【药物名称】亚砷酸  Arsenious Acid
分子式成分:三氧化二砷 arsenious acid ，本品主要成分为三氧化二砷，其分子式为AS2O3，分子量为198。本品为无色澄明液体，味微咸。

【药理毒理】
本品对急性早幼粒细胞白血病（APL）有一定疗效，其作用机制尚不明确。目前的研究显示，染色体t易位（15：17）是急性早幼粒细胞性白血病的重要细胞遗传学特征，该易位导致早幼粒细胞白血病基因PML和维甲酸受体a（RARa）基因融合，表达PML-RARa蛋白，这种融合蛋白的过度表达是APL发病的主要机制之一，过度表达的PML-RARa可抑制细胞的分化凋亡。实验发现，三氧化二砷通过调节NB4细胞内PML-RARa的水平，使细胞重又纳入程序化死亡的正常轨道。
经维甲酸预处理的NB4细胞，三氧化二砷诱导其发生凋亡的作用并没有受到影响，这说明该药以一种不依赖于维甲酸调节途径的方式在发挥作用，二者之间不存在交叉耐药。
三氧化二砷可显著抑制人肝癌细胞株SMMC-7721细胞生长，其机制与诱导肝癌细胞发生凋亡有关，且凋亡呈剂量依赖性和时间依赖性。细胞周期分析显示，1　μg/mL三氧化二砷作用24-72h，使该细胞生长阻止于G2/M期。经三氧化二砷处理4天的食管癌细胞株EC8712和EC1.71出现显著的凋亡特征，并表现为剂量和时间依赖关系。
动物毒性试验结果表明　：比格犬以0.1、0.3、3.0 mg/kg连续静脉注射给药90天，低、中剂量组动物在给药末期出现心率下降　；高剂量组动物红细胞和血红蛋白均显著降低。停药时进行病理组织学检查见该组动物多数出现肝细胞变性，少数发生肝细胞坏死，肾小球萎缩，肾小球囊内可见嗜酸性细胞、坏死细胞及炎性细胞浸润。睾丸中大部分曲细精管细胞层次减少、精子生成受抑制。

【药代动力学】
本品静脉给药，组织分布较广，停药时检测组织中砷含量由高到低次为皮肤、卵巢、肝脏、肾脏、脾脏、肌肉、睾丸、脂肪、脑组织等。停药四周后检测，皮肤中砷含量与停药时基本持平，脑组织中含量有所增加，其他组织中砷含量均有所下降。8例APL患者的药代动力学参数显示，在开始静滴后4小时达到峰浓度，随即被血浆快速清除，每日尿砷排泄量约为每日药物剂量的1～8%。停药后尿砷即开始下降，停药1-2个月尿砷排泄可下降25～75%不等。

【适应症】
主要适用于急性早幼粒细胞性白血病，也可用于治疗部分其他血液系统恶性肿瘤（如多发性骨髓瘤、淋巴瘤等）及部分实体瘤（如肝癌等）。

【不良反应】
主要不良反应为皮肤干燥、丘疹、红斑或色素沉着，恶心，胃肠胀满，指尖麻木，血清转氨酶升高。 相互作用:在本品的使用过程中，未发现与其他药品之间有药物相互作用。
　　
【用法用量】
成人 一次5-10 mg，用5%葡萄糖注射液或0.9%氯化钠注射液500 mL稀释后静脉滴注，一日一次，4－6周为一疗程　；儿童　每次0.16 mg/kg，用法同上。 尚未发现因亚砷酸注射液用药过量引起不良反应的报道。如使用本品过量引起急性中毒，可用二巯基丙醇（BAL）抢救。

【注意事项】
请在专科医生指导下观察使用。有肝、肾功能损害者慎用。使用过程中如出现肝、肾功能损害应即停药，并进行对症治疗，待恢复后再继续使用。如肝功能异常是因血病细胞浸润所致者，应同时并用保肝治疗。
对妊娠和哺乳的影响：孕妇禁用，哺乳期妇女用药的安全性尚不明确。
对儿童的影响：未发现儿童用药引起异常情况的报道。
对老年患者的影响：未发现老年患者使用本品引发异常情况的报道。

Second line treatment of relapsed or refractory APL following ATRA plus an anthracycline.

