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近日，美国食品药品监督管理局（FDA）批准注射药物Istodax（romidepsin）用于治疗一种名为皮肤T细胞淋巴瘤（CTCL）的罕见癌症。
皮肤T细胞淋巴瘤是一种名为T-淋巴细胞的抗感染白细胞缓慢生长的癌症。大多数病例在开始时伴有皮肤干燥、红疹和瘙痒，并可能加重。可能发生肿瘤的皮肤会出现溃疡并引发感染。在一些病例中，CTCL可扩散至血液、淋巴结或内部器官。在美国，每年约有1500个新的CTCL病例。伴有皮肤局部CTCL的患者可接受局部药物或光疗治疗，一旦病情恶化，则可能需要进行化疗。
Istodax可干扰细胞复制程序。该药被计划用于在已使用至少一种其他类型的化疗后病情仍趋于恶化或复发的CTCL患者。FDA药物评估和研究中心的肿瘤药品办公室主任Richard Pazdur博士表示，“这次批准证明了FDA有关发展和批准用于治疗罕见和少见疾病药物的承诺。”FDA于2009年11月6日批准Istodax上市。之前已批准用于治疗CTCL的药物包括Zolinza （vorinostat）、Ontak （denileukin difitox）和Targretin （bexarotene）。
Istodax的评估是基于2项共纳入167名患者的临床研究。在这 2项试验中约有35%的患者出现治疗反应，表现为肿瘤的大小减小。在其中1项研究中，治疗反应的持续中位时间为15个月，另一项研究为11个月。研究中有 6%的患者已完成治疗，并通过体格、实验室和X-射线检查未发现肿瘤迹象。
常见副作用包括恶心、疲劳、感染、呕吐、食欲减退、血红细胞计数降低、血小板计数减少以及白细胞组成减少。Istodax可能引起心电图（ECG）改变。在伴有某些心律异常风险的患者中应考虑做定期的血液检验以监测电解质，以及定期的ECG监测。Istodax由位于美国马萨诸塞州剑桥市的Gloucester制药公司销售.
批准日期：2009年11月5日；公司：Gloucester Pharmaceuticals
Istodax(romidepsin)注射剂使用
作用机制
Romidepsin是一种组蛋白去乙酰化酶(HDAC)抑制剂。HDACs在组蛋白中催化从乙酰化赖氨酸残基去除乙酰基，导致基因表达的调节。HDACs还脱去乙酰基非-组蛋白蛋白，例如转录因子。在体外，romidepsin引起乙酰化组蛋白的蓄积，和诱导细胞周期停止和某些癌症细胞株凋亡有IC50值在纳克分子范围。在非临床和临床研究中观察到Romidepsin的抗肿瘤作用机制的特点尚未完全确定。
适应证和用途
ISTODAX是一种组蛋白去乙酰化酶(HDAC)抑制剂适用于：
(1）在已接受至少1次既往全身治疗的患者中皮肤T-细胞淋巴瘤的治疗(CTCL)
剂量和给药方法
(1）28天疗程的第1，8和15天分别在4小时过程静脉输注14 mg/m2。每28天重复1个疗程，提供患者继续获益并耐受药物。
(2）为处理不良药物反应可能需要停止治疗或中断本品，减低或不减低剂量至10mg/m2。
剂型和规格
注射用ISTODAX，10mg，提供1小瓶含2 mL(可输送容积)稀释液。
禁忌证
无。
警告和注意事项
(1）由于QT延长的风险给予ISTODAX前确保钾和镁是在正常范围内。
(2）用ISTODAX治疗曾伴有血小板减少，白细胞减少(中性粒细胞减少和淋巴细胞减少)，和贫血；所以，用ISTODAX治疗期间监查这些血液学参数，必要时修改剂量。
(3）曾观察到心电图(ECG)变化。有先天性长QT综合征患者中，明显心血管病史，和使用导致显著QT延长药品患者，考虑心血管监查警惕(5.3)。
(4）根据其作用机制，ISTODAX可能引起胎儿危害当给予妊娠妇女。劝告妇女对胎儿潜在危害。
(5）ISTODAX与雌激素受体结合。劝告有生育潜能妇女ISTODAX可能 may 减低含雌激素避孕药的疗效。
不良反应
在研究1中最常见不良反应是恶心，疲劳，感染，呕吐，和厌食；而在研究2中为恶心，疲劳，贫血，血小板减少，ECG T-波变化，中性粒细胞减少，和淋巴细胞减少。
药物相互作用
(1）在同时给予ISTODAX和香豆定[Coumadin]衍生物患者中仔细监查凝血酶原时间(PT)和国际标准化比率(INR)(7.1)。
(2）强CYP3A4抑制剂可能增加ISTODAX的浓度和应当避免。
(3）强CYP3A4诱导剂可能减低ISTODAX的浓度和应当避免。
ISTODAX® is indicated for treatment of cutaneous T-cell
lymphoma (CTCL) in patients who have received at
least one prior systemic therapy.
ISTODAX® is indicated for treatment of peripheral T-cell
lymphoma (PTCL) in patients who have received at
least one prior therapy.
These indications are based on response rate. Clinical
benefit such as improvement in overall survival has not
been demonstrated.
Important Safety Information
WARNINGS AND PRECAUTIONS
•Treatment with ISTODAX® (romidepsin) has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary
•Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX. The risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy
•Electrocardiographic (ECG) changes have been observed with ISTODAX
•In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment
•Ensure that potassium and magnesium are within the normal range before administration of ISTODAX
•Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate
•ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)
ADVERSE REACTIONS
Peripheral T-Cell Lymphoma
The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).
Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.
The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).
Cutaneous T-Cell Lymphoma
The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (N=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (N=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).
Infections were the most common type of serious adverse event reported in both Study 1 (N=102) and Study 2 (N=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.
The most common adverse reactions regardless of causality in Study 1 (N=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%), and in Study 2 (N=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).
DRUG INTERACTIONS
•Monitor prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX (romidepsin) and warfarin sodium derivatives
•Romidepsin is metabolized by CYP3A4
◦Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors
◦Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4
•Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors
USE IN SPECIFIC POPULATIONS
•Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother
•Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution
Please see Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.
If you have any questions, please call 1-888-423-5436.
ISTODAX Rx
Manufacturer:
Celgene Corp
Pharmacological Class:
Antineoplastic (histone deacetylase inhibitor)
Active Ingredient(s):
Romidepsin 10mg/vial; pwd for IV infusion after reconstitution and dilution; contains povidone.
Indication(s):
Cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.
Pharmacology:
Histone deacetylases catalyze the removal of acetyl groups from acetylated lysine residues in histones and non-histone proteins, affecting the expression of genes. Inhibitors of this enzyme, such as romidepsin, interfere with activities mediated by histones and transcription proteins. In vitro, romidepsin has been shown to cause the accumulation of acetylated histones and to induce cell cycle arrest and apoptosis in some cancer cell lines, but its exact mechanism of action in treating CTCL has not been elucidated.
Clinical Trials:
Two multicenter, single-arm clinical studies were used to evaluate the efficacy of romidepsin in treating CTCL. Patients were treated with the study drug at the recommended dose until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated using a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells. The primary endpoint for each study was overall objective disease response rate (ORR), defined as the proportion of patients with confirmed complete response or partial response.
Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. The ORR in this study was 34% (complete response 6% + partial response 28%). Median duration of response was 15 months.
Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or at least one systemic therapy. In this study, the ORR was 35% (complete response 6% + partial response 30%). Median duration of reponse was 11 months.
The median time to first response was 2 months in both studies. The median time to complete response was 6 months in Study 1 and 4 months in Study 2.
Legal Classification:
Rx
Adults:
≥18yrs: Give by IV infusion over 4hrs. 14mg/m2 on days 1, 8, and 15 of a 28-day cycle; repeat cycle every 28 days; continue as tolerated and as beneficial. May interrupt, reduce dose to 10mg/m2, or discontinue based on toxicities (see literature).
Children:
<18yrs: not recommended.
Precaution(s):
Correct electrolyte imbalances (esp. K+, Mg++) before starting. Monitor ECG and electrolytes in congenital long QT syndrome, significant cardiovascular disease. Moderate to severe hepatic impairment. End-stage renal disease. Monitor CBC with differential. Pregnancy (Cat.D; may cause fetal harm). Nursing mothers: not recommended.
Interaction(s):
May interfere with hormonal (estrogen) contraceptives. Caution with other drugs that can cause QT prolongation (monitor). Monitor PT/INR with warfarin. Potentiated by drugs that inhibit P-glycoprotein and CYP3A4; avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, clarithromycin, nefazodone). Caution with moderate CYP3A4 inhibitors. Antagonized by strong CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin; avoid. Concomittant St. John’s Wort: not recommended.
Adverse Reaction(s):
GI upset, fatigue, infections, anorexia, anemia, thrombocytopenia, ECG T-wave changes, neutropenia, lymphopenia.
How Supplied:
Kit—1 (single-use vial + diluent and supplies)
Last Updated:
3/4/2010
完整使用说明附件1：http://www.drugsdb.eu/drug.php?d=Istodax&m=Celgene%20Corporation&id=e9012000-7305-11df-86e6-0002a5d5c51b.xml
完整使用说明附件2：http://www.dailymedplus.com/monograph/view/setid/6005c345-ccf9-4fff-8660-3fd73485b0d9
Istodax（romidepsin）属注射类药物，用于治疗皮肤T淋巴细胞瘤（CTCL）
CTCL为一种生长缓慢并且能够影响T淋巴细胞的肿瘤。大多数病例以皮肤干燥、红疹和瘙痒为首发症状，并且症状会逐渐加重。皮肤形成肿瘤后可发生溃疡，进而引发感染。在某些情况下CTCL可播散至血液、淋巴结及内脏器官。美国每年约有1500例新发病例。
皮肤局限性CTCL患者可采用局部药物治疗或光疗，如果肿瘤进展则可使用化疗。Istodax能够干扰细胞增殖的关键进程。当CTCL患者出现病情恶化或化疗后复发时，可考虑将Istodax用于治疗。两项共涉及167例患者的临床试验对Istodax进行了评价，研究中均有约35%的患者出现肿瘤缓解，其中一项研究的平均缓解时间为15个月，另一项为11个月，研究中有6%的患者出现完全缓解。
Istodax常见的副作用包括恶心、疲劳、感染、呕吐、食欲减退、红细胞降低、血小板减少和白细胞降低。Istodax还可能导致心电图（ECG）发生变化。使用该药物时应定期监测电解质，具有心律不齐风险者应定期监测ECG。Istodax可能对胎儿具有不良影响，因此女性在使用期间应避免受孕。
既往批准治疗CTCL的药物包括伏立诺他（Zolinza，vorinostat）、一种白介素融合2毒素（Ontak，denileukin difitox）和贝沙罗汀（Targretin，bexarotene）。 |
