近日，抗癌新药Adcetris（brentuximab vedotin）获FDA批准扩大适应症，用于接受干细胞移植后具有复发高风险的霍奇金淋巴瘤（HL）患者。此前，FDA已于2011年加速批准Adcetris用于干细胞移植失败或至少2种多药化疗方案治疗失败且不适合干细胞移植的HL患者，以及至少1种多药化疗方案治疗失败的系统性间变性大细胞淋巴瘤（sALCL）患者。 Adcetris是一种抗体偶联药物（ADC），由靶向CD30蛋白的一种单克隆抗体和一种微管破坏剂（单甲基auristatin E，MMAE）通过一种蛋白酶敏感的交联剂偶联而成，该偶联技术为西雅图遗传学公司（Seattle Genetics）的专有技术。CD30蛋白是经典霍奇金淋巴瘤（HL）及系统性间变性大细胞淋巴瘤（sALCL）的明确标志物，而Auristatin E可通过抑制微管蛋白的聚合作用阻碍细胞分裂。Adcetris在血液中可稳定存在，在被CD30阳性肿瘤细胞内化后，可释放出MMAE。Adcetris于2011年8月获FDA加速批准、于2012年10月获欧盟有条件批准、于2013年2月获加拿大批准。 批准日期：2011年8月19日；公司：Seattle Genetics, Inc ADCETRIS (brentuximab vedotin) 注射液, 供静脉使用 美国初步批准: 2011 警告: 渐进多焦点白质 (PML) 查看完整的盒装警告的完整处方信息。 JC 病毒感染导致的 PML 和死亡可能发生在接受 ADCETRIS 的病人。 最近的重大变化 适应症和用法, 原发性皮肤间变性大细胞淋巴瘤和 CD30-expressive 真菌病蕈: 11/2017 用量及用药剂量: 11/2017 警告和预防措施, 胃肠并发症: 11/2017 作用机制 CD30 是肿瘤坏死因子受体家族的成员。CD30表达在sALCL细胞的表面和在智利的金氏芦苇-(小时) 细胞, 并在健康的组织和细胞表达有限。体外数据表明, 通过CD30-CD30L绑定信号可能会影响细胞的生存和增殖。 Brentuximab vedotin是一个ADC。抗体是一个嵌合体IgG1针对CD30。小分子MMAE是微管干扰剂。MMAE通过链接器与抗体共价键相连。有意数据表明, ADCETRIS的抗癌活性是由于ADC对CD30-expressing细胞的束缚, 其次是ADC‑CD30 复合体的内化, 以及通过蛋白水解分裂释放 MMAE。MMAE 对蛋白的束缚扰乱了细胞内的微管网络, 进而诱导细胞周期骤停和细胞凋亡。此外, 体外数据为抗体依赖性细胞吞噬功能 (ADCP) 提供了证据。 适应症和用法 ADCETRIS 是一种 CD30-directed 抗体-药物共轭表明治疗成人患者: 经典霍奇金淋巴瘤 (智利) 高风险复发或进展为自体造血干细胞移植 (自动 HSCT) 整合。 经典的霍奇金淋巴瘤失败后自动 HSCT 或失败后, 至少两个前多剂化疗机制的患者谁不是自动HSCT 候选人。 系统性间变性大细胞淋巴瘤(SALCL)失败后至少有一个多剂化疗机制。 根据总体反应率, 批准了 SALCL指示的加速核准。继续批准这一指示可能取决于验证性试验的临床益处的核实和说明 原发性皮肤间变性大细胞淋巴瘤(PcALCL)或CD30-expressive真菌蕈(MF) 谁曾接受过系统治疗。 剂量和管理 仅在30分钟内每3周进行一次静脉输液。 建议剂量为1.8毫克/千克, 最高可达180mg。 减少轻度肝功能损害患者的剂量。 剂型和强度 注射: 在单剂量瓶中50毫克冻干粉。 禁忌 伴有肺毒性的博莱霉素伴随使用。 警告和预防措施 周围神经病变: 监护病人的神经病变和研究所剂量的修改相应。 过敏和输液反应: 如果发生输液反应, 打断输液。如果发生过敏反应, 立即停止输液。 血液毒性: 在每次剂量 ADCETRIS 前监测完整的血液计数。监测病人发烧。如果3或4级的中性粒细胞减少, 考虑剂量延迟, 降低, 停止, 或G脑脊液预防与随后剂量。 严重感染和机会性感染: 密切监测患者的出现细菌, 真菌或病毒感染。 肿瘤溶解综合征: 密切监测快速增殖肿瘤或高肿瘤负担的患者。 肝毒性: 监测肝脏酶和胆红素。 肺部毒性: 监测病人出现新的或恶化的症状。 严重的皮肤病反应: 如果史蒂文斯-约翰逊综合征或毒性表皮坏死发生停止。 胃肠道并发症: 监测病人出现新的或恶化的症状。 胚胎-胎儿毒性: 可引起胎儿伤害。向雌性提供对胎儿潜在危险的生殖潜能, 并避免怀孕。 不良反应 最常见的不良反应(≥20%) 为外围传感器神经病变、疲劳、恶心、腹泻、中性粒细胞减少、上呼吸道感染和发热。 药物相互作用 伴随使用强CYP3A4抑制剂或诱导剂, 或p-GP抑制剂, 有可能影响接触单甲基auristatin e(MMAE) 在特定人群中使用 中度或重度肝损害或严重肾损害: MMAE 暴露和不良反应增加。避免使用。 哺乳: 建议妇女不要母乳喂养。 包装提供/存储和处理 如何提供 ADCETRIS (brentuximab vedotin) 为注射提供无菌, 白色到白色无防腐剂的冻干蛋糕或粉末在单独盒装单剂量瓶: NDC (51144-050-01), 50毫克 brentuximab vedotin。 存储 储存瓶在 2–8°C (36–46°F) 在原纸箱, 以防止光。 特殊处理 ADCETRIS是一种抗肿瘤产品。遵循特殊处理和处置procedures1。 完整说明书附件： 1）：https://www.medicines.org.uk/emc/product/2859/smpc 2）；http://www.info.pmda.go.jp/go/pack/4291425D1021_1_04/ 3）：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3904f8dd-1aef-3490-e48f-bd55f32ed67f ADCETRIS(brentuximab vedotin) for Injection ADCETRIS Indications ADCETRIS® (brentuximab vedotin) is indicated for the treatment of: •Previously untreated Stage III/IV classical Hodgkin lymphoma (cHL) Adult patients with previously untreated Stage III/IV cHL in combination with chemotherapy •cHL post-auto-HSCT consolidation Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation •Relapsed cHL Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates •Relapsed sALCL Adult patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen •Relapsed pcALCL or CD30-expressing