三氧化二砷（Arsenic trioxide ，ATO，Trisenox）临床研究表明ATO可通过作用于肿瘤细胞直接调节抗肿瘤活性也可通过在骨髓微环境中抑制骨髓瘤细胞生长及存活因子的产物间接调节抗肿瘤活性，从而有望将ATO应用于骨髓瘤的治疗。砷剂(三氧化二砷、硫化砷)可诱导MM细胞凋亡,抑制血管新生和IL-6及血管内皮细胞生长因子(VEGF)的分泌。ATO还可通过增加淋巴因子活化性杀伤细胞的免疫学机制诱导抗肿瘤活性。体外研究显示药理学浓度的ATO可优先触发骨髓瘤细胞（而不杀伤正常髓细胞）凋亡，且IL-6不能阻止其诱导的骨髓瘤细胞凋亡。
基于亚砷酸体外抗骨髓瘤细胞活性及动物肿瘤模型的研究结果，ATO已处于临床III期评估阶段。采用亚砷酸静脉输注0.15mg/kg/d，结果显示14名复发难治性骨髓瘤患者中有3例对治疗有反应。副作用包括血细胞减少需要G-CSF支持等。临床前期研究数据显示，亚砷酸、地塞米松及维生素C有协同作用。含有ATO的MAC化疗方案已应用于临床治疗难治复发性骨髓瘤，并已取得一定疗效。

急性前骨髄球性白血病治療剤「トリセノックス注10mg」

の新発売について日本新薬は、再発又は難治性の急性前骨髄球性白血病治療剤「トリセノックス注10mg」を12月8日から新発売します。本剤はセルセラピューティクス社（本社：米国シアトル市、社長：Dr. James Bianco）から2002年12月に導入した品目で、2003年6月に承認申請を行い、本年10月に輸入承認を取得しました。
急性前骨髄球性白血病（APL）は、急性骨髄性白血病の一種で、日本では年間人口10万人あたり2～3人発生する急性骨髄性白血病の約15～20％を占める希少疾病です。そして、その中でも、再発又は難治性のAPLに対しては、現在、特に有用な治療法がなく新たな薬剤が切望されていました。
トリセノックス(一般名:三酸化ヒ素)は再発又は難治性APLに対して高い有効率を示し、既に販売されている欧米では第一選択薬として使用されています。今回の日本での発売により、国内においても本剤はAPLの治療上不可欠な薬剤となることが期待されます。

（APL：Acute Promyelocytic Leukemia）

白血病APL新药Trisenox（三氧化二砷）在日本获准上市

Cell Therapeutics, Inc（简称 CTI）宣布，日本新药公司 (Nippon Shinyaku Co., Ltd.) 在获得日本厚生省 (Japanese Ministry of Health) 定价批准后已在日本推出了 TRISENOX（三氧化二砷），该药物旨在治疗患有复发性或顽固性急性早幼粒细胞白血病 (APL) 的病人。CTI 一直在美国和欧洲销售
TRISENOX。 
CTI 总裁兼首席执行官、医学博士 James A. Bianco 表示：“我们很高兴我们的合作伙伴日本新药公司现能够为复发性或顽固性急性早幼粒细胞白血病患者提供这个可能挽救生命的疗方。我们将继续投资TRISENOX 的开发和商业化进程，因为我们相信它为患者提供了一种不同于标准化疗的安全而有效的选择。” 
CTI 今天还宣布已与来自拉丁美洲、东欧、以色列、土耳其和南非的5家经销商签署了关于 TRISENOX 的协议。今年初，该公司宣布美国专利商标局 (U.S. Patent and Trademark) 已颁发一项关于 TRISENOX 的专利，从而使 CTI 对该药的独家销售权从2007年拓展至2018年。

