作者：Jill Taylor 齣處：WebMD醫學新聞 　　January 2 2009 — 美國食品藥物管理局(FDA)核準clofarabine注射劑、dexmedetomidine HCl注 FDA安全標示變更：Clolar、Precedex、Treanda - 趣味新聞網

發表日期 2009-01-13T08:48:16+08:00

     作者：Jill Taylor
齣處：WebMD醫學新聞

January 2, 2009 — 美國食品藥物管理局(FDA)核準clofarabine注射劑、dexmedetomidine HCl注射劑、與bendamustine HCl注射劑等三項製劑的安全標示變更。

【Clofarabine (Clolar) 與增加感染風險、孕婦緻命傷害有關】
2008年10月17日，FDA核準嘌呤核苷代謝抑製劑 clofarabine (Clolar 靜脈注射劑，Genzyme公司製造)變更安全標示，以提供新版的全血與血小闆計數的資訊、增加感染風險、監控腫瘤溶解癥候群以及細胞激素釋齣，觀察肝膽酵素值增加、接受過造血乾細胞移植病患之肝毒性潛在風險、懷孕時的潛在緻命風險。

Clofarabine注射劑用於治療小兒(年齡1至21歲)病患，於至少兩次處方之後復發或者難治型急性淋巴性白血病。有多種語言介紹全部的警語和注意事項。血液毒性包括以clofarabine靜脈注射治療期間需監控血球與血小闆數量。感染病患必須監控感染的徵兆與癥狀，並且適當治療。

對於高尿酸血癥(腫瘤溶解癥候群)，醫師需指示在整個5天的clofarabine治療中提供靜脈液體輸注，以減少腫瘤溶解癥候群以及其他不良反應的效果，且若預期有高尿酸時，可給予allopurinol。

病患全身發炎反應癥狀、微血管滲漏癥狀與器官功能不佳恢復穩定之後，醫師也須指示以減量25%來恢復clofarabine治療，並使用預防性類固醇，以避免細胞激素釋齣的徵兆與癥狀。有關肝膽酵素增加的資訊現在登載於不良反應段落。

對於肝腎不佳者，曾經接受造血乾細胞移植的病患，併用clofarabine (40 mg/m2) 、etoposide (100 mg/m2)和cyclophosphamide (440 mg/m2)者，潛在增加靜脈阻塞性疾病的肝毒性風險。正在進行中的1/2期小兒復發或難治型急性白血病患者之閤併治療研究，也指齣嚴重的肝毒性事件。

根據新版標簽，Clofarabine也可能會引起孕婦的緻命傷害。

至於不良反應，更新的資料包括根據器官係統分類(N = 115;匯整分析)最常被報告的(整體≧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見(1%-4%病患)的不良反應包括盲腸炎和胰髒炎；高膽紅素血癥；過敏；細菌感染；菌血癥；黴菌感染；敗血癥；病毒感染；肺炎；鼻竇炎；血中肌酸酐值增加；心智狀態改變；肺水腫。

給予clofarabine治療後引起的實驗室異常也會發生；超過半數病患發生等級3以上的異常，包括白血球減少(87.7%)、淋巴球減少 (82.3%)、血小闆減少(79.8%)、貧血(75.4%)以及嗜中性白血球減少(63.7%)。

上市後的不良反應事件，包括骨髓衰竭、造血乾細胞移植後成年病患之嚴重靜脈阻塞性疾病的肝毒性不良反應，併用allopurinol或者抗生素治療的病患也曾發生過史蒂文-強生癥候群與毒性錶皮壞死。

65歲以上年長病患的clofarabine安全性與有效性尚未建立。

【Dexmedetomidine HCl (Precedex) 加入諮商訊息、手術鎮靜的新資料】
2008年10月17日，FDA核準dexmedetomidine HCl (Precedex 注射劑，Hospira公司製造)的安全標示變更，以包括諮商訊息以及手術鎮靜、緻癌、發生突變與不孕癥的資料。

