Dasatinib(SPRYCEL)
药品介绍：
达沙替尼（Dasatinib/Sprycel），用于已经治疗，包括甲磺酸伊马替尼（Imatinib mesylate/Gleevec）耐药或不能耐受的慢性骨髓性白血病所有病期（慢性期、加速期、淋巴系细胞急变期和髓细胞急变期）的成人患者。同时，FDA也经正常程序批准达沙替尼治疗对其他疗法耐药或不能耐受的费城染色体阳性的急性成淋巴细胞性白血病成人患者。
达沙替尼属多酪氨酸激酶抑制剂，此次主要是依据来自总计包括911例患者的4项国际性、多中心Ⅱ期试验的安全性和疗效结果及其他支持性数据而获准用于上述两适应证的。它在临床研究中最常报告的副反应有体液潴留、胃肠道症状和出血事件等；最常报告的严重副反应是发热、胸膜积液、发热性中性白细胞减少、胃肠道出血、肺炎、血小板减少、呼吸困难、贫血、腹泻和心脏衰竭等。
对Imatinib耐药病人的基因研究发现，这些病人的BCR–ABL蛋白的激酶结构域发生了突变，干扰了Imatinib和激酶的结合。Imatinib只和ABL激酶的一种独一无二的非活性构形结合，这种构形特异性的结合方式是imatinib与ABL选择性结合的原因。ABL激酶结构域的突变会破坏这种构形的形成，造成imatinib无法与之结合。因此，假如某种抑制剂不是采用这种构形严格性的结合方式，那它对imatinib耐药突变的白血病细胞应该仍保留活性。Dasatinib是一种口服多激酶抑制剂，抑制的激酶包括BCR–ABL、SRC家族激酶、c-KIT和PDGFR- 。Dasatinib和ABL的结合对构形的要求并不严格，对imatinib耐药突变细胞仍有活性。Dasatinib对除T315I突变株的其他imatinib耐药突变细胞株都有活性。事实上，dasatinib可抑制来自于imatinib敏感或耐药病人体内BCR-ABL阳性骨髓前体细胞的增殖，延长imatinib耐药的白血病小鼠的生存时间。
临床试验
4项正在进行的单组临床试验考察了dasatinib的安全性和有效性，参加的病人是CML或费城染色体阳性的急性淋巴母细胞白血病病人，病人对imatinib 耐药或无法耐受。186名为CML慢性期病人，107名为CML加速期病人，74为髓系CML急变期病人，78名为淋巴系CML急变期病人。CML慢性期的首要有效性终点是主要细胞遗传学反应(MCyR)，定义为Ph+阳性细胞完全清除（完全细胞遗传学反应）或实质性减少（减少至少65%）。CML加速期和急变期以及急性淋巴母细胞白血病的首要有效性终点是主要血液学反应(MaHR)，定义为或者为完全血液学反应，或者无白血病迹象。  
dasatinib(70mg，口服，每日两次)的治疗使各期CML病人和急性淋巴母细胞白血病患者获得了细胞遗传学和血液学反应：慢性期CML 病人的McyR率为45%，完全反应率为33%。加速期病人的MaHR率为59%，髓系急变期病人的MaHR率为32%，淋巴系急变期病人的MaHR率为31%。Ph+急性淋巴母细胞白血病的MaHR率为42%。在CML慢性期、加速期和髓系急变期病人的6个月随访期内，血液学和细胞遗传学反应保持稳定。淋巴系急变期MaHR持续的中位时间为3.7个月，Ph+急性淋巴母细胞白血病人MaHR持续的中位时间为4.8个月。。
适应症
Dasatinib被FDA批准用于治疗对之前治疗耐药或无法耐受的成人慢性期、加速期、髓系或淋巴系慢性髓性白血病。Dasatinib的有效性是以血液学和遗传学反应为基础，目前还没有对照试验来显示dasatinib的临床益处，例如疾病相关症状的改善或生存时间的延长。Dasatinib也被批准用来治疗对之前治疗耐药或不能耐受的Ph+急性淋巴母细胞白血病人。