在这之后，为了促进 TRISENOX 在欧洲的销售，该公司在8个重要市场国增派了销售代表以扩充其欧洲销售队伍。 

Bianco 表示：“我们发现，全球患者现在更易获得 TRISENOX，这些经销商协议将为我们进一步的市场拓展打下根基。我们期望与新的合作伙伴展开强大而富有成效的合作。” 
据报道，Ｃｅｌｌ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ（ＣＴＩ）10月２５日宣布，日本新药公司的Ｔｒｉｓｅｎｏｘ（三氧化二砷）经日本卫生部批准在日本上市，用于治疗复发性或顽固性急性早幼粒细胞白血病（ＡＰＬ）。 

【原产地英文商品名】TRISENOX-10mg/10mL/Ampule
【原产地英文药品名】ARSENIC TRIOXIDE
【原产地英文化合物名称】ARSENIC TRIOXIDE
【中文参考商品译名】萃克森-10毫克/10毫升/支,10支/
【中文参考化合物名称】三氧化二砷,砒霜
【生产厂家英文名】Cell Therapeutic

TRISENOX (arsenic trioxide) injection, solution
[Cephalon, Inc.]

For Intravenous Use Only

10 mg/10 mL (1mg/mL) ampule
DESCRIPTION

TRISENOX is a sterile injectable solution of arsenic trioxide. The molecular formula of the drug substance in the solid state is As2O3, with a molecular weight of 197.8 g.

TRISENOX is available in 10 mL, single-use ampules containing 10 mg of arsenic trioxide. TRISENOX is formulated as a sterile, nonpyrogenic, clear solution of arsenic trioxide in water for injection using sodium hydroxide and dilute hydrochloric acid to adjust to pH 8. TRISENOX is preservative-free. Arsenic trioxide, the active ingredient, is present at a concentration of 1.0 mg/mL. Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) and hydrochloric acid, which is used to adjust the pH to 7.5 - 8.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha.

Pharmacokinetics

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (AsIII).  AsIII is the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (AsV) a product of AsIII oxidation. The pharmacokinetics of arsenical species ([AsIII], [AsV], [MMAV], [DMAV]) were determined in 6 APL patients following once daily doses of 0.15 mg/kg for 5 days per week. Over the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear.  Peak plasma concentrations of arsenious acid (AsIII), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of AsIII declined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase.  The daily exposure to AsIII (mean AUC0-24) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2-fold accumulation. The primary pentavalent metabolites, MMAV and DMAV, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does AsIII.  The mean estimated terminal elimination half-lives of the metabolites MMAV and DMAV are 32 hours and 72 hours, respectively.  Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single dose administration.  AsV is present in plasma only at relatively low levels.

Distribution

The volume of distribution (Vss) for AsIII is large (mean 562 L, N=10) indicating that AsIII is widely distributed throughout body tissues.  Vss is also dependent on body weight and increases as body weight increases.

Metabolism

Much of the AsIII is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by methyltransferases primarily in the liver. The metabolism of arsenic trioxide also involves oxidation of AsIII to AsV, which may occur in numerous tissues via enzymatic or nonenzymatic processes.  AsV is present in plasma only at relatively low levels following administration of arsenic trioxide.   

Excretion

Approximately 15% of the administered TRISENOX dose is excreted in the urine as unchanged AsIII.  The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine.  The total clearance of AsIII is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on body weight or dose administered over the range of 7-32 mg.

Special Populations

Effect of Age, Gender, and Race

The effect of age, gender, or race on the pharmacokinetics of TRISENOX has not been studied.

Pediatric Patients

Following IV administration of 0.15 mg/kg/day of arsenic trioxide in 10 APL patients (median age = 13.5 years, range 4-20 years), the daily exposure to AsIII (mean AUC0-24h) was 317 ng·hr/mL on Day 1 of Cycle 1 (see PRECAUTIONS, Pediatric Use).

Effect of Renal Impairment

The effect of renal impairment on the pharmacokinetics of AsIII, AsV, and the pentavalent metabolites MMAV and DMAV was evaluated in 20 patients with advanced malignancies.  Patients were classified as having normal renal function (creatinine clearance [CrCl] > 80 mL/min, n=6), mild renal impairment (CrCl 50-80 mL/min, n=5), moderate renal impairment (CrCl 30-49 mL/min, n=6), or severe renal impairment (CrCl < 30 mL/min, n=3).  Following twice weekly administration of 0.15 mg/kg over a 2-hour infusion, the mean AUC0-∞ for AsIII was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC0-∞ for AsIII was approximately 48% higher than that in the normal group.