MF Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy Important Safety Information BOXED WARNING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients Contraindication — ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation). Warnings and Precautions — •Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly. •Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid. •Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Administer G-CSF primary prophylaxis starting with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III/IV cHL. Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses. •Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections. •Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden. •Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment. •Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.•Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS. •PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. •Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement. •Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy. •Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately. •Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.   Adverse Reactions — Most Common (≥20%) Adverse Reactions: Neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia.  Drug Interactions — Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).  Use in Specific Populations — Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use. Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS. ----------------------------------------------------- 产地国家：美国 原产地英文商品名: ADCETRIS FOR INJECTION 50MG/VIAL  原产地英文药品名: BRENTUXIMAB VEDOTIN 中文参考商品译名: ADCETRIS注射剂 50毫克/瓶 中文参考药品译名: 帕姆布罗珠单抗 生产厂家中文参考译名: 西雅图遗传技术公司 生产厂家英文名: SEATTLE GENETICS ----------------------------------------------------- 产地国家：德国 原产地英文商品名: ADCETRIS Pulver Infusionslösung 50mg   1Stk 原产地英文药品名:  brentuximab vedotin 中文参考商品译名: ADCETRIS冻干粉注射剂 50毫克/瓶 1瓶 中文参考药品译名: 帕姆布罗珠单抗 生产厂家英文名: Takeda Austria GmbH ----------------------------------------------------- 产地国家：德国 原产地英文商品名: ADCETRIS Pulver Infusionslösung 50mg   1Stk 原产地英文药品名:  brentuximab vedotin 中文参考商品译名: ADCETRIS冻干粉注射剂 50毫克/瓶  1瓶/盒 中文参考药品译名: 帕姆布罗珠单抗 生产厂家英文名: Haemato Pharm GmbH ----------------------------------------------------- 产地国家：瑞士 原产地英文商品名: ADCETRIS Trockensub 50mg 1Stk 原产地英文药品名: brentuximab vedotin 中文参考商品译名: ADCETRIS冻干粉注射剂 50毫克/瓶 1瓶 中文参考药品译名: 帕姆布罗珠单抗 生产厂家英文名: Takeda Pharma AG ----------------------------------------------------- 产地国家：瑞士 原产地英文商品名: ADCETRIS Trockensub 50mg 2Stk 原产地英文药品名: brentuximab vedotin 中文参考商品译名: ADCETRIS冻干粉注射剂 50毫克/瓶 2瓶 中文参考药品译名: 帕姆布罗珠单抗 生产厂家英文名: Takeda Pharma AG  ----------------------------------------------------- 产地国家：瑞士 原产地英文商品名: ADCETRIS Trockensub 50mg 10Stk 原产地英文药品名: brentuximab vedotin 中文参考商品译名: ADCETRIS冻干粉注射剂 50毫克/瓶 10瓶 中文参考药品译名: 帕姆布罗珠单抗 生产厂家英文名: Takeda Pharma AG  ----------------------------------------------------- 产地国家：日本 原产地英文商品名: ADCetris（アドセトリス点滴静注用）50MG/VIAL 原产地英文药品名: Brentuximab Vedotin（Genetical Recombination） 中文参考商品译名: ADCetris（アドセトリス点滴静注用）50毫克/瓶  中文参考药品译名: 帕姆布罗珠单抗重组 生产厂家中文参考译名: 武田药品 生产厂家英文名: Takeda