【中文商品译名】达沙替尼
【原英文商品名】Sprycel
【英文名通用名】Dasatinib
【适应症】
本品适用于对包括甲磺酸伊马替尼在内的治疗方案耐药或不能耐受的慢性髓细胞样白血病（CML）所有病期（慢性期、加速期、淋巴细胞急变期和髓细胞急变期）的成人患者.另外，本品可用于对以往治疗药物耐药或不能耐受的费城染色体阳性急性淋巴细胞性白血病（Ph+All）成年患者。
【药理作用】
本品为多酪氨酸激酶抑制剂，可抑制BCR-ABL、SRC家族（SRC、LCK、YES、FYN）、c-KIT、EPHA2和PDGFRS等激酶。在体外，本品对多种不同的伊马替尼敏感或耐药的白血病细胞株有活性，可抑制BCR-ABL来表达的CML和ALL细胞株的生长。
本品的最大血药浓度（Cmax）出现在口服后0.5~6小时。在一日15~240mg 范围内，AUC及体内消除参数与剂量存在线性相关，总体平均终末半衰期（t1/2)为3~5小时。本品的表观分布容积为2505L，显示本品纠纷分布广泛。题外试验中，本品与积极其活性代谢物血浆蛋白结合率为96%和93%，在100~500ml浓度范围内基本恒定。本品在人体内被广泛代谢，主要代谢酶为细胞色素P450(CYP)3A4.
【临床评价】
4项单组多中心临床研究考察了本品对伊马替尼或不耐受的CML或PH+ALL患者78例及髓细胞急变期患者74例。大部分患者有很长的病史并经过大量药物治疗（包括伊马替尼、细胞毒化疗药物、干扰素和干细胞移植等）。经过本品治疗的所有患者均获得了血液学和细胞遗传学反应。慢性期CML患者的显著细胞遗传学缓解率（McyR）为45%。完全缓解率为33%；急变期CML患者的显著血液学缓解率(MaHR)为59%；髓细胞急变期、淋巴细胞急变期及Ph+All患者的MaHR率分别为32%、31%和42%。
【不良反应】
本品最常见不良反应包括体液潴留（胸腔积液）、胃肠道反应（包括腹泻、恶心、腹痛和呕吐）及出血事件。最常见严重不良反应包括发热（9%）、胸腔积液（6%）、肺炎（6%）、血小板减少症（5%）、发热性中性粒细胞减少症（7%）、胃肠道出血（6%）、血小板减少症（5%）、呼吸困难（4%）、贫血（3%）和腹泻（2%）等。
【注意事项】
本品可导致严重的血小板减少症、中性粒细胞减少和贫血。骨髓抑制在晚期CML或PH+ALL患者中发生率较慢性期CML患者高。此外，本品在体外还可导致血小板功能不良，在接受本品治疗的患者中约有1%发生严重中枢神经系统出血，甚至死亡。
【原产地英文商品名】DASATINIB(Sprycel Equivalent)70mg/Tablet 60Tablets/bottle
【原产地英文药品名】DASATINIB
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请以电话咨询为准！
·扑瑞赛 140毫克/片 30片/瓶
·扑瑞赛 80毫克/片 30片/瓶
·扑瑞赛 100毫克/片 30片/瓶
【中文参考药品译名】达沙替尼
【生产厂家中文参考译名】百时美施贵宝
【生产厂家英文名】Bristol Myers Squibb

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·扑瑞赛-20毫克/片，60片/瓶
·扑瑞赛-50毫克/片，60片/瓶
·扑瑞赛-70毫克/片，60片/瓶
·扑瑞赛-70毫克/片，60片/瓶
·扑瑞赛 70毫克/片 60片/瓶
·扑瑞赛 50毫克/片 60片/瓶
·扑瑞赛 20毫克/片 60片/瓶
【中文参考药品译名】达沙替尼
【生产厂家中文参考译名】百时美施贵宝
【生产厂家英文名】Bristol Myers Squibb

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·达沙替尼(扑瑞赛仿制药) 70毫克/片 60片/瓶
·达沙替尼(扑瑞赛仿制药) 50毫克/片 60片/瓶
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【中文参考药品译名】达沙替尼

Sprycel
Generic Name: dasatinib (da SAT in ib)
Brand Names: Sprycel
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What is Sprycel?
Sprycel (dasatinib) is a cancer medication that slows the growth and spread of cancer cells in the body.
Sprycel is used to treat chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) when other cancer treatments have not been effective.

Sprycel may also be used for purposes not listed in this medication guide.
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Important information about Sprycel
Do not use Sprycel if you are pregnant. It could harm the unborn baby. Use birth control to prevent pregnancy while you are receiving Sprycel, whether you are a man or a woman. Sprycel use by either parent may cause birth defects.
Before taking Sprycel, tell your doctor if you have liver disease, low levels of potassium or magnesium in your blood, heart disease or a heart rhythm disorder, or if you have a personal or family history of "Long QT syndrome."
Do not crush, chew, or break a Sprycel tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time. There are many other drugs that can interact with Sprycel. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.
Sprycel can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Visit your doctor regularly.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.
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Before taking Sprycel
You should not use Sprycel if:
you have not first received a medication called imatinib (Gleevec); or
if you are pregnant or planning to become pregnant during treatment with Sprycel.