Systemic exposure to MMAV and DMAV tended to be larger in patients with renal impairment; however, the clinical consequences of this increased exposure are not known. AsV plasma levels were generally below the limit of assay quantitation in patients with impaired renal function (see PRECAUTIONS).  The use of arsenic trioxide in patients on dialysis has not been studied.

Effect of Hepatic Impairment

The effect of pharmacokinetics of AsIII, AsV, and the pentavalent metabolites MMAV and DMAV was evaluated following administration of 0.25-0.50 mg/kg of arsenic trioxide in patients with hepatocellular carcinoma. Patients were classified as having normal hepatic function (n=4), mild hepatic impairment (Child-Pugh class A, n=12), moderate hepatic impairment (Child-Pugh class B, n=3), or severe hepatic impairment (Child-Pugh class C, n=1). No clear trend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC in the mild and moderate hepatic impairment groups. However, the one patient with severe hepatic impairment had mean dose-normalized AUC0‑24 and Cmax values 40% and 70% higher, respectively, than those patients with normal hepatic function. The mean dose-normalized trough plasma levels for both MMAV and DMAV in this severely hepatically impaired patient were 2.2-fold and 4.7-fold higher, respectively, than those in the patients with normal hepatic function (see PRECAUTIONS).

Drug Interactions

No formal assessments of pharmacokinetic drug-drug interactions between TRISENOX and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes.

In vitro incubation of arsenic trioxide with human liver microsomes showed no inhibitory activity on substrates of the major cytochrome P450 (CYP) enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11.  The pharmacokinetics of drugs that are substrates for these CYP enzymes are not expected to be affected by concomitant treatment with arsenic trioxide  (see PRECAUTIONS).

CLINICAL STUDIES

Clinical Studies Experience

TRISENOX has been investigated in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen, in an open-label, single-arm, non-comparative study. Patients received 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or up to a maximum of 60 days. The CR (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells with a confirmatory bone marrow ≥ 30 days later) rate in this population of previously treated patients was 28 of 40 (70%). Among the 22 patients who had relapsed less than one year after treatment with ATRA, there were 18 complete responders (82%). Of the 18 patients receiving TRISENOX ≥ one year from ATRA treatment, there were 10 complete responders (55%). The median time to bone marrow remission was 44 days and to onset of CR was 53 days. Three of 5 children, 5 years or older, achieved CR. No children less than 5 years old were treated.

Three to six weeks following bone marrow remission, 31 patients received consolidation therapy with TRISENOX, at the same dose, for 25 additional days over a period up to 5 weeks. In follow-up treatment, 18 patients received further arsenic trioxide as a maintenance course. Fifteen patients had bone marrow transplants. At last follow-up, 27 of 40 patients were alive with a median follow-up time of 484 days (range 280 to 755) and 23 of 40 patients remained in complete response with a median follow-up time of 483 days (range 280 to 755).

Cytogenetic conversion to no detection of the APL chromosome rearrangement was observed in 24 of 28 (86%) patients who met the response criteria defined above, in 5 of 5 (100%) patients who met some but not all of the response criteria, and 3 of 7 (43%) of patients who did not respond. Reverse Transcriptase – Polymerase Chain Reaction conversions to no detection of the APL gene rearrangement were demonstrated in 22 of 28 (79%) of patients who met the response criteria, in 3 of 5 (60%) of patients who met some but not all of the response criteria, and in 2 of 7 (29%) of patients who did not respond.

Responses were seen across all age groups tested, ranging from 6 to 72 years. The ability to achieve a CR was similar for both genders. There were insufficient patients of Black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in members of each group.

Another single center study in 12 patients with relapsed or refractory APL, where patients received TRISENOX (arsenic trioxide) injection doses generally similar to the recommended dose, had similar results with 9 of 12 (75%) patients attaining a CR.

