达沙替尼,达沙替尼片Dasatinib (SPRYCEL 20MG TBL FLM 60)

药店国别:

产地国家:意大利

处方药:

所属类别: 20毫克/片 60片/瓶

包装规格: 20毫克/片 60片/瓶

计价单位:

生产厂家中文参考译名:

生产厂家英文名:Bristol Myers Squibb

原产地英文商品名:SPRYCEL 20MG TBL FLM 60

原产地英文药品名:dasatinib

中文参考商品译名:扑瑞赛 20毫克/片 60片/瓶

中文参考药品译名:达沙替尼

曾用名:

简介

部份中文达沙替尼处方资料(仅供参股)
通用名:达沙替尼片
英文名:SPRYCEL(dasatinib tablets)

生产厂家:百时美施贵宝

批准日期:2006年6月28日

药品简介

SPRYCEL(达沙替尼[dasatinib])片,口服用使用

最初美国批准:2006

最近重要修改适应证和用途:10/2010

剂量和给药方法,对不良反应剂量调整:10/2010

警告和注意事项,出血相关事件:10/2010充血性心衰,左室功能不全,和心肌梗死:10/2010

作用机制

达沙替尼,在纳克分子浓度抑制下列激酶:BCR-ABL,SRC家族(SRC,LCK,YES,FYN),c-KIT,EPHA2,和PDGFRβ。根据模型研究,预计达沙替尼与ABL激酶的多种构象结合。

在体外,达沙替尼在甲磺酸伊马替尼敏感和耐药病的血病细胞株代表变种有活性。达沙替尼抑制过表达BCR-ABL的慢性粒性白血病(CML)和急性淋巴细胞白血病(ALL)细胞株的生长。在分析条件下,达沙替尼能克服来自BCR-ABL激酶结构区突变导致伊马替尼耐药性,激活SRC家族激酶(LYN, HCK)另外涉及信号通路,和多药抗药基因过表达。

适应证和用途

SPRYCEL是一种激酶抑制剂适用于下列治疗

(1)新诊断的有费城染色体-阳性(Ph+)慢性期慢性粒细胞白血病(CML)成年。将需要正进行试验和进一步资料确定长期结局。

(2)有慢性,加速,或粒性或淋巴原始细胞期Ph+CML对既往治疗包括伊马替尼[imatinib]有耐药或不能耐受的成年。

(3)有费城染色体-阳性急性淋巴细胞白血病(Ph+ALL)对既往治疗耐药或不能耐受的成年。

剂型和规格片剂:20mg,50mg,70mg,80mg,100mg,和140mg。

禁忌证:无。

警告和注意事项

骨髓抑制:可能发生严重血小板减少,中性粒细胞减少,和贫血和需要中断给药或减量。定期监测完全血细胞计数。

出血相关事件(大多数伴随严重血小板减少):曾发生CNS和胃肠道出血,包括死亡。严重出血可能需要中断治疗和输血。在需要抑制血小板功能或抗凝剂药物患者中慎用SPRYCEL。

液体潴留:SPRYCEL伴随液体潴留,有时严重,包括腹水,水肿,和胸和心包积液。用适当支持治疗措施处理。

QT延长:在已经或可能发生QT间隔延长患者中慎用SPRYCEL。

充血性心衰,左室功能不全和心肌梗死:监查患者对与心功能不全一致征象和症状和适当治疗。

当给予妊娠妇女可能危害胎儿,应忠告妇女对胎儿潜在危害和避免成为怀孕。

不良反应

有新诊断的慢性期CML患者中最常见不良反应(≥10%)包括骨髓抑制,液体潴留,腹泻,头痛,肌肉骨骼痛,和皮疹。

在有耐药或不能耐受对既往伊马替尼治疗患者中最常见不良反应(≥20%)包括骨髓抑制,液体潴留事件,腹泻,头痛,呼吸困难,皮疹,疲劳,恶心,和出血。

药物不良反应

(1)CYP3A4抑制剂:可能增加达沙替尼药物水平和应避免。如不能避免同时给药,严密监视和考虑减低SPRYCEL剂量。

(2)CYP3A4诱导剂:可能减低达沙替尼药物水平。如不能避免同时给药, 考虑增加SPRYCEL剂量。

(3)抗酸药:可能减低达沙替尼药物水平。避免同时给药,如需要,SPRYCEL给药前至少2小时或后2小时给予抗酸药.