To make sure you can safely take Sprycel, tell your doctor if you have any of these other conditions:
liver disease;
low levels of potassium or magnesium in your blood;
heart disease or a heart rhythm disorder; or
a personal or family history of "Long QT syndrome."

FDA pregnancy category D. Do not use Sprycel if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use birth control to prevent pregnancy while you are receiving Sprycel, whether you are a man or a woman. Sprycel use by either parent may cause birth defects. A man taking Sprycel should use a condom during any sexual activity. It is not known whether dasatinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while taking Sprycel. This medication may affect fertility (your ability to have children), whether you are a man or a woman.

Sprycel tablets contain lactose. Talk to your doctor before using this medication if you are lactose-intolerant.
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How should I take Sprycel?
Take Sprycel exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
This medicine is usually taken once in the morning and once in the evening. Follow your doctor's instructions. You may take the medication with or without food.
Your doctor may occasionally change your dose to make sure you get the best results.
Take Sprycel tablets with a full glass of water. Do not crush, chew, or break a Sprycel tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time. Do not use a pill that has been accidentally broken. Dasatinib from a crushed or broken Sprycel tablet can be dangerous if it gets in your eyes, mouth, or nose, or on your skin. If this occurs, wash your skin with soap and water or rinse your eyes with water. Ask your doctor or pharmacist how to safely handle and dispose of a broken tablet.
Sprycel can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Visit your doctor regularly.
Store Sprycel at room temperature away from moisture and heat.
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What happens if I miss a dose?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
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What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
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What should I avoid while taking Sprycel?
Avoid taking an antacid within 2 hours before or 2 hours after you take Sprycel. Use only the type of antacid your doctor recommends. Some antacids can make it harder for your body to absorb Sprycel.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.
Grapefruit and grapefruit juice may interact with Sprycel and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.
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Sprycel side effects
Get emergency medical help if you have any of these signs of an allergic reaction to Sprycel: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:
pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;
easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
fever, chills, body aches, flu symptoms, sores in your mouth and throat;
black, bloody, or tarry stools;
coughing up blood or vomit that looks like coffee grounds; or
swelling in your hands, ankles, or feet.

Less serious Sprycel side effects may include:
headache;
tired feeling;
nausea, diarrhea; or
mild skin rash;

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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What other drugs will affect Sprycel?
Tell your doctor about all other medicines you use, especially:
alfentanil (Alfenta), fentanyl (Actiq, Duragesic);
bosentan (Tracleer);
conivaptan (Vaprisol);
cyclosporine (Gengraf, Neoral, Sandimmune);
dexamethasone (Decadron, Hexadrol);
ergotamine (Ergomar, Cafergot, Migergot);
imatinib (Gleevec);
isoniazid (for treating tuberculosis);
pimozide (Orap);
rifabutin (Mycobutin), rifampin (Rifadin, Rifater, Rifamate), or rifapentine (Priftin);
St. John's wort;
an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), or telithromycin (Ketek);
an antidepressant such as nefazodone;
antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Extina, Ketozole, Nizoral, Xolegal), or voriconazole (Vfend);
phenobarbital (Solfoton) and other barbiturates;
a blood thinner such as warfarin (Coumadin);
heart or blood pressure medication such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others;
HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), saquinavir (Invirase), or ritonavir (Kaletra, Norvir);
medicines to treat narcolepsy, such as armodafanil (Nuvigil) or modafanil (Progivil);
medication used to prevent blood clots, such as bivalirudin (Angiomax), clopidogrel (Plavix), dalteparin (Fragmin), dipyridamole (Persantine, Aggrenox), enoxaparin (Lovenox), fondaparinux (Arixtra), lepirudin (Refludan), ticlopidine (Ticlid);
medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune), or tacrolimus (Prograf);
seizure medication such as carbamazepine (Carbatrol, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenytoin (Dilantin), or primidone (Mysoline); or
stomach acid reducers such as cimetidine (Tagamet), esomeprazole (Nexium), famotidine (Pepcid), lansoprazole (Prevacid), nizatidine (Axid), omeprazole (Prilosec, Zegerid), pantoprazole (Protonix), rabeprazole (Aciphex), or ranitidine (Zantac).

This list is not complete and there are many other drugs that can interact with Sprycel. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

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Where can I get more information?
Your pharmacist can provide more information about Sprycel.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects.