INDICATIONS AND USAGE

TRISENOX is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (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.

The response rate of other acute myelogenous leukemia subtypes to TRISENOX has not been examined.

CONTRAINDICATIONS

TRISENOX is contraindicated in patients who are hypersensitive to arsenic.

WARNINGS

(See boxed WARNING)

TRISENOX should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia.

APL Differentiation Syndrome

(See boxed WARNING)

Nine of 40 patients with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome (see boxed WARNING and ADVERSE REACTIONS).

Hyperleukocytosis

Treatment with TRISENOX has been associated with the development of hyperleukocytosis (≥ 10 x 10³/uL) in 20 of 40 patients. A relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts. Hyperleukocytosis was not treated with additional chemotherapy. WBC counts during consolidation were not as high as during induction treatment.

QT Prolongation

(See boxed WARNING)

QT/QTc prolongation should be expected during treatment with arsenic trioxide and torsade de pointes as well as complete heart block has been reported. Over 460 ECG tracings from 40 patients with refractory or relapsed APL treated with TRISENOX were evaluated for QTc prolongation. Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned towards baseline by the end of 8 weeks after TRISENOX infusion. In these ECG evaluations, women did not experience more pronounced QT prolongation than men, and there was no correlation with age.

Complete AV block

Complete AV block has been reported with arsenic trioxide in the published literature including a case of a patient with APL.

Carcinogenesis

Carcinogenicity studies have not been conducted with TRISENOX by intravenous administration. The active ingredient of TRISENOX, arsenic trioxide is a human carcinogen.

Pregnancy

TRISENOX may cause fetal harm when administered to a pregnant woman. Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. The reproductive toxicity of arsenic trioxide has been studied in a limited manner. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were observed in rats administered 10 mg/kg of arsenic trioxide on gestation day 9 (approximately 10 times the recommended human daily dose on a mg/m² basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite, (approximately 5 times the projected human dose on a mg/m² basis) on gestation days 6, 7, 8 or 9. Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m² basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.

There are no studies in pregnant women using TRISENOX. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

Laboratory Tests

The patient’s electrolyte, hematologic and coagulation profiles should be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase. ECGs should be obtained weekly, and more frequently for clinically unstable patients, during induction and consolidation.

Drug Interactions

No formal assessments of pharmacokinetic drug-drug interactions between TRISENOX and other agents have been conducted. Caution is advised when TRISENOX is coadministered with other medications that can prolong the QT interval (e.g., certain antiarrhythmics or thioridazine) or lead to electrolyte abnormalities (such as diuretics or amphotericin B).

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section for information on carcinogenesis. Arsenic trioxide and trivalent arsenite salts have not been demonstrated to be mutagenic to bacteria, yeast or mammalian cells. Arsenite salts are clastogenic in vitro (human fibroblast, human lymphocytes, Chinese hamster ovary cells, Chinese hamster V79 lung cells). Trivalent arsenic produced an increase in the incidence of chromosome aberrations and micronuclei in bone marrow cells of mice. The effect of arsenic on fertility has not been adequately studied.

Pregnancy

Pregnancy Category D. See WARNINGS section.

Nursing Mothers

Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TRISENOX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

There are limited clinical data on the pediatric use of TRISENOX. Of 5 patients below the age of 18 years (age range: 5 to 16 years) treated with TRISENOX, at the recommended dose of 0.15 mg/kg/day, 3 achieved a complete response.

In an additional study, the toxicity profile observed in 13 pediatric patients with APL between the ages of 4 and 20 receiving TRISENOX at 0.15 mg/kg/day was similar to that observed in adult patients (see ADVERSE REACTIONS).

Safety and effectiveness in relapsed APL pediatric patients below the age of 4 years have not been studied.

Patients with Renal Impairment

Exposure of arsenic trioxide may be higher in patients with severe renal impairment (See CLINICAL PHARMACOLOGY, Special Populations.). Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be closely 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 (see CLINICAL PHARMACOLOGY, Special Populations).  Patients with severe hepatic impairment (Child-Pugh class C) should be closely monitored for toxicity when these patients are treated with TRISENOX.

