POTIGA(ezogabine 依佐加滨)片剂是一种钙通道开放剂，获美国FDA批准适用在年龄18岁和以上患者作为部分发作的癫痫发作的辅助治疗
商用名：Potiga
通用名：Retigabine
中文名：依佐加滨
活性成分：EZOGABINE
分子式：C16H18FN3O2
分子量：303.331 g/mol
给药途径：口服
批准日期： 2011年6月13日；公司：GlaxoSmithKline和Valeant Pharmaceuticals International

概述
2011年6月13日，美国FDA批准依佐加滨Potiga（ezogabine）片剂用于成人部分性癫痫发作的辅助治疗，该药是第一个治疗癫痫的神经元钾通道开放剂。
Potig(Ezogabine Tablets)获准用于局部癫痫发作，这是一种最常见类型癫痫。癫痫属于脑部疾病，癫痫患者大脑中的神经细胞出现异常或活动过度。部分性发作癫痫仅影响大脑有限或局部区域，但会扩散到大脑的其它部分。癫痫发作可引起广泛症状，包括重复的肢体运动（痉挛）、行为异常、意识丧失和抽搐。
使用现有的治疗手段约有三分之一癫痫患者病情无法获得满意控制，因此能为患者提供多种治疗选择就显得十分重要。也就是说本品对癫痫症状未能获得控制的患者带来了希望。
Potiga是首个神经元钾通道开放制剂。美国食品和药品监督管理局批准抗惊厥药Potiga(ezogabine)作为癫痫患者局部癫痫的辅助用药，其活性成分于今年3月份获得欧洲药品管理局的批准，将于年底进入美国市场。癫痫患者有复发癫痫倾向，由突发脑电活动诱发，导致大脑超负荷。脑细胞间的信息传播系统出现短暂紊乱。局部癫痫仅影响大脑部分区域，但可传导至大脑其他部位。

POTIGA (依佐加滨 ezogabine)片  供口服使用
美国初次批准：2011
适应症和用途
POTIGA是一种钙通道开放剂适用在年龄18岁和以上患者作为部分发作的癫痫发作的辅助治疗
剂型和规格
片，50mg、200mg、300mg和400mg
用法用量
1.每天分3次给药，有或无食物。
2.初始剂量应是100mg每天3次(300mg/天)共1周。
3.通过增加剂量在每周间隔不超过150mg/天递增调整至维持剂量。
4.优化有效剂量间200mg每天3次(600mg/天)至400mg每天3次(1,200mg/天)。
5.在对照临床试验中，400mg每天3次(1,200mg/天)与300mg每天3次(900mg/天)比较显示有限的改善，增加不良反应和终止药物。
6.当终止POTIGA时，逐渐减低剂量跨越时期至少3周。
7.对老年人患者和有中度至严重肾或肝受损患者许亚萍调整剂量。
不良反应
最常见不良反应(发生率≥4%和接近安慰剂2倍)为头晕，嗜睡，疲乏，混乱状态，眩晕，震颤，异常协调, 复视，注意障碍，记忆障碍，虚弱，视力模糊，步态不稳，失语症，构音障碍，和平衡障碍。
药物相互作用
1.Ezogabine血浆水平可能减低通过同时给予苯妥英[phenytoin]或卡马西平[carbamazepine]。当添加苯妥英或卡马西平时应考虑增加POTIGA剂量。
2.Ezogabine的N-乙酰代谢物可能抑制地高辛的肾清除率，一种P-糖蛋白底物。监视地高辛水平。
特殊人群中使用
妊娠：根据动物资料，可能致胎儿危害。可得到妊娠注册。
儿童使用：尚未确定18岁以下患者中安全性和有效性。
注意事项
1.尿潴留：应仔细监视患者泌尿症状。
2.神经精神症状：监视混乱状态，精神病症状，和幻觉。
3.眩晕和嗜睡： 监视眩晕和嗜睡。
4.QT延长：同时服用已知增加QT间隔药物或有某些心脏情况患者中应监视QT间隔。
5.自杀行为和观念：监视自杀想法和行为。
药理作用
在传统的MES(最大电休克惊厥) 试验中,给小鼠和大鼠腹腔注射retigabine后采用超大电流刺激, 本品表现出有效的抗惊厥作用, 其 ED50分别为9.3和5.1 mg.kg-1,且经口给予本品也可产生同样疗效,表明本品具良好的系统生物利用度。一系列的小鼠试验显示,本品还可有效拮抗化学诱导的癫痫发作,如可剂量依赖性地抑制皮下注射戊四氮和印防己病毒所致阵挛性惊厥, ED50分别为13.5和18.6 mg.kg-1；缓解侧脑室注射N 2甲基2 D-天冬氨酸(NMDA, 3μg/5μL或012 μg/5μL)所致强直性前肢伸展或阵挛性癫痫；但未见其对皮下注射荷包牡丹碱和士的宁达30 mg.kg-1诱导的癫痫发作产生拮抗作用。　
常用的人类复杂性部分发作型癫痫预防模型——杏仁核电点燃局灶性癫痫大鼠模型试验显示,经口和腹腔注射给药后,本品能极为有效地产生剂量依赖性抗惊厥作用,即在低剂量[0.01(ip)和 0.1(po)mg.kg-1]下可显著增加后放电阈值,且在高剂量[2.5～5(ip)和10～15(po)mg.kg-1]下还会影响模型大鼠的其他癫痫发作参数,如发作的严重度和持续时程以及后放电时程；在015mg.kg-1(ip) 剂量下可显著抑制杏仁核点燃性癫痫发作, 但 0.1和1mg.kg-1(ip)剂量下无效。
最初有关本品抗惊厥作用机制的研究显示,本品可阻断钠和钙电流,增强神经元细胞中GABA所诱导的电流。另有研究显示,本品可较其他对照化合物更有效地逆转4-氨基吡啶诱导海马脑片区过度兴奋和癫痫样放电的作用,并致海马脑片中新合成的GABA量增加。最新研究表明,本品为一种神经元钾通道开放剂和GABA增强剂,可降低神经元兴奋性。由此可见,本品的抗惊厥作用具有多重机制。而目前大多数抗癫痫药物均是作用于钠和钙通道或不同的GABA受体。　
