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近日，抗癌新药Trisenox(arsenic trioxide，三氧化二砷）注射剂获美国FDA批准上市，用于再发性或难治性急性早幼粒细胞白血病治疗。
Trisenox中的活性物质是三氧化二砷。它可以将癌变的白血细胞转变成正常白血细胞。砷制剂疗法早已用于治疗白血病，但已被现代的化疗方法和抗生素治疗所代替。
批准日期：2000年9月 公司：梯瓦（Teva）
TRISENOX（三氧化二砷[arsenic trioxide]）注射液，用于静脉注射
美国最初批准：2000年
警告：分化综合症和心脏传导异常
查看完整的盒装警告的完整处方信息。
•接受TRISENOX治疗的患者可能会出现分化综合症，这可能是致命的。如果出现症状，立即启动高剂量类固醇并监测血流动力学。
•TRISENOX可引起QT间期延长和室性心律失常，这可能是致命的。在给予TRISENOX之前，评估QT间期，纠正电解质异常，并考虑停用已知toprolong QT间期的药物。不要给患有心室性心律失常或长期QTcF的患者服用TRISENOX。
最近的重大变化
适应症和用法：01/2018
剂量和用法：01/2018
警告和注意事项：01/2018
作用机制
TRISENOX的作用机制尚不完全清楚。 三氧化二砷引起细胞凋亡的形态变化和DNA断裂特征在NB4人类早幼粒细胞白血病细胞体外。
三氧化二砷还引起融合蛋白早幼粒细胞白血病（PML） - 视黄酸受体（RAR）-α的损伤或降解。
适应症和用法
TRISENOX是一种砷化学品：
•与维甲酸联合用于治疗患有新诊断的低风险早幼粒细胞白血病（APL）的成人，其APL的特征在于存在t（15; 17）易位或PML/RAR-α基因表达。
•用于诱导APL患者的缓解和巩固，这些患者因类维生素A和蒽环类化疗难以治愈或复发，且其APL特征在于存在t（15; 17）易位或PML/RAR-α基因表达。
剂量和给药
新诊断的低风险APL：
•诱导：每天静脉注射0.15mg/kg与维甲酸组合，直至骨髓缓解。感应不要超过60天。
•巩固：每周5天静脉注射0.15mg/kg，在8周周期的第1-4周内，与维甲酸组合使用共4个周期。
复发或难治性APL：
•诱导：每天静脉注射0.15mg/kg，直至骨髓缓解。注意60剂量的总诱导。
•巩固：每天静脉注射0.15mg/kg，连续25次，最多5次
周。
剂量形式和强度
注射：在单剂量小瓶中，在6mL中加入12mg三氧化二砷。
禁忌症
对砷过敏。
警告和注意事项
•肝毒性：用TRISENOXin联合维甲酸治疗新诊断的低危或中度风险APL患者，肝转氨酶升高≥3级。在TRISENOX治疗期间，每周至少监测两次肝功能检查。
•致癌作用：三氧化二砷是一种人类致癌物质。监测患者的第二原发恶性肿瘤的发展。
•胚胎 - 胎儿毒性：可能导致胎儿伤害。建议对胎儿有潜在风险和使用有效避孕措施。
不良反应
最常见的不良反应（大于30％）是白细胞增多，中性粒细胞减少，血小板减少，恶心，呕吐，腹泻，腹痛，肝毒性，
发烧，严酷，疲劳，失眠，心动过速，QTc延长，水肿，高血糖，低钾血症，低镁血症，呼吸困难，咳嗽，皮疹或瘙痒，喉咙痛，关节痛，头痛，感觉异常和头晕。
用于特定人群
•哺乳期：建议女性不要母乳喂养。
•肾功能损害：用TRISENOX治疗时，监测严重肾功能不全（肌酐清除率低于30mL/min）的患者的毒性;剂量减少可能是有道理的。
•肝功能损害：用TRISENOX治疗严重肝功能损害患者（Child-PughClass C）的毒性。
包装提供/存储和处理
提供
TRISENOX（三氧化二砷）注射液以10mL玻璃单剂量小瓶的无菌透明无色溶液形式提供。
NDC 63459-601-06 12毫克/6毫升（2毫克/毫升）小瓶，装在10个小瓶中。
存储和处理
储存在20°-25°C（68°-77°F）; 允许偏移15°-30°C（59°- 86°F）（见USP受控室温）。不要冻结。
TRISENOX是一种细胞毒性药物。 遵循适用的特殊处理和处理程序
完整说明书附件：http://www.trisenox.com/trisenox-prescribing-information.pdf
U.S. FDA Approval of TRISENOX® (arsenic trioxide) Injection for First Line Treatment of Acute Promyelocytic Leukemia
Trisenox (Arsenic Trioxide Injection)
U.S. Food and Drug Administration (FDA) has approved the use of TRISENOX® (arsenic trioxide) injection in combination with tretinoin for the treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. The approval was based on a Priority Review by the FDA on data from published scientific literature and a review of Teva’s global safety database for arsenic trioxide.