ADVERSE REACTIONS

Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of TRISENOX. Forty patients in the Phase 2 study received the recommended dose of 0.15 mg/kg of which 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Most patients experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.

Serious adverse events (SAEs), grade 3 or 4 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to TRISENOX in the Phase 2 study of 40 patients with refractory or relapsed APL included APL differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2).

The following table describes the adverse events that were observed in patients treated for APL with TRISENOX at the recommended dose at a rate of 5% or more. Similar adverse event profiles were seen in the other patient populations who received TRISENOX.

Adverse Events (any grade) Occurring in ≥ 5% of 40 Patients with APL who Received TRISENOX (arsenic trioxide) injection at a dose of 0.15 mg/kg/day

System organ class/Adverse Event		All Adverse Events, Any Grade			Grade 3 & 4 Events
		n	%		n	%
General disorders and administration site conditions
	Fatigue	25	63		2	5
	Pyrexia (fever)	25	63		2	5
	Edema - non-specific	16	40
	Rigors	15	38
	Chest pain	10	25		2	5
	Injection site pain	8	20
	Pain - non-specific	6	15		1	3
	Injection site erythema	5	13
	Injection site edema	4	10
	Weakness	4	10		2	5
	Hemorrhage	3	8
	Weight gain	5	13
	Weight loss	3	8
	Drug hypersensitivity	2	5		1	3
Gastrointestinal disorders
	Nausea	30	75
	Anorexia	9	23
	Appetite decreased	6	15
	Diarrhea	21	53
	Vomiting	23	58
	Abdominal pain (lower & upper)	23	58		4	10
	Sore throat	14	35
	Constipation	11	28		1	3
	Loose stools	4	10
	Dyspepsia	4	10
	Oral blistering	3	8
	Fecal incontinence	3	8
	Gastrointestinal hemorrhage	3	8
	Dry mouth	3	8
	Abdominal tenderness	3	8
	Diarrhea hemorrhagic	3	8
	Abdominal distension	3	8
Metabolism and nutrition disorders
	Hypokalemia	20	50		5	13
	Hypomagnesemia	18	45		5	13
	Hyperglycemia	18	45		5	13
	ALT increased	8	20		2	5
	Hyperkalemia	7	18		2	5
	AST increased	5	13		1	3
	Hypocalcemia	4	10
	Hypoglycemia	3	8
	Acidosis	2	5
Nervous system disorders
	Headache	24	60		1	3
	Insomnia	17	43		1	3
	Paresthesia	13	33		2	5
	Dizziness (excluding vertigo)	9	23
	Tremor	5	13
	Convulsion	3	8		2	5
	Somnolence	3	8
	Coma	2	5		2	5
Respiratory
	Cough	26	65
	Dyspnea	21	53		4	10
	Epistaxis	10	25
	Hypoxia	9	23		4	10
	Pleural effusion	8	20		1	3
	Post nasal drip	5	13
	Wheezing	5	13
	Decreased breath sounds	4	10
	Crepitations	4	10
	Rales	4	10
	Hemoptysis	3	8
	Tachypnea	3	8
	Rhonchi	3	8
Skin & subcutaneous tissue disorders
	Dermatitis	17	43
	Pruritus	13	33		1	3
	Ecchymosis	8	20
	Dry skin	6	15
	Erythema - non-specific	5	13
	Increased sweating	5	13
	Facial edema	3	8
	Night sweats	3	8
	Petechiae	3	8
	Hyperpigmentation	3	8
	Non-specific skin lesions	3	8
	Urticaria	3	8
	Local exfoliation	2	5
	Eyelid edema	2	5
Cardiac disorders
	Tachycardia	22	55
	ECG QT corrected interval prolonged > 500 msec	16	40
	Palpitations	4	10
	ECG abnormal other than QT interval prolongation	3	8
Infections and infestations
	Sinusitis	8	20
	Herpes simplex	5	13
	Upper respiratory tract infection	5	13		1	3
	Bacterial infection - non-specific	3	8		1	3
	Herpes zoster	3	8
	Nasopharyngitis	2	5
	Oral candidiasis	2	5
	Sepsis	2	5		2	5
Musculoskeletal, connective tissue and bone disorders
	Arthralgia	13	33		3	8
	Myalgia	10	25		2	5
	Bone pain	9	23		4	10
	Back pain	7	18		1	3
	Neck pain	5	13
	Pain in limb	5	13		2	5
Hematologic disorders
	Leukocytosis	20	50		1	3
	Anemia	8	20		2	5
	Thrombocytopenia	7	18		5	13
	Febrile neutropenia	5	13		3	8
	Neutropenia	4	10		4	10
	Disseminated intravascular coagulation	3	8		3	8
	Lymphadenopathy	3	8
Vascular disorders
	Hypotension	10	25		2	5
	Flushing	4	10
	Hypertension	4	10
	Pallor	4	10
Psychiatric disorders
	Anxiety	12	30
	Depression	8	20
	Agitation	2	5
	Confusion	2	5
Ocular disorders
	Eye irritation	4	10
	Blurred vision	4	10
	Dry eye	3	8
	Painful red eye	2	5
Renal and urinary disorders
	Renal failure	3	8		1	3
	Renal impairment	3	8
	Oliguria	2	5
	Incontinence	2	5
Reproductive system disorders
	Vaginal hemorrhage	5	13
	Intermenstrual bleeding	3	8
Ear disorders
	Earache	3	8
	Tinnitus	2	5