药动学与毒性
在大鼠和犬中进行的药动学试验显示,由于缺乏广泛的首过效应, retigabine单剂量经口给药,即可达到较高的血药浓度和较低的血浆药物清除率,且在犬体内终末半衰期较长；大鼠间的药动学个体差异小；在犬体内,本品的血浆蛋白结合率较低,足以避免其与具高蛋白结合率药物发生相互作用。　
在大鼠和犬实验中,未观察到本品具有任何急性和亚慢性毒性作用,也未见有遗传毒性作用。临床研究　在一项大规模的Ⅱ期临床试验中,受试患者被分成4组,分别接受retigabine 600、900和 1200mg.d-1及安慰剂的治疗。结果, 4组受试患者每月癫痫发作率中值分别减少23%、29%、35%及 13% ,可见本品两高剂量组的疗效明显高于安慰组。在73名部分发作型癫痫患者中进行的一项随机临床试验比较了本品3种给药方案的安全性:所有受试者最初均接受剂量为300mg.d-1的本品治疗,随后治疗剂量逐渐递增至目标剂量1200mg.d-1 ,其中剂量快速递增组、中速递增组和慢速递增组分别于第 13、25和42天后达到目标剂量。结果,各组中因不良反应而退出治疗的受试者分别为43.5%、31.8% 和13.0%。　
在另一项双盲、随机临床试验中, 399名顽固性部分发作型癫痫患者分别接受安慰剂和本品(200、300或400mg, tid)治疗,且均同时合用其他抗癫痫药物,结果总共有220名受试者完成试验,并参加了接下来的延长期开标记试验。在开标记试验中,受试者同时接受本品(300mg, tid；随后剂量减少或增至最大剂量1200mg.d-1)和其他抗癫痫药物的联合治疗。到开标记试验结束时,与治疗前相比,受试者每月总的部分发作频次下降率中值为48.3%；在第3和6个月,主要因中枢神经系统不良反应而退出试验的受试者分别为8%和18%。　
葛兰素史克/Valeant制药公司最近已在欧美递交了retigabine用于辅助治疗部分发作型癫痫的上市申请,该上市申请是基于两项关键性Ⅲ期临床试验。其中一项名为RESTORE 1 的试验涉及 306名顽固性部分发作型癫痫患者,受试者在使用一种其他抗癫痫药物的同时, 分别接受本品 (1200mg, tid)或安慰剂治疗；而另一项RESTORE 2试验中, 1000多名受试患者在接受正常的抗癫痫药物治疗的同时,也分别服用本品600、900mg或安慰剂。结果,两项试验均达到了其共同的主要终点考察指标预期,即本品受试患者28天总的部分与作频次减少28%～40%(安慰剂组为16%)以及疗效反应率(28天发作频次减少50%以上的受试者比例)达39%～47%(安慰剂组为19%)；常见不良反应包括头晕、疲劳、精神恍惚、眩晕、震颤、协调性异常、复视、注意障碍、虚弱和视力模糊。　
此外,目前本品用于治疗疱疹后神经痛的Ⅱ期临床试验也在进行中。
临床试验
在3个多中心，随机，双盲，安慰剂对照研究在1239成人患者局部发作的辅助治疗功效的Potiga成立。主要终点包括在双盲治疗阶段的基线发作频率的百分比变化。
参加研究的患者有部分癫痫发作W/W/O二级概括和1至3伴随抗癫痫药物，W/W/O伴随刺激迷走神经没有得到充分控制。超过75％的患者服用2个或更多伴随抗癫痫药物。在为期8周的基线期，患者没有发作的时间超过3至4周，平均每28天至少有4个部分发作。癫痫的平均时间为22年。横跨3项研究中，中位数基线发作频率从每月8日至12缉获。统计学意义的标准是P <0.05；
患者被随机600mg/day，900mg/day，或1200毫克/天，每3剂量相等的总日常维护剂量。在滴定所有3个研究阶段，治疗开始300mg/day增长目标维持剂量150mg剂量每周递增。 600mg/day剂量（研究1）与Potiga观察统计学显着的效果，在900mg/day（研究1和3），并在1200毫克/天（研究2和3）中位数在28％减少 - 一天发作频率（基线双盲阶段）相比，在所有3项研究的安慰剂。
POTIGA(EZOGABINE)TABLET ORAL
PRESCRIBING HIGHLIGHTS:  Please see package insert for additional information and possible updates to ensure safe and effective use of this medication. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. Please read the disclaimer carefully BEFORE accessing or using this site. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
(DESCRIPTION) 
These highlights do not include all the information needed to use POTIGA safely and effectively. See full prescribing information for POTIGA.
