部份中文达尼托昔单抗处方资料（仅供参考） 【药品商标】Unituxin 【英文名称】Dinutuximab 【中文名称】达尼托昔单抗 【生产厂家】United Therapeutics Corporation 【药品剂型】注射液：17.5mg/5mL(3.5mg/mL)在一个单次使用小瓶。 【批准日期】2015年3月10日 【作用机制】Dinutuximab与糖脂GD2结合。神经母细胞瘤细胞上和神经外胚层来源正常细胞上，包括中枢神经系统和周边神经，表达这个糖脂。Dinutuximab结合至细胞表面GD2和诱导GD2表达细胞至抗体-依赖细胞-介导细胞毒性(ADCC)和补体-依赖细胞毒性(CDC)的细胞溶解。 【适 应 症】Unituxin是一种GD2-结合单克隆抗体适用与粒细胞-巨噬细胞集落刺激因子(GM-CSF)，白介素-2(IL-2)，和13-顺-视黄酸(RA)联用，为一线多药，多模式治疗前实现至少部分缓解反应有高风险神经母细胞瘤儿童患者的治疗。 【用法用量】每个疗程Unituxin开始前证实患者有适当血液学，呼吸，肝，和肾功能。 每次Unituxin输注开始前需要给予预先药物和水化[见剂量和给药方法。 Unituxin的推荐剂量是17.5mg/m2/day历时10至20小时静脉输注给予共4连续天共最大5个疗程。 输注速率开始为0.875mg/m2/hour共30分钟。输注速率可被逐渐地增加当对最大速率1.75 mg/m2/hour耐受。 【不良反应】最常见不良药物反应(≥25%)是疼痛，发热，血小板减少，淋巴细胞减少，输注反应，低血压，低钠血症，谷丙转氨酶增加，贫血，呕吐，腹泻，低钾血症，毛细血管渗漏综合征，中性粒细胞减少，荨麻疹，低白蛋白血症，谷草转氨酶增加，和低钙血症。 最常见严重不良反应(≥ 5%)是感染，输注反应，低钾血症，低血压，疼痛，发热，和毛细血管渗漏综合征。 【注意事项】尚不明确 【禁    忌】在有对dinutuximab过敏反应史患者禁忌Unituxin。  【药理毒理】尚不明确 【孕妇及哺乳用药】 妊娠 根据其作用机制，当给予至某个妊娠妇女Unituxin可能致胎儿危害[见临床药理学(12.1)]。没有在妊娠妇女研究和在动物中没有生殖研究告知药物关联风险。单克隆抗体跨越胎盘转运以线性形式当妊娠进展，在妊娠第三个三个月转运量最大。忠告妊娠妇女对胎儿潜在风险。不知道对适用人群主要出生缺陷和流产的背景风险。但是，在美国一般人群主要出生缺陷背景风险是2-4%和流产是临床上识别妊娠的15-20%。 哺乳 在人乳汁中dinutuximab的存在，药物对哺乳喂养婴儿的影响，或药物对乳汁生成的影响没有可得到的信息。但是，人乳汁存在IgG。因为对哺乳喂养婴儿中严重不良反应潜能，忠告一位哺乳妇女用Unituxin治疗期间终止哺乳喂养。  【药物过量】尚不明确 【贮    藏】用前Unituxin小瓶贮存在冰箱2°C至8°C。不要冻结或摇动小瓶。为了避光保护保存在外纸盒内。 【有 效 期】尚不明确 Unituxin：2017年板本修改资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d66bdf0d-9d65-45de-ae5b-a58617c27492 FDA批准Unituxin注射剂为治疗神经母细胞瘤药品   神经母细胞瘤是未成熟神经细胞演变成的一种罕见肿瘤，通常始发于肾上腺，也可能发作于腹部、胸部或临近脊柱的神经组织，常见于小于5岁的儿童。根据美国国立癌症研究所的统计，神经母细胞瘤在儿童中的发病率为1/100000，在男孩中相对常见一些。美国每年有新确诊神经母细胞瘤患者约650例。如果给予积极治疗，这类患者中40%~50%有长期生存的机会。   Unituxin是一种抗体药物，可以结合在神经母细胞瘤细胞的表面，此次被批准为神经母细胞瘤综合治疗方案中的一线药物，适用于对既往综合治疗方案至少产生部分应答的神经母细胞瘤患者。   美国FDA药品评价和研究中心血液疾病和肿瘤产品办公室主任Richard Pazdur博士表示：  “Unituxin是FDA批准的首个特异性针对高风险神经母细胞瘤患者的治疗药物，可在一定程度上满足高风险神经母细胞瘤儿童延长存活期的需求”。   Unituxin的安全性和疗效在一项涉及226例高风险神经母细胞瘤患儿的临床试验中得到证实。这些患儿的肿瘤在接受了骨髓移植、多药化疗和手术后缩小或消失。受试者随机接受维甲酸、异维A酸、Unituxin+IL-2+GM-CSF。治疗后3年，Unituxin联合用药组中63%的患者存活和无肿瘤生长或复发，异维甲酸组为46%。在最新的生存分析中，Unituxin联合用药组存活比例为73%，异维甲酸组为58%。   Unituxin的药品标签中附有黑框警告，提示患者和卫生保健人员Unituxi会刺激神经细胞，从而导致严重疼痛并需要使用静脉麻醉药品治疗，Unituxi还可能会发生导致神经损伤和危及生命的注射反应，包括上呼吸道肿胀、呼吸困难、低血压。Unituxin的其他严重副作用包括感染、眼科问题、电解质异常和骨髓抑制。   Unituxin最常见的副作用包括严重疼痛、发热、低血小板计数、输注反应、低血压、低钠血症、肝酶升高、贫血、呕吐、腹泻、低钾血症、毛细血管渗漏综合征、中性粒细胞减少和淋巴细胞减少、荨麻疹和低钙血症。 Dinutuximab (Unituxin) for high risk neuroblastoma–maintenance therapy FDA Approves Unituxin(dinutuximab) for the Treatment of Pediatric High-Risk Neuroblastoma Unituxin™ (dinutuximab) Injection (formerly called ch14.18), in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.  Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the United States of approximately 700 patients, of whom 50% are diagnosed as having high-risk disease.  Unituxin is a chimeric biologic antibody that induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytoxicity (ADCC) and complement-dependent cytoxicity (CDC) and is part of an immunotherapeutic regimen to treat pediatric high-risk neuroblastoma. The approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) conducted by the Children's Oncology Group (COG).  The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm.  Patients in each arm received six cycles of treatment.  The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6).  Patients were 11 months to 15 years of age (median age 3.8 years). The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death.  At the seventh interim analysis, an improvement in EFS [HR 0.57 (95% CI: 0.37, 0.89); p = 0.01, log-rank test] was demonstrated and four remaining patients undergoing treatment on the RA arm crossed over to receive Unituxin/RA.  The median EFS was not reached (3.4 years, NR) in the Unituxin/RA arm and was 1.9 years (1.3, NR) in the RA arm.  An analysis of overall survival (OS) conducted three years later documented an improvement in OS in the Unituxin/RA arm compared to the RA arm [HR 0.58 (95% CI: 0.37, 0.91)].  