The following additional adverse events were reported as related to TRISENOX treatment in 13 pediatric patients (defined as ages 4 through 20): gastrointestinal (dysphagia, mucosal inflammation/stomatitis, oropharyngeal pain, caecitis), metabolic and nutrition disorders (hyponatremia, hypoalbuminemia, hypophosphatemia, and lipase increased), cardiac failure congestive, respiratory (acute respiratory distress syndrome, lung infiltration, pneumonitis, pulmonary edema, respiratory distress, capillary leak syndrome), neuralgia, and enuresis. Pulmonary edema (n=1) and caecitis (n=1) were considered serious reactions.

Post-Marketing Experience

The following reactions have been reported from clinical trials and/or world-wide post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Cardiac disorders: ventricular extrasystoles in association with QT prolongation, and ventricular tachycardia in association with QT prolongation

Nervous system disorders: peripheral neuropathy

Hematologic disorders: pancytopenia

Respiratory, thoracic, and mediastinal disorders: A differentiation syndrome, like retinoic acid syndrome, has been reported with the use of TRISENOX for the treatment of malignancies other than APL. See boxed WARNING.

OVERDOSAGE

If symptoms suggestive of serious acute arsenic toxicity (e.g., convulsions, muscle weakness and confusion) appear, TRISENOX (arsenic trioxide) injection should be immediately discontinued and chelation therapy should be considered. A conventional protocol for acute arsenic intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided. Thereafter, penicillamine at a dose of 250 mg orally, up to a maximum frequency of four times per day (≤ 1 g per day), may be given.

DOSAGE AND ADMINISTRATION

TRISENOX should be diluted with 100 to 250 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, using proper aseptic technique, immediately after withdrawal from the ampule. The TRISENOX ampule is single-use and does not contain any preservatives. Unused portions of each ampule should be discarded properly. Do not save any unused portions for later administration. Do not mix TRISENOX with other medications.

TRISENOX should be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.

Stability

After dilution, TRISENOX is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.

Dosing Regimen

TRISENOX is recommended to be given according to the following schedule:

Induction Treatment Schedule: TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Total induction dose should not exceed 60 doses.

Consolidation Treatment Schedule: Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy. TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

TRISENOX (arsenic trioxide) injection is supplied as a sterile, clear, colorless solution in 10 mL glass, single-use ampules.

NDC 63459-600-10 10 mg/10 mL (1 mg/mL) ampule in packages of ten ampules.

Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). Do not freeze.

Do not use beyond expiration date printed on the label.

REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004:165.
2. OSHA Technical Manual. TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society

Rx only

Manufactured for:

Cephalon, Inc.
Frazer, PA 19355

TRI-007

Revised June 2010