FDA安全标示变更:Clolar、Precedex、Treanda


  January 2, 2009 — 美国食品药物管理局(FDA)核准clofarabine注射剂、dexmedetomidine HCl注射剂、与bendamustine HCl注射剂等三项制剂的安全标示变更。
  
  【Clofarabine (Clolar) 与增加感染风险、孕妇致命伤害有关】
  2008年10月17日,FDA核准嘌呤核苷代谢抑制剂 clofarabine (Clolar 静脉注射剂,Genzyme公司制造)变更安全标示,以提供新版的全血与血小板计数的信息、增加感染风险、监控肿瘤溶解症候群以及细胞激素释出,观察肝胆酵素值增加、接受过造血干细胞移植病患之肝毒性潜在风险、怀孕时的潜在致命风险。
  
  Clofarabine注射剂用于治疗小儿(年龄1至21岁)病患,于至少两次处方之后复发或者难治型急性淋巴性白血病。有多种语言介绍全部的警语和注意事项。血液毒性包括以clofarabine静脉注射治疗期间需监控血球与血小板数量。感染病患必须监控感染的征兆与症状,并且适当治疗。
  
  对于高尿酸血症(肿瘤溶解症候群),医师需指示在整个5天的clofarabine治疗中提供静脉液体输注,以减少肿瘤溶解症候群以及其它不良反应的效果,且若预期有高尿酸时,可给予allopurinol。
  
  病患全身发炎反应症状、微血管渗漏症状与器官功能不佳恢复稳定之后,医师也须指示以减量25%来恢复clofarabine治疗,并使用预防性类固醇,以避免细胞激素释出的征兆与症状。有关肝胆酵素增加的信息现在登载于不良反应段落。
  
  对于肝肾不佳者,曾经接受造血干细胞移植的病患,并用clofarabine (40 mg/m2) 、etoposide (100 mg/m2)和cyclophosphamide (440 mg/m2)者,潜在增加静脉阻塞性疾病的肝毒性风险。正在进行中的1/2期小儿复发或难治型急性白血病患者之合并治疗研究,也指出严重的肝毒性事件。
  
  根据新版卷标,Clofarabine也可能会引起孕妇的致命伤害。
  
  至于不良反应,更新的资料包括根据器官系统分类(N = 115;汇整分析)最常被报告的(整体≧5%)不良事件;急性淋巴性白血病或者急性骨髓性白血病患者最不常见(1%-4%病患)的不良反应包括盲肠炎和胰脏炎;高胆红素血症;过敏;细菌感染;菌血症;霉菌感染;败血症;病毒感染;肺炎;鼻窦炎;血中肌酸酐值增加;心智状态改变;肺水肿。
  
  给予clofarabine治疗后引起的实验室异常也会发生;超过半数病患发生等级3以上的异常,包括白血球减少(87.7%)、淋巴球减少 (82.3%)、血小板减少(79.8%)、贫血(75.4%)以及嗜中性白血球减少(63.7%)。
  
  上市后的不良反应事件,包括骨髓衰竭、造血干细胞移植后成年病患之严重静脉阻塞性疾病的肝毒性不良反应,并用allopurinol或者抗生素治疗的病患也曾发生过史蒂文-强生症候群与毒性表皮坏死。
  
  65岁以上年长病患的clofarabine安全性与有效性尚未建立。
  
  【Dexmedetomidine HCl (Precedex) 加入谘商讯息、手术镇静的新资料】
  2008年10月17日,FDA核准dexmedetomidine HCl (Precedex 注射剂,Hospira公司制造)的安全标示变更,以包括谘商讯息以及手术镇静、致癌、发生突变与不孕症的资料。
  
  Dexmedetomidine是相对选择性的alpha2肾上腺素致效剂,用于加护病房初次插管与机械辅助呼吸病患之镇静,也用于术前和/或术中非插管病患之镇静。
  
  根据病患谘商信息,接受输注超过6小时的病患需被告知,48小时后可能会有紧张、燥动和头痛,或者在48小时内可能发生虚弱、混乱、过度出汗、体重减轻、腹痛、渴求盐分、腹泻、便秘、头晕或头昏眼花。
  