At the time of this survival analysis, median OS had not been reached in either arm. The most common serious adverse reactions (greater than or equal to 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. The most common adverse drug reactions (greater than or equal to 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%). "This approval has been a collaborative effort between the National Cancer Institute (NCI), the Children's Oncology Group and United Therapeutics for the first approved therapy for pediatric high-risk neuroblastoma," said Roger Jeffs, Ph.D., United Therapeutics' President and Co-Chief Executive Officer.  "We are grateful for the FDA's thorough review and collaboration on this program, and we look forward to expanding our research efforts in the area of pediatric oncology."  "The FDA approval of dinutuximab represents the culmination of a remarkably productive collaboration between researchers of the NCI-supported Children's Oncology Group, the manufacturing and clinical research groups of NCI, and the oncology team at United Therapeutics," said Malcolm Smith, MD, Ph.D., Associate Branch Chief, Pediatrics in the Cancer Therapy Evaluation Program at NCI.  Children with neuroblastoma will benefit from this collaboration, and the drug development pathway blazed by dinutuximab will likely be followed in the future to develop other novel agents directed against pediatric cancer therapeutic targets." "After decades of pursuits, I am pleased to see that dinutuximab has received FDA approval and may now benefit high risk neuroblastoma patients," said Alice Yu, M.D., Ph.D., University of California San Diego and Principle Investigator of the registration study conducted by the COG.  "This is not only the first successful immunotherapeutic to target a non-protein antigen, but also to be developed from an Investigational New Drug application through phase 3 trials largely through investigator-initiated effort and NCI support." The recommended dose and schedule for Unituxin is 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles.  Patients require intravenous treatment with opioids prior to, during, and for 2 hours following the Unituxin infusion to mitigate neuropathic pain.  Prior to each Unituxin dose, administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics. In connection with the Unituxin approval, United Therapeutics agreed to certain postmarketing requirements (PMRs) and certain postmarketing commitments (PMCs). PMRs and PMCs are studies that sponsors conduct after FDA approval to gather additional information about a product's safety, efficacy, or optimal use. PMRs are required studies, whereas a sponsor voluntarily commits to conduct PMCs. About Unituxin Unituxin (dinutuximab) is a disialoganglioside, GD2-binding chimeric monoclonal antibody (formerly called ch14.18) indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.The safety and effectiveness of Unituxin was evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma. All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease.  Important Safety Information for Unituxin Boxed WARNING •Serious Infusion Reactions •Serious and potentially life threatening infusion reactions (facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension) occurred in 26% of patients treated with Unituxin •Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion •Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion •Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis •Neuropathy •Unituxin causes severe neuropathic pain in the majority of patients •Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion •Severe (Grade 3) peripheral sensory neuropathy ranged from 2% to 9% in patients with neuroblastoma •In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy was observed in adults.  