Dexmedetomidine是相對選擇性的alpha2腎上腺素緻效劑，用於加護病房初次插管與機械輔助呼吸病患之鎮靜，也用於術前和/或術中非插管病患之鎮靜。

根據病患諮商資訊，接受輸注超過6小時的病患需被告知，48小時後可能會有緊張、燥動和頭痛，或者在48小時內可能發生虛弱、混亂、過度齣汗、體重減輕、腹痛、渴求鹽分、腹瀉、便秘、頭暈或頭昏眼花。

警告與注意事項也修改指齣，短期輸注(< 6小時) dexmedetomidine之後未發現有戒斷癥狀。手術中鎮靜的不良反應資料來自兩個試驗、318名成人病患，包括低血壓(54%)、心搏徐緩(14%)以及口乾(3%)等最常見。

dexmedetomidine用於年長病患的手術鎮靜資料指齣，65歲以上病患發生低血壓比率(72%)、75歲以上病患發生低血壓比率(74%)高於65歲以下病患。對於65歲以上病患，另一個建議是降低起始劑量為0.5 μg/kg、給予10分鍾，並且降低維持輸注。

【Bendamustine(Treanda) 新增警告與注意事項】
2008年10月31日，FDA核準bendamustine (Treanda，Cephalon公司製造)注射劑的安全標示變更，這是一種烷化基藥劑，用於治療使用rituximab或者含rituximab處方治療6個月仍有惡化之慢性淋巴球性白血病(CLL)以及無痛的B細胞非何傑金氏淋巴瘤(NHL)。

警告與注意事項的安全標示變更包括來自兩個試驗的骨髓抑製資料，其中98%的病患有等級3至4骨髓抑製，2%病患死於骨髓抑製相關不良反應(嗜中性白血球缺乏之敗血癥、彌漫性肺泡齣血與等級3血小闆過低、伺機性感染引起的肺炎。

有關皮膚反應的資料也加入警告與注意事項，一個是毒性錶皮壞死案例，發生於併用bendamustine (90 mg/m2)與rituximab的研究。Rituximab曾有毒性錶皮壞死報告，但是尚未確認毒性錶皮壞死與bendamustine的關聯。

警告與注意事項也增加其他惡性腫瘤新生，指齣以bendamustine治療的病患發生癌前病變與惡性疾病。Bendamustine與這些疾病的關聯尚未確定。其他狀況包括骨髓造血不良癥候群、骨髓增生性疾病、急性骨髓性白血病、支氣管癌。

對於不良反應，更新的資料包括非齣血不良反應，根據器官係統分類(N = 176)，發生在5%以上以bendamustine治療的NHL病患。根據器官係統分類，一般不良反應惡心(75%、胃腸道)、疲勞(57%、全身)、食慾缺乏(23%、代謝與營養)、咳嗽(22%、呼吸道)、頭痛(21%、神經係統)、疹子(16%、皮膚與皮下組織)；也提到血液實驗室異常：等級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%)與血小闆(25%)值降低。最常見的嚴重不良反應包括發熱性嗜中性球減少癥以及肺炎。

有關特定類型病患的新增資訊，包括年長(>65歲)與年輕病患(< 65歲)的效果相似，兩性之間的效果也沒有差異。這些病患包括CLL與NHL兩種研究。

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 tract), fatigue (57%, general), anorexia (23%, metabolism and nutrition), cough (22%, respiratory tract), headache (21%, nervous system), and rash (16%, skin and subcutaneous tissue). Hematologic laboratory abnormalities were also added: patients with grade 3 to 4 disease had decreased levels of lymphocytes (94%), leukocytes (56%), hemoglobin (11%), neutrophils (60%), and platelets (25%). The most common serious adverse reactions included febrile neutropenia and pneumonia.

Information added to address specific patient populations included similar efficacy between geriatric patients (> age 65 years) and younger patients (< age 65 years) and no difference in efficacy between the sexes. Both of these patient populations were included in CLL and NHL studies.

Clolar Prescribing Information

Precedex Prescribing Information

Treanda Prescribing Information

[ 本帖最後由 goodcat1111 於 2009-1-15 00:23 編輯 ]

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