皮肤癌新药ZOLINZA(VORINOSTAT)CAPSULE ORAL获FDA批准上市。为治疗皮肤T细胞淋巴瘤（CTCL），该药可用于皮肤癌持续恶化、其他药物治疗期间或以后复发。 通用名：伏立诺他胶囊 英文名称：vorinostat 商品名： Zolinza 规格：100mg/粒 标准来源：美国 作用机制 组蛋白去乙酰酶HDAC1，HDAC2和HDAC3(类别I)和HDAC6(类别II)在纳摩尔浓度(IC50<86 nM)时伏立诺他抑制酶活性。这些酶催化从蛋白质，包括组蛋白和转录因子的赖氨酸残基上去除乙酰基。在有些癌细胞中，有HDACs过表达，或异常补充HDACs至致癌转录因子致核心核小体组蛋白的低乙酰化。组蛋白的低乙酰化伴随压缩的染色质结构和基因转录的遏制。HDAC活性的抑制允许对组蛋白赖氨酸残基上积蓄乙酰基导致打开染色质结构和转录激活。在体外，伏立诺他致乙酰化组蛋白的积蓄和诱发细胞周期停止和/或某些转化细胞凋亡。尚未完全描述伏立诺他抗肿瘤作用机制的特征。 适应证和用途 ZOLINZA是一种组蛋白去乙酰酶(HDAC)抑制剂适用为： （1）有皮肤T细胞淋巴瘤(CTCL)患者已进展，持续或复发疾病用两种全身治疗或后皮肤的表现的治疗。 剂量和给药方法 （1）1400mg口服每天1次有食物。 （2）如患者对治疗不能耐受，剂量可能被减低至每天1次300mg与食物口服。如必要时，剂量可能进一步减低至300 mg每天1次有食物每周共连续5天。 剂型和规格 （1）胶囊：100mg 禁忌证 （1）严重肝损伤 警告和注意事项 （1）曾报道肺栓塞和深静脉血栓形成。监视患者相关的体征和症状。 （2）曾发生剂量相关血小板减少和贫血和可能需要调整剂量或终止。 （3）曾报道胃肠道功能紊乱(如，恶心，呕吐和腹泻)。患者可能需要止吐药，止泻药和液体和电解质替代(防止脱水)。 （4）有轻度和中度肝受损患者应谨慎治疗。 （5）曾观察到高血糖。调整饮食和/或可能需要治疗葡萄糖增加。 （6）在基线时和治疗期间定期监视电解质。 （7）监视血细胞计数和化学测试，包括电解质，葡萄糖和血清肌酐，治疗的头2个月期间每2周和其后每月。 （8）曾报道ZOLINZA和其他HDAC抑制剂同时使用(如，丙戊酸[valproic acid])严重血小板减少和胃肠道出血。监视血小板计数。 （9）当妊娠妇女给药时可能发生胎儿危害。应忠告妇女对胎儿潜在危害。 不良反应 （1）最常见不良反应(发生率≥20%)是腹泻，疲乏，恶心，血小板减少，食欲不振和味觉障碍。 药物相互作用 （1）香豆素衍生物抗凝剂：同时使用曾观察到延长凝血酶原时间和国际标准化比值。仔细监视。 供应/贮存和处置 ZOLINZA胶囊，100mg，是白色，不透明硬明胶胶囊在胶囊体上用黑色墨汁在半径棒内在“100mg”上印有“568”。供应如下： NDC 0006-0568-40。每瓶含120粒胶囊. 贮存和处置 贮存在20-25°C(68-77°F)，外出允许15-30°C(59-86°F)间。[见USP控制室温] 应考虑适当处置和遗弃抗癌药物的方法。这个题目曾发表几个指导原则。1-5对指导原则推荐所有方法是必须或适当没有一般协议。 ZOLINZA(伏立诺他vorinostat)胶囊不应被打开或粉碎。应避免皮肤或粘膜直接接触ZOLINZA胶囊内粉，如果发生这类接触，如参考文献概述彻底冲洗。人员应避免暴露于粉碎和/或破坏的胶囊[见非临床毒理学]。 Zolinza (vorinostat, MK0683) ZOLINZA Rx Generic Name and Formulations: Vorinostat 100mg; caps. Company: Merck & Co., Inc Indications for ZOLINZA: Refractory cutaneous T-cell lymphoma. Adult: Take with food. Swallow whole. 400mg once daily. If not tolerated, may reduce to 300mg once daily, then to 300mg once daily 5 days/week if needed. Continue until disease progression or not tolerated. Children: <18yrs: not recommended. Warnings/Precautions: Renal or hepatic impairment. Monitor for DVT, pulmonary embolism. Correct electrolyte disturbances before starting therapy. Maintain adequate hydration. Diabetes. Monitor CBC, platelets, blood glucose, serum creatinine, electrolytes (esp. potassium, calcium, magnesium) every 2 weeks for 1st 2 months, then monthly. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Increased risk of thrombocytopenia and GI bleed with other HDAC inhibitors (eg, valproic acid). Concomitant warfarin: monitor PT, INR. Pharmacological Class: Histone deacetylase inhibitor. Adverse Reactions: GI upset, fatigue, chills; thrombocytopenia, anemia (may need to modify dose or discontinue); anorexia, dysgeusia, pulmonary embolism, DVT, hyperglycemia. How Supplied: Caps—120 On October 6, 2006, the U.S. Food and Drug Administration granted approval to vorinostat (Zolinza™, Merck & Co., Inc.), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The major trial supporting approval was a single-arm open-label trial conducted at 18 centers in the U.S. and Canada that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). All patients received vorinostat at a dose of 400 mg once daily which could be reduced for toxicity to 300 