  警告与注意事项也修改指出,短期输注(< 6小时) dexmedetomidine之后未发现有戒断症状。手术中镇静的不良反应资料来自两个试验、318名成人病患,包括低血压(54%)、心搏徐缓(14%)以及口干(3%)等最常见。
  
  dexmedetomidine用于年长病患的手术镇静资料指出,65岁以上病患发生低血压比率(72%)、75岁以上病患发生低血压比率(74%)高于65岁以下病患。对于65岁以上病患,另一个建议是降低起始剂量为0.5 μg/kg、给予10分钟,并且降低维持输注。
  
  【Bendamustine(Treanda) 新增警告与注意事项】
  2008年10月31日,FDA核准bendamustine (Treanda,Cephalon公司制造)注射剂的安全标示变更,这是一种烷化基药剂,用于治疗使用rituximab或者含rituximab处方治疗6个月仍有恶化之慢性淋巴球性白血病(CLL)以及无痛的B细胞非何杰金氏淋巴瘤(NHL)。
  
  警告与注意事项的安全标示变更包括来自两个试验的骨髓抑制资料,其中98%的病患有等级3至4骨髓抑制,2%病患死于骨髓抑制相关不良反应(嗜中性白血球缺乏之败血症、弥漫性肺泡出血与等级3血小板过低、伺机性感染引起的肺炎。
  
  有关皮肤反应的资料也加入警告与注意事项,一个是毒性表皮坏死案例,发生于并用bendamustine (90 mg/m2)与rituximab的研究。Rituximab曾有毒性表皮坏死报告,但是尚未确认毒性表皮坏死与bendamustine的关联。
  
  警告与注意事项也增加其它恶性肿瘤新生,指出以bendamustine治疗的病患发生癌前病变与恶性疾病。Bendamustine与这些疾病的关联尚未确定。其它状况包括骨髓造血不良症候群、骨髓增生性疾病、急性骨髓性白血病、支气管癌。
  
  对于不良反应,更新的资料包括非出血不良反应,根据器官系统分类(N = 176),发生在5%以上以bendamustine治疗的NHL病患。根据器官系统分类,一般不良反应恶心(75%、胃肠道)、疲劳(57%、全身)、食慾缺乏(23%、代谢与营养)、咳嗽(22%、呼吸道)、头痛(21%、神经系统)、疹子(16%、皮肤与皮下组织);也提到血液实验室异常:等级3至4疾病包括淋巴球 (94%)、白血球(56%)、血色素(11%)、嗜中性白血球(60%)与血小板(25%)值降低。最常见的严重不良反应包括发热性嗜中性球减少症以及肺炎。
  
  有关特定类型病患的新增信息,包括年长(>65岁)与年轻病患(< 65岁)的效果相似,两性之间的效果也没有差异。这些病患包括CLL与NHL两种研究。

FDA Safety Changes: Clolar, Precedex, Treanda

By Jill Taylor
Medscape Medical News

January 2, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions for clofarabine injection, dexmedetomidine HCl injection, and bendamustine HCl injection.

Clofarabine (Clolar) Linked to Increased Risk for Infection, Fetal Harm During Pregnancy

On October 17, 2008, the FDA approved safety labeling revisions for the purine nucleoside metabolic inhibitor clofarabine (Clolar injection for intravenous use; Genzyme Corp) to provide new or updated information regarding monitoring of complete blood and platelet counts, an increased risk for infection, monitoring for tumor lysis syndrome and cytokine release, observed elevations in hepatobiliary enzyme levels, potential risk for hepatotoxicity in patients who have undergone hematopoietic stem-cell transplantation, and potential fetal harm during pregnancy.

Clofarabine injection is indicated for the treatment of pediatric patients (ages 1 - 21 years) with relapsed or refractory acute lymphoblastic leukemia after at least 2 previous regimens.

Additional language was included under all warnings and precautions. Hematologic toxicity now includes a statement to monitor blood counts and platelet counts during therapy with clofarabine intravenous injection. Patients with infections should be monitored for signs and symptoms of infection and treated promptly.

For hyperuricemia (tumor lysis syndrome), clinicians are instructed to provide intravenous infusion fluids throughout the 5 days of clofarabine treatment to reduce the effects of tumor lysis syndrome and other adverse events and to administer allopurinol if hyperuricemia is expected.

Clinicians are also instructed to reinstitute clofarabine treatment at a 25% dose reduction for patients regaining stability after systemic inflammatory response syndrome or capillary leak syndrome and organ dysfunction, and the use of a prophylactic steroid to prevent signs and symptoms of cytokine release is suggested. Data regarding elevations in hepatobiliary enzyme levels are now addressed in the section on adverse reactions.