(4)H2拮抗剂/质子泵抑制剂:可能减低达沙替尼药物水平,考虑抗酸药代替H2拮抗剂或质子泵抑制剂。

在特殊人群中使用

• 肝损伤:在有肝损伤患者中慎用SPRYCEL。

贮藏

SPRYCEL® 片应贮存在25° C(77° F); 外出允许15°–30°C间(59°–86°F)[见USP控制室温]。

处置和遗弃应考虑抗癌药适当处置和遗弃。关于这个问题有几个已发布的指导原则[见文献].SPRYCEL(达沙替尼)片核心片的组成(含活性原料药),周围被薄膜包衣防止药房和临床人员暴露于活性原料药。

但是,如药片被无意压碎或破裂,药学和临床人员应用一次用化疗手套。妊娠人员应避免暴露于压碎或破裂片。

达沙替尼口服片(Sprycel)现已完全获准治疗慢性骨髓性白血病美国食品和药品监督管理局2010年10月28日批准Sprycel(达沙替尼)治疗一种罕见血癌当首次被诊断时。此癌被称为费城染色体阳性慢性粒性白血病慢性期(Ph+ CP-CML)是一种缓慢进展的与遗传异常关联的血液和骨髓疾病。

其它被FDA-批准的其它药物治疗各种形式的CML包括2001年5月批准的Gleevec(伊马替尼),和2007年批准的Tasigna(尼罗替尼[nilotinib])。FDA许可优先审评Sprycel对Ph+ CP-CML。这是在加速批准下被批准对Ph+ CP-CML的第三个药物。

FDA的药品评价和研究中心肿瘤产品室主任Richard Pazdur, M.D.博士说“这些药物对CML患者生命有急剧变化”“来自CML附加研究的结果继续证实在疾病较早期研究癌症药物的重要性”。

英文版说明

SPRYCEL(dasatinib)INDICATIONSSPRYCEL® (dasatinib) is indicated for the treatment of adults with:•Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP)•Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib•Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapySPRYCEL® (dasatinib) IMPORTANT SAFETY INFORMATIONMyelosuppression:Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.•In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated•In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated•Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reductionIn clinical studies, myelosuppression may have also been managed by discontinuation of study therapyHematopoietic growth factor has been used in patients with resistant myelosuppressionBleeding-Related Events:SPRYCEL caused thrombocytopenia in human subjects. In addition, dasatinib caused platelet dysfunction in vitro. In all CML or Ph+ ALL clinical studies, ≥grade 3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of ≥grade 3 hemorrhage occurred in 2% of patients.•Most bleeding events in clinical studies were associated with severe thrombocytopenia•Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhageFluid Retention:SPRYCEL may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients.•Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be eva luated promptly with a chest x-ray or additional diagnostic imaging as appropriate•Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids•Severe pleural effusion may require thoracentesis and oxygen therapy•Consider dose reduction or treatment interruptionCardiovascular Events:After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse events occurred:•Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinibMonitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.Pulmonary Arterial Hypertension (PAH):SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.•eva luate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinuedQT Prolongation:In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval).•In clinical trials of patients treated with SPRYCEL at all doses (n=2440), 16 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms•In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 to 13.4 ms•SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapyCorrect hypokalemia or hypomagnesemia prior to and during SPRYCEL administrationSevere Dermatologic Reactions:Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.•Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identifiedTumor Lysis Syndrome (TLS):TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.•Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels•Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequentlyEmbryo-Fetal Toxicity:Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.•Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final doseLactation:No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats.•Because of the potential for serious adverse reactions in nursing infants from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final doseDrug Interactions:SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.•Drugs that may increase SPRYCEL plasma concentrations are:CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction should be consideredStrong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease or temporary discontinuation should be consideredGrapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided•Drugs that may decrease SPRYCEL plasma concentrations are:CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be consideredStrong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicitySt John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoidedAntacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCELH2 antagonists/proton pump inhibitors (eg, famotidine and omeprazole): Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended•Drugs that may have their plasma concentration altered by SPRYCEL are:CYP3A4 substrates (eg, simvastatin) with a narrow therapeutic index should be administered with caution in patients receiving SPRYCELAdverse Reactions:The safety data reflects exposure to SPRYCEL at all doses tested in clinical studies including 324 patients with newly diagnosed chronic phase CML and 2388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL.The median duration of therapy in all 2712 SPRYCEL-treated patients was 19.2 months (range 0–93.2 months). Median duration of therapy in:•1618 patients with chronic phase CML was 29 months (range 0–92.9 months)Median duration for 324 patients in the newly diagnosed chronic phase CML trial was approximately 60 months•1094 patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months)In the newly diagnosed chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%.In the overall population of 2712 SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.Among the 1618 SPRYCEL-treated patients with chronic phase CML, drug-related adverse events leading to discontinuation were reported in 329 (20.3%) patients.•In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated patients with a minimum of 60 months of follow-upAmong the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse events leading to discontinuation were reported in 191 (17.5%) patients.Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.•In newly diagnosed chronic phase CML patients:Drug-related serious adverse events (SAEs) were reported for 16.7% of SPRYCEL-treated patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)The most common adverse reactions (≥15%) included myelosuppression, fluid retention, and diarrheaGrade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)•In patients resistant or intolerant to prior imatinib therapy:Drug-related SAEs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)The most common adverse reactions (≥15%) included myelosuppression, fluid retention events, diarrhea, headache, fatigue, dyspnea, skin rash, nausea, hemorrhage and musculoskeletal painGrade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative grade 3/4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)•Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CMLElevations in transaminases or bilirubin were usually managed with dose reduction or interruptionPatients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

 

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