mg orally daily or 300 mg orally five days a week. The median age of patients was 61 years. Sixty-one patients (82 percent) had stage IIB or higher CTCL and 30 patients (41 percent) had Sézary syndrome. The median duration of protocol treatment was 118 days. Skin disease response was assessed using a Severity Weighted Assessment Tool (SWAT). This tool calculated an overall score based on the percentages of the total body surface area involved with patch, plaque, or tumor lesions, with weighting of each by factors of one, two, and four, respectively. Response was defined as a 50 percent or greater decrease in the SWAT score and disease progression as a 50 percent increase in the score from the nadir. In this study, 30 percent experienced responses; the estimated median response duration was 168 days and the median time to tumor progression was 202 days An additional single center study enrolled 33 patients with similar baseline and demographic features as in the major trial. Thirteen of the 33 were treated at the same dose of 400 mg/day. The responses in these 13 patients were similar to those observed in the major efficacy trial. Adverse events (AEs) were reported irrespective of the relation to the study drug. In the major efficacy trial, the most common clinical AEs of any grade were diarrhea (51 percent), fatigue (51 percent), nausea (43 percent), and anorexia (27 percent). Grade 3, 4, or 5 clinical AEs included fatigue (7 percent), and pulmonary embolism (5.4 percent). Chemistry laboratory abnormalities observed were hypercholesterolemia (66 percent), hypertriglyceridemia (66 percent), hyperglycemia (64 percent), and increased creatinine (45 percent). Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine. Hematologic laboratory abnormalities were anemia (54 percent), thrombocytopenia (42 percent), low white blood cell (WBC) count (24 percent), and low neutrophil count (14 percent). Most of these were of grades 1 or 2 in severity. For safe use of vorinostat, patients must be kept well hydrated and blood counts and chemistry tests should be obtained every two weeks during the first two months of therapy and monthly thereafter. Adjustments in diet and drugs may be necessary in patients with diabetes. ——美国FDA批准Zolinza胶囊为治疗皮肤癌以及皮肤T淋巴细瘤 注：本品在2006年被批准，在此作为表观遗传学蛋白质家族：对药物发现一个新前沿一文中被FDA批准的实例。 2006年10月26日美国食品和药品监督管理局(FDA)批准Zolinza(伏立诺他vorinostat)胶囊为治疗皮肤T细胞淋巴瘤(CTCL)，一类皮肤癌，将被用于当疾病持续，变坏，或期间或用其他药物治疗后返回。 Zolinza被批准作为FDA的孤儿药物程序的一部分，提供公司财政奖励开发对一年影响少于200,000美国患者疾病的药物。在美国每年每1百万人约有3人被诊断为皮肤T细胞淋巴瘤(CTCL)。有CTCL大多数人是男性平均年龄50岁。 FDA的药物评价和研究中心主任Steven Galson，M.D.说：“这个批准是现代研究集中提供处方者对所有癌症类型，包括那些影响相对少的患者，安全和有效治疗效益的另一个实例”。. 在两项临床研究有107例皮肤T细胞淋巴瘤(CTCL)患者在其疾病其他治疗复发后接受Zolinza发展Zolinza的安全性和有效性的证据。一个反应，通过在一个计分计分皮肤病变，在30%患者接受Zolinza和持续平均168天确定。最常见严重不良事件是肺栓塞(肺中血凝固)，脱水，深静脉血栓形成和贫血。最常见其他不良事件是胃肠道症状(包括腹泻，恶心，食欲不振，呕吐和便秘); 疲乏; 畏寒；和味觉障碍。. 在妊娠妇女尚未研究Zolinza，但动物研究的结果提示当妊娠期间给药药物可能致胎儿危害。 Zolinza由在加拿大，安大略省米西索加， Pantheon公司制造，为新泽西州白宫站Merck & Co.，公司。 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=CD86EE78-2781-468B-930C-3C4677BCC092 https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=9465