ZELBORAF(vemurafenib)片-美国FDA2011年8月17日批准治疗转移黑色素瘤
美国初始批准：2011
适应证和用途
ZELBORAF™是一种激酶抑制剂适用于有不可切除或转移黑色素瘤有用FDA-批准的检验检测BRAFV600E突变患者的治疗。(1, 5.10)
使用限制：有野生型BRAF黑色素瘤患者中建议不使用ZELBORAF。(5.10, 14)
剂量和给药方法
（1）推荐剂量：960 mg口服bid。(2.1)
（2）接近12小时间隔给予ZELBORAF有或无进餐。 (2.1)
（3）应用一杯水完整吞服ZELBORAF。不应咀嚼或压碎ZELBORAF。(2.1)
（4）症状性不良药物反应的处理可能需要减低剂量，中断治疗，或终止ZELBORAF治疗。不建议减低剂量导致剂量低于480 mg。(2.2)
剂型和规格
膜衣片：240 mg(3)
Manufacturer:
Genentech, Inc.
Pharmacological Class:
Kinase inhibitor.
Active Ingredient(s):
Vemurafenib 240mg; tabs.
Indication(s):
Treatment of unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
Pharmacology:
Vemurafenib is a low molecular weight inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAFV600E.
Clinical Trials:
The efficacy and safety of vemurafenib in patients with treatment naive, BRAFV600E mutation-positive unresectable or metastatic melanoma as detected by the cobas 4800 BRAF V600 Mutation Test were assessed in an international, randomized trial. This trial involved 675 patients who were given either vemurafenib 960mg by mouth twice daily or dacarbazine 1000mg/m2 IV on Day 1 every 3 weeks. The major efficacy outcome measures were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate. The median survival of patients who received vemurafenib has not been reached (77% still living) while the median survival for those who received dacarbazine was 7.9 months (64% still living). The median PFS for vemurafenib was 5.3 months compared to 1.6 months for dacarbazine. The overall response rate in the vemurafenib arm was 48.4% (95% CI: 41.6%, 55.2%) compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm.
Legal Classification:
Rx
Adults:
Swallow whole with water. Take in the AM and PM (approx. 12 hours apart). ≥18 years: 960mg twice daily; until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see literature. Dose reductions <480mg twice daily: not recommended.
Children:
<18 years: not recommended.
Warnings/Precautions:
Not for use in wild-type BRAF melanoma. Confirm BRAFV600E mutation-positive melanoma with FDA-approved test before treating. Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65 years, prior skin cancer, chronic sun exposure; if occurs, do excision and continue without dose adjustment. Do dermatologic evaluation before therapy, every 2 months during, and consider monitoring 6 months after. Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended. Monitor electrolytes before therapy and after dose adjustments. Monitor ECG at Day 15 of treatment, monthly during the 1st 3 months, then every 3 months thereafter, or more as needed. If QTc >500ms, interrupt therapy, correct electrolytes, and control cardiac risk factors. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before therapy and monthly, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat. D); avoid. Use adequate contraception during therapy and for at least 2 months after. Nursing mothers: not recommended.
Interaction(s):
Concomitant CYP3A4, CYP1A2 or CYP2D6 substrates with narrow therapeutic indices: not recommended; if CYP1A2 or CYP2D6 substrates unavoidable, consider dose reduction of substrates. Caution with concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin) or inducers (eg, phenytoin, rifampin). May potentiate warfarin; monitor INR.
Adverse Reaction(s):
Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; cuSCC, severe hypersensitivity or dermatologic reactions (discontinue if occurs), prolonged QTc, uveitis.
How Supplied:
Tabs—120
Last Updated:
11/11/2011
美国FDA2011年8月17日批准Zelboraf(vemurafenib)片治疗转移黑色素瘤
美国FDA2011年8月17日批准Plexxikon Inc. HOFFMAN-LA ROCHE公司Zelboraf(vemurafenib)片治疗转移黑色素瘤。
美国食品和药品监督管理局批准Zelboraf(vemurafenib)，药物治疗后期(转移)或不可切除黑色素瘤，最危险的皮肤癌类型患者。
Zelboraf是特别适用于治疗肿瘤表达基因突变被称BRAFV600E黑色素瘤患者。在用FDA批准的诊断黑色素瘤该突变检验阴性患者中尚未研究药物。
FDA的药物评价和研究中心肿瘤药品办公室主任Richard Pazdur, M.D.说“对有后期黑色素瘤患者今年是重要一年。Zelboraf是证实改善总生存的第二个被批准新抗癌药物” “3月我们批准了Yervoy(ipilimumab)，为后期黑色素瘤另一个新治疗，接受药物后也显示延长患者生存。”
Zelboraf的评审是在FDA的优先审评计划对治疗中有重要进展或没用适当治疗的药物提供加快6个月审评药物。在药物目标日期2011年10月28日前正在批准Zelboraf和其伴随的BRAF V600E检验而伴随诊断目标日期是2011年11月12日。
在一项单个675例既往未接受治疗有BRAF V600E突变后期黑色素瘤患者国际试验确定Zelboraf'的安全性和疗效。患者被赋予接受或Zelboraf或达卡巴嗪 [dacarbazine]，另一种抗-癌治疗。试验被设计成测量总生存(患者开始治疗和死亡间时间长度)。接受Zelboraf患者未曾达到中位生存(治疗后患者生存时间长度)(77%仍生存)而接受达卡巴嗪患者中位生存为8个月(64%仍生存)。
FDA的设备和放射健康部中的在体外诊断设备评价和安全性办公室主任Alberto Gutierrez, Ph.D说：“今天批准的Zelboraf和cobas检验是发展伴随诊断和使用以保证患者以安全方式被暴露至高度有效，更个体化治疗一个大实例。”
FDA批准cobas 4800 BRAF V600突变检验是根据来自临床研究的数据也评价Zelboraf的安全性和有效性。收集患者的黑色素瘤组织样品为检验突变。