Resolution of motor neuropathy was not documented in all cases •Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy CONTRAINDICATIONS Unituxin is contraindicated in patients with a history of anaphylaxis to dinutuximab. WARNINGS AND PRECAUTIONS •Serious Infusion Reactions •Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension. Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion. Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases.  •Severe (Grade 3or4) infusion reactions occurred in 35(26%)patients in the Unituxin/13-cis-retinoic acid(RA)group compared to 1(1%)patient receiving RA alone •Pain and Peripheral Neuropathy •Pain:  114(85%)patients treated in the Unituxin/RA group experienced pain despite pre-treatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5(5%)patients in the RA group.  •Peripheral Neuropathy: Severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2(1%)patients in the Unituxin/RA group •Capillary Leak Syndrome •Severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the Unituxin/RA group and in no patients treated with RA alone •Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin •Hypotension •Severe (Grade 3 or 4) hypotension occurred in 22(16%) patients in the Unituxin/RA group compared to no patients in the RA group •Prior to each Unituxin infusion, administer required intravenous hydration  •Closely monitor blood pressure during Unituxin treatment •Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin •Infection •Severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA alone.  Sepsis occurred in 24 (18%) of patients in the Unituxin/RA group and in 10 (9%) patients in the RA group •Monitor patients closely for signs and symptoms of systemic infection and temporarily discontinue Unituxin in patients who develop systemic infection until resolution of the infection •Neurological Disorders of the Eye •Neurological disorders of the eye experienced by two or more patients treated with Unituxin included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema •Interrupt Unituxin in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss •Upon resolution and if continued treatment with Unituxin is warranted, decrease the Unituxin dose by 50%  •Permanently discontinue Unituxin in patients with recurrent eye disorder following dose reduction and in patients who experience loss of vision •Bone Marrow Suppression •Severe (Grade 3 or 4)thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%) and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the Unituxin/RA group compared to patients treated with RA alone •Monitor peripheral blood counts closely during Unituxin therapy •Electrolyte Abnormalities •Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the Unituxin/RA group, respectively, compared to 2% and 4% of patients in the RA group •Monitor serum electrolytes daily during therapy with Unituxin •Atypical Hemolytic Uremic Syndrome •Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in two patients following receipt of the first cycle of Unituxin •Permanently discontinue Unituxin and institute supportive management •Embryo-Fetal Toxicity •Unituxin may cause fetal harm •Advise pregnant women of the potential risk to a fetus •Advise females of reproductive potential to use effective contraception during treatment, and for two months after the last dose of Unituxin ADVERSE REACTIONS The most common adverse drug reactions (greater than or equal to 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%) infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%). The most common serious adverse reactions (greater than or equal to 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. Please see Full Prescribing Information including Boxed WARNING for Unituxin, available at http://www.unither.com/UFullPrescribingInformation.PDF.