“Today’s approval to expand the indication of TRISENOX is a testament to Teva’s commitment to providing solutions to advance cancer care,” said Paul Rittman, Senior Vice President and General Manager, Teva Oncology. “This label expansion represents an important benefit as TRISENOX is now an FDA-approved first line treatment option for patients with acute promyelocytic leukemia.”
TRISENOX® (arsenic trioxide) Injection IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME AND CARDIAC CONDUCTION ABNORMALITIES
Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with TRISENOX have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multi-organ dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Temporary discontinuation of TRISENOX may be required.
Cardiac Conduction Abnormalities: Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a torsade de pointes-type ventricular arrhythmia, which can be fatal. Before initiating therapy, assess the QTc interval, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTcF.
Contraindications: TRISENOX is contraindicated in patients who are hypersensitive to arsenic.
Differentiation Syndrome: In clinical trials, 16-23% of patients treated with TRISENOX for APL developed differentiation syndrome. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. When TRISENOX is used in combination with tretinoin, prednisone prophylaxis is advised.
Cardiac Conduction Abnormalities: In the clinical trials of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin, 11% experienced QTc prolongation>450 msec for men and>460 msec for women throughout the treatment cycles. In the clinical trial of patients with relapsed or refractory APL treated with TRISENOX monotherapy, 40% had at least one ECG tracing with a QTc interval greater than 500 msec.A prolonged QTc was observed between 1 and 5 weeks after start of TRISENOX infusion, and it usually resolved by 8 weeks after TRISENOX infusion. There are no data on the effect of TRISENOX on the QTc interval during the infusion of the drug.
The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. The risk may be increased when TRISENOX is co-administered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).
Hepatotoxicity: In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of TRISENOX and/or tretinoin. During treatment with TRISENOX, monitor liver chemistries at least 2-3 times per week through recovery from toxicities. Withhold treatment with TRISENOX and/or tretinoin if elevations in AST), alkaline phosphatase, and/or serum bilirubin occur to greater than 5 times the upper limit of normal.
Long-term liver abnormalities can occur in APL patients treated with TRISENOX in combination with tretinoin. In a published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at a median of 7 years (range 0-14 years) after treatment with arsenic trioxide in combination with tretinoin.
Carcinogenesis: The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.
Embryo-Fetal Toxicity: TRISENOX can cause fetal harm when administered to a pregnant woman. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Conduct pregnancy tests prior to starting treatment and advise pregnant women of the potential risk to a fetus. Advise patients of reproductive potential to use effective contraception during treatment with TRISENOX and after treatment for 6 months in females and 3 months in males. TRISENOX may also impair fertility in males.
Lactation: TRISENOX is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, discontinue breastfeeding during treatment with TRISENOX and for two weeks after the final dose.
Patients with Renal Impairment: Exposure of arsenic trioxide may be higher in patients with severe renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied.
Patients with Hepatic Impairment: Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.
Most Common Adverse Reactions: The most common adverse reactions (greater than 30%) were leukocytosis, neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, abdominal pain, hepatic toxicity, fever, rigors, fatigue, insomnia, tachycardia, QTc prolongation, edema, hyperglycemia, hypokalemia, hypomagnesemia, dyspnea, cough, rash or itching, sore throat, arthralgia, headaches, paresthesia, and dizziness.
Indications
TRISENOX is indicated:
In combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
For induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
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