine).

The medicine can only be obtained with a prescription.

How is Caelyx used?

Caelyx should be given under the supervision of a doctor who is qualified in the use of cytotoxic (cell-killing) medicines. It cannot be interchanged with other medicines containing doxorubicin hydrochloride.

The recommended starting dose of Caelyx for breast or ovarian cancer is 50 mg per square metre body surface area (calculated using the patient’s height and weight) every four weeks for as long as the disease does not get worse and the patient can tolerate the treatment. For Kaposi’s sarcoma, the dose is 20 mg/m2 every two to three weeks for two to three months, and for multiple myeloma, it is 30 mg/m2 on day four of each three-week cycle of bortezomib treatment, for as long as the patient continues to benefit from the treatment and can tolerate it.

Treatment should be stopped or the dose reduced in patients who experience certain side effects or who have liver problems. Caelyx is not recommended for patients whose spleen has been removed. For more information, see the package leaflet.

How does Caelyx work?

The active substance in Caelyx, doxorubicin hydrochloride, is a cytotoxic medicine that belongs to the group ‘anthracyclines’. It works by interfering with the DNA within cells, preventing them from making more copies of DNA and making proteins. This means that cancer cells cannot divide and eventually die. Caelyx accumulates in areas in the body where the blood vessels have an abnormal shape, such as within tumours, where its action is concentrated.

Doxorubicin hydrochloride has been available since the 1960s. In Caelyx, it is contained in ‘pegylated liposomes’ (tiny fatty spheres that are coated with a chemical called polyethylene glycol). This reduces the rate at which the active substance is broken down, allowing it to circulate in the blood for longer. It also reduces its effects on non-cancer tissues and cells, so it is less likely to cause some side effects.

How has Caelyx been studied?

Caelyx has been studied in a total of 2,512 patients in seven main studies.

For metastatic breast cancer, Caelyx has been compared with standard doxorubicin in one main study involving 509 women.

For advanced ovarian cancer, Caelyx has been compared with topotecan (another anticancer medicine) in one study involving 474 women who had received platinum-based chemotherapy in the past.

For AIDS-related Kaposi’s sarcoma, the effectiveness of Caelyx was studied in two main studies involving 384 patients, including 77 who had received treatment before. Further studies compared Caelyx with the combination of doxorubicin, bleomycin and vincristine (other anticancer medicines) in 258 patients and with the combination of bleomycin and vincristine in 241 patients.

For multiple myeloma, the effectiveness of the combination of Caelyx and bortezomib was compared with that of bortezomib alone in 646 patients.

The main measure of effectiveness was time until the disease got worse or, for Kaposi’s sarcoma, the number of patients who responded to treatment.

What benefit has Caelyx shown during the studies?

In the treatment of breast cancer, Caelyx was as effective as standard doxorubicin: the time until the disease got worse was around 7.5 months in both groups. However, patients receiving Caelyx were less likely to experience heart problems.

For ovarian cancer, Caelyx was as effective as topotecan in extending time until the disease got worse.

For Kaposi’s sarcoma, around 70% of the patients had a complete or partial response to treatment, with similar results in the study of patients who had been treated before. The additional studies showed that Caelyx was also more effective than the comparator combinations.

For multiple myeloma, adding Caelyx to bortezomib increased the time until the disease got worse from 6.5 to 9.3 months

What is the risk associated with Caelyx?

The side effects with Caelyx depend on the type of cancer being treated. The most common side effect seen in all types of cancer (in more than 1 patient in 10) is nausea (feeling sick). Other very common side effects include palmar-plantar erythrodysaesthesia syndrome (redness and pain on the hands and feet), vomiting, stomatitis (inflammation of the lining of the mouth), rash, asthenia (weakness), low blood cell counts, loss of appetite, alopecia (hair loss), fatigue (tiredness), diarrhoea, constipation and mucositis (inflammation of the mouth and throat). For the full list of all side effects reported with Caelyx, see the package leaflet.

Caelyx should not be used in people who may be hypersensitive (allergic) to doxorubicin hydrochloride or any of the other ingredients. Caelyx must not be used to treat Kaposi’s sarcoma that could be treated effectively with ‘local’ treatments that only affect the site of the tumour or with whole-body alfa interferon treatment.

Why has Caelyx been approved?

The CHMP decided that Caelyx’s benefits are greater than its risks and recommended that it be given marketing authorisation.

Other information about Caelyx

The European Commission granted a marketing authorisation valid throughout the European Union for Caelyx on 21 June 1996. The marketing-authorisation holder is Janssen-Cilag International NV. The marketing authorisation is valid for an unlimited period.