亨廷顿舞蹈病治疗药Xenazine通过FDA批准 
  
FDA近日批准了Prestwick公司用于治疗亨廷顿舞蹈病（Huntington’s Disease）的药物Xenazine (tetrabenazine)，这是首个在美国获准治疗该症的治疗药。它获准的依据是一项III期临床实验结果显示，这种具有选择性作用功能的多巴胺耗竭治疗药疗效显著，并且安全性和耐受性良好。
 
Prestwick表示Xenazine将在一项经FDA批准的风险评估项目下进行销售，这个评估项目主要防止该药有可能导致的抑郁和自杀倾向等不良反应。此前，该药也已被指定为罕见病治疗药，它在美国具有7年的独家销售权。
 
该药获准后在美国受到欢迎，当地约有3万名患者深受这种疾病的困扰。美国遗传性疾病基金会表示，舞蹈病不仅给患者带来不便，它还会严重影响患者在步行、说话、工作和看电视等各方面的能力。 目前，该药已在其他14个国家通过批准，新近获准的国家包括荷兰、瑞典和瑞士。

XENAZINE

Indication(s):

Huntington's chorea.

Pharmacology:

Huntington's disease is a progressive neurodegenerative disorder characterized by chorea (involuntary movements), rigidity, and changes in mood, cognition, and functional capacity over time.

Clinical Trials:

A randomized, double-blind, placebo-controlled trial was conducted in 84 ambulatory patients with Huntington's chorea. The trial included a 7-week dose titration period followed by a 5-week maintenance period and a 1-week washout period. The primary endpoint was the Total Chorea Score, which rates the chorea on a scale from 0 to 4 in seven different parts of the body. Total scores range from 0 to 28. During maintenance therapy, the Total Chorea Scores in the drug treatment group declined by about 5 units compared to 1.5 units in the placebo group, a significant effect. One week after discontinuing the study medication, the Total Chorea Scores returned to baseline. Patients given tetrabenazine were more likely to experience an improvement in chorea scores. A Physician-rated Global Impression favored tetrabenazine statistically. In general, measures of functional capacity and cognition showed no difference between tetrabenazine and placebo.

Legal Classification:

Rx

Adults:

Individualize. Initially 12.5mg once daily in the AM, then 12.5mg twice daily after one week. Titrate slowly at weekly intervals by 12.5mg.Doses of 37.5–50mg/day should be given in a 3 times/day regimen, max 25mg/dose. Patients who require doses ≥50mg/day should be genotyped for CYP2D6. Poor metabolizers (CYP2D6): max 25mg/dose and 50mg/day; extensive and intermediate metabolizers: max 37.5mg/dose and 100mg/day. Concomitant strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine): reduce tetrabenazine dose by 1/2; moderate to weak CYP2D6 inhibitors: not evaluated. Retitrate if therapy interrupted for more than 5 days.

Children:

Not recommended.

Contraindication(s):

Depression. Suicidal ideation. Hepatic impairment. Concomitant monoamine oxidase inhibitors (MAOIs). During or within 20 days of stopping reserpine.

Warnings/Precautions:

Avoid in congenital long QT syndrome or history of cardiac arrhythmias. Bradycardia. Hypokalemia. Hypomagnesemia. Recent MI. Unstable heart disease. Cardiovascular disease. History of depression, suicidal ideation, or breast cancer. Monitor for depression, emotional lability, akathisia. Poor metabolizers (CYP2D6). Reevaluate periodically. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interaction(s):

See Contraindications. Avoid other drugs that can cause QT prolongation (eg, chlorpromazine, thioridazine, ziprasidone, moxifloxacin, quinidine, procainamide, amiodarone, sotalol). Potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Increased risk of neuroleptic malignant syndrome, extrapyramidal syndrome with neuroleptics, dopamine antagonists. Additive CNS depression with alcohol, other CNS depressants.

Adverse Reaction(s):

Sedation, fatigue, insomnia, depression, dysphagia, akathisia, nausea, parkinsonism, QTc prolongation, orthostatic hypotension, elevated serum prolactin; rarely: neuroleptic malignant syndrome, tardive dyskinesia, extrapyramidal effects.

How Supplied:

Tabs—112

Last Updated:

1/23/2009
Xenazine(四苯喹嗪(tetrabenazine))
批准日期：2008年8月15日；公司：Prestwick Pharmaceuticals, Inc.

一般描述：
XENAZINE (tetrabenazine)是一种口服给药单胺耗竭剂。相对分子量317.43，pKa为6.51。四苯喹嗪是hexahydro-dimethoxy-benzoquinolizine衍生物和有下列化学名：顺外消旋 –1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2Hbenzo[a]quinolizin-2-one。经验方程式C19H27NO3 结构式如下：

适应证和用途：
XENAZINE适用于伴亨廷顿氏病舞蹈的治疗。

剂量和给药方法：
伴亨廷顿氏病舞蹈患者中，适当给予XENAZINE涉及小心滴定调整治疗以确定对每例患者个体化剂量。当首次开处方时，XENAZINE治疗应在几周内缓慢滴定调整以允许确定为慢性使用剂量减轻舞蹈又很好耐受。对许多患者不推荐用超过100 mg/day剂量。

禁忌证：
积极自杀患者或未治疗或不适宜治疗的抑郁症患者禁忌用XENAZINE。肝功能受损患者禁忌用XENAZINE。服用单胺氧化酶抑制剂患者禁忌XENAZINE。服用利血平(reserpine) 患者禁忌XENAZINE。在开始XENAZINE前至少停用利血平20天。

不良反应：
最常报道不良事件(超过10%，和大于安慰剂至少5%)是镇静/嗜睡 (31%相比安慰剂3%)、疲乏(22%相比安慰剂13%)、失眠(22%相比安慰剂0%)、抑郁(19%相比安慰剂0%)、静坐不能(19%相比安慰剂0%)、和恶心 (13%相比安慰剂7%)。

黑框警告：
抑郁和自杀倾向
亨廷顿氏病患者中XENAZINE可增加抑郁和自杀的念头和行为(自杀倾向)的风险。任何人考虑使用XENAZINE必须权衡抑郁和自杀倾向风险与为控制舞蹈运动症状临床需求。应伴治疗严密观察患者抑郁、自杀倾向出现或恶化，或不寻常行为变化。应告知患者，他们的看护，和家庭抑郁和自杀倾向的风险和应教导他们关注的行为并及时报告治疗医生。应特别留意正在治疗患者有抑郁史或既往自杀意向或观念，增加亨廷顿氏病频率。积极自杀患者，和未治疗过或不适当治疗抑郁的患者禁忌用XENAZINE。