For hepatic and renal impairment, a potential increased risk for hepatotoxicity suggestive of veno-occlusive disease after clofarabine administration (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2) is noted for patients who have previously undergone hematopoietic stem-cell transplantation. Severe hepatotoxic events are also noted for an ongoing phase 1/2 combination study in pediatric patients with relapsed or refractory acute leukemia.

Clofarabine may also cause fetal harm when administered to a pregnant woman, according to the updated label.

For adverse reactions, data have been updated to include the most commonly reported (? 5% overall) adverse events by organ system class (N = 115; pooled analysis). The least common adverse reactions in 1% to 4% of patients with acute lymphoblastic leukemia or acute myelogenous leukemia were added, including cecitis and pancreatitis; hyperbilirubinemia; hypersensitivity; bacterial infection; bacteremia; fungal infection; sepsis; virus infection; pneumonia; sinusitis; increased blood creatinine levels; mental status change; and pulmonary edema.

The incidence of treatment-emergent laboratory abnormalities after clofarabine administration may occur; the abnormalities occurring in more than half of patients at grade 3 or higher are leukopenia (87.7%), lymphopenia (82.3%), thrombocytopenia (79.8%), anemia (75.4%), and neutropenia (63.7%).

Adverse reactions noted from postmarketing experience include bone marrow failures, serious hepatotoxic adverse reactions of veno-occlusive disease in adult patients after hematopoietic stem-cell transplantation, and occurrences of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients treated with concomitant medications (allopurinol or antibiotics).

The safety and effectiveness of clofarabine have not been established in geriatric patients 65?years and older.

Dexmedetomidine HCl (Precedex) Adds Counseling Information, New Data for Procedural Sedation

On October 17, 2008, the FDA approved safety labeling revisions for dexmedetomidine HCl (Precedex injection; Hospira, Inc) to include counseling information and data for procedural sedation, carcinogenesis, mutagenesis, and impairment of fertility.

Dexmedetomidine is a relatively selective alpha2-adrenergic agonist indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive-care setting and sedation of nonintubated patients before and/or during surgical and other procedures.

According to patient counseling information, patients who receive an infusion for more than 6?hours should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours or symptoms that may occur within 48 hours such as weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness, or lightheadedness.

The section for warnings and precautions has been amended to note that withdrawal symptoms were not seen after discontinuation of short-term (< 6 hours) infusions of dexmedetomidine. Data regarding adverse reactions during procedural sedation were derived from 2?trials in 318 adult patients, for which hypotension (54%), bradycardia (14%), and dry mouth (3%) were the most common adverse reactions.

Data regarding the use of dexmedetomidine for procedural sedation in geriatric patients indicated that hypotension occurred at a higher incidence in patients 65 years or older (72%) and in those 75 years or older (74%) vs patients younger than 65 years. For patients older than 65?years, a recommendation was added for a reduced loading dose of 0.5 μg/kg given for 10?minutes and a reduction in the maintenance infusion.

Bendamustine (Treanda) Receives Additional Warnings and Precautions

On October 31, 2008, the FDA approved safety labeling revisions for bendamustine (Treanda; Cephalon, Inc) for injection, an alkylating drug indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Safety changes for warnings and precautions included data for myelosuppression from 2 studies in which 98% of patients had grade 3 to 4 myelosuppression, and 2% of patients died of myelosuppression-related adverse reactions (neutropenic sepsis, diffuse alveolar hemorrhage with grade 3 thrombocytopenia, pneumonia from opportunistic infection).

Data regarding skin reactions were added to warnings and precautions, for which 1 case of toxic epidermal necrolysis occurred in a study of bendamustine (90 mg/m2) in combination with rituximab. Toxic epidermal necrolysis has been reported for rituximab, but the relationship of toxic epidermal necrolysis to bendamustine has not been determined.

Other malignant neoplasms were added to warnings and precautions, noting reports of premalignant and malignant diseases that developed in patients treated with bendamustine. The link of bendamustine with these diseases has not been determined. Conditions included myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma.

For adverse reactions, data have been updated to include nonhematologic adverse reactions occurring in 5% or more of patients with NHL treated with bendamustine by organ system class (N = 176). Common adverse reactions by organ system class included nausea (75%, gastrointestinal

    



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