POTIGA (ezogabine) Tablets Initial U.S. Approval: 2011
CLINICAL PHARMACOLOGY: 
Mechanism of Action
The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.
Elimination:
Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%.
Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t 1/2) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is actively secreted into the urine.
INDICATIONS AND USAGE
POTIGA is a potassium channel opener indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older.
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. Pregnancy registry available.
Pediatric use: Safety and effectiveness in patients under 18 years of age have not been established
CONTRAINDICATIONS 
None.
DRUG INTERACTIONS
Ezogabine plasma levels may be reduced by concomitant administration of phenytoin or carbamazepine. An increase in dosage of POTIGA should be considered when adding phenytoin or carbamazepine.
N-acetyl metabolite of ezogabine may inhibit renal clearance of digoxin, a P-glycoprotein substrate. Monitor digoxin levels.
WARNINGS AND PRECAUTIONS
Urinary retention: Patients should be carefully monitored for urologic symptoms.
Neuropsychiatric symptoms: Monitor for confusional state, psychotic
symptoms, and hallucinations.
Dizziness and somnolence: Monitor for dizziness and somnolence.
QT prolongation: QT interval should be monitored in patients taking concomitant medications known to increase the QT interval or with certain heart conditions.
Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
ADVERSE REACTIONS
The most common adverse reactions (incidence 4% and approximately twice placebo) are dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, disturbance in attention, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder.
DOSAGE AND ADMINISTRATION  
Summary:
•Administer in 3 divided doses daily, with or without food.
•The initial dosage should be 100 mg 3 times daily (300 mg per day) for 1 week.
•Titrate to maintenance dosage by increasing the dosage at weekly intervals by no more than 150 mg per day.
•Optimize effective dosage between 200 mg 3 times daily (600 mg per day) to 400 mg 3 times daily (1,200 mg per day).
In controlled clinical trials, 400 mg 3 times daily (1,200 mg per day) showed limited improvement compared to 300 mg 3 times daily (900 mg per day) with an increase in adverse reactions and discontinuations.
•When discontinuing POTIGA, reduce the dosage gradually over a period of at least 3 weeks.
•Dosing adjustments are required for geriatric patients and patients with moderate to severe renal or hepatic impairment
DOSING:
The initial dosage should be 100 mg 3 times daily (300 mg per day). The dosage should be increased gradually at weekly intervals by no more than 50 mg 3 times daily (increase in the daily dose of no more than 150 mg per day) up to a maintenance dosage of 200 to 400 mg 3 times daily (600 to 1,200 mg per day), based on individual patient response and tolerability.
This information is summarized in Table 1 under General Dosing. In the controlled clinical trials, 400 mg 3 times daily showed limited evidence of additional improvement in seizure reduction, but an increase in adverse events and discontinuations, compared to the 300 mg 3 times daily dosage. The safety and efficacy of doses greater than 400 mg 3 times daily (1,200 mg per day) have not been examined in controlled trials.
No adjustment in dosage is required for patients with mild renal or hepatic impairment. Dosage adjustment is required in patients with moderate and greater renal or hepatic impairment.
POTIGA should be given orally in 3 equally divided doses daily, with or without food.
POTIGA Tablets should be swallowed whole.
If POTIGA is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal.
Table 1:

HOW SUPPLIED 
HOW SUPPLIED/STORAGE AND HANDLING
POTIGA is supplied as film-coated immediate-release tablets for oral administration containing 50, 200, 300, or 400 mg of ezogabine in the following packs:
50-mg Tablets: purple, round, film-coated tablets debossed with “RTG 50” on one side in bottles of 90 (NDC 0173-0810-59).
200-mg Tablets: yellow, oblong, film-coated tablets debossed with “RTG-200” on one side in bottles of 90 (NDC 0173-0812-59).
300-mg Tablets: green, oblong, film-coated tablets debossed with “RTG-300” on one side in bottles of 90 (NDC 0173-0813-59).
400-mg Tablets: purple, oblong, film-coated tablets debossed with “RTG-400” on one side in bottles of 90 (NDC 0173-0814-59).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature.]
REFERENCE
Package Insert data: 
POTIGA is a trademark of Valeant Pharmaceuticals North America.
Manufactured by Catalent Pharma Solutions Somerset, NJ 08873
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c60979b-489d-4e7b-8893-468ae00c44bb