慢性髓细胞白血病治疗药物：Dasatinib

2006年6月，百时美施贵宝公司的酪氨酸受体激酶抑制剂dasatinib (Sprycel) 获得FDA批准，用于治疗对其他治疗耐药或不能耐受的成人慢性髓细胞白血病和费城染色体阳性的急性淋巴母细胞白血病。慢性髓细胞白血病一般分为3个阶段，慢性期、加速期和急变期，病程可持续几年，但到了急变期常常在半年内死亡。大多数CML病例会出现9 和22号染色体的部分互换，产生了一个截短的22号染色体，即费城染色体。融合的基因编码BCR–ABL蛋白,是CML的分子标记。BCR–ABL蛋白激酶抑制剂被认为可靶向治疗CML，Imatinib既是成功的例子。Imatinib已经成为CML的一线治疗药物，可以使大部分病人，特别是慢性期病人缓解，但每年仍有约4%的病人对Imatinib产生耐药，因此开发新的抑制剂仍是当务之急。

开发基础
对Imatinib耐药病人的基因研究发现，这些病人的BCR–ABL蛋白的激酶结构域发生了突变，干扰了Imatinib和激酶的结合。Imatinib只和ABL激酶的一种独一无二的非活性构形结合，这种构形特异性的结合方式是imatinib与ABL选择性结合的原因。ABL激酶结构域的突变会破坏这种构形的形成，造成imatinib无法与之结合。因此，假如某种抑制剂不是采用这种构形严格性的结合方式，那它对imatinib耐药突变的白血病细胞应该仍保留活性。Dasatinib是一种口服多激酶抑制剂，抑制的激酶包括BCR–ABL、SRC家族激酶、c-KIT和PDGFR- 。Dasatinib和ABL的结合对构形的要求并不严格，对imatinib耐药突变细胞仍有活性。Dasatinib对除T315I突变株的其他imatinib耐药突变细胞株都有活性。事实上，dasatinib可抑制来自于imatinib敏感或耐药病人体内BCR-ABL阳性骨髓前体细胞的增殖，延长imatinib耐药的白血病小鼠的生存时间。

临床试验
4项正在进行的单组临床试验考察了dasatinib的安全性和有效性，参加的病人是CML或费城染色体阳性的急性淋巴母细胞白血病病人，病人对imatinib 耐药或无法耐受。186名为CML慢性期病人，107名为CML加速期病人，74为髓系CML急变期病人，78名为淋巴系CML急变期病人。CML慢性期的首要有效性终点是主要细胞遗传学反应(MCyR)，定义为Ph+阳性细胞完全清除（完全细胞遗传学反应）或实质性减少（减少至少65%）。CML加速期和急变期以及急性淋巴母细胞白血病的首要有效性终点是主要血液学反应(MaHR)，定义为或者为完全血液学反应，或者无白血病迹象。dasatinib(70mg，口服，每日两次)的治疗使各期CML病人和急性淋巴母细胞白血病患者获得了细胞遗传学和血液学反应：慢性期CML 病人的McyR率为45%，完全反应率为33%。加速期病人的MaHR率为59%，髓系急变期病人的MaHR率为32%，淋巴系急变期病人的MaHR率为31%。Ph+急性淋巴母细胞白血病的MaHR率为42%。在CML慢性期、加速期和髓系急变期病人的6个月随访期内，血液学和细胞遗传学反应保持稳定。淋巴系急变期MaHR持续的中位时间为3.7个月，Ph+急性淋巴母细胞白血病人MaHR持续的中位时间为4.8个月。

适应症
Dasatinib被FDA批准用于治疗对之前治疗耐药或无法耐受的成人慢性期、加速期、髓系或淋巴系慢性髓性白血病。Dasatinib的有效性是以血液学和遗传学反应为基础，目前还没有对照试验来显示dasatinib的临床益处，例如疾病相关症状的改善或生存时间的延长。Dasatinib也被批准用来治疗对之前治疗耐药或不能耐受的Ph+急性淋巴母细胞白血病人。

新药开发现状

其他几种BCR–ABL酪氨酸激酶抑制剂正处于临床前或临床开发阶段，其中进展最迅速的是 nilotinib,是一种比imatinib活性更强的BCR–ABL抑制剂。 与dasatinib一样,其中的几种化合物也具有多重抑制活性，可抑制ABL和SRC激酶家族的多个成员。其中两个化合物SKI-606和INNO-406(NS-187)已进入I期临床试验阶段。 Imatinib, dasatinib和nilotinib对T315I突变细胞系都没有活性，但一种aurora激酶抑制剂MK 0457(VX 680)则对该突变细胞也有活性。其他T315I抑制剂还有AT9283、KW2449和homoharringtonine。但这些双重抑制剂的延长生存时间的临床益处还有待证实。CML的长期治疗可能需要激酶抑制剂、法尼酯转移酶抑制剂以及其他作用机制化合物的联合应用。可以控制和清除残余癌细胞的免疫疗法也是有价值的。