2010年3月,美国FDA批准了Salix制药有限公司的利福昔明(rifaximin)550mg片剂Xifaxan的新药申请,用于减少≥18岁终末期肝病患者的显性肝性脑病复发风险。
利福昔明(Rifaximin)为利福霉素的衍生物，通过与细菌DNA-依赖RNA聚合酶的β-亚单位不可逆的结合而抑制细菌RNA的合成，最终抑制细菌蛋白质的合成。是第一个非氨基糖苷类肠道用抗生素。临床主要用于对利福昔明敏感的病原菌引起的肠道感染。
2010年3月25日，美国食品药品管理局（FDA）宣布批准利福昔明（Xifaxan）用于降低肝性脑病（HE）的复发风险。此前Xifaxan曾作为治疗旅行者腹泻药物获批。此次利福昔明作为罕见病药获优先审评的资格并批准此新适应症。
一项安慰剂随机对照临床试验评估了Xifaxan治疗HE的有效性，该临床试验的受试者由美国、加拿大和俄罗斯的成年患者组成。参加试验的肝病患者为无HE症状或有轻度HE症状者，与使用安慰剂治疗的患者相比，使用Xifaxan治疗的患者更少出现肝性脑病。
Xifaxan在严重肝病患者中的疗效尚未得以确认。在试验过程中，由于大部分患者同时服用了半乳糖甙果糖（一种合成糖，有助于阻止肠道的氨吸收进入血液），因此，无法评估Xifaxan作为单独治疗HE的确切疗效。
Xifaxan的常见不良反应主要为上下肢肿胀（外周性水肿）、恶心、嗳气和头痛。

制造商：
Salix制药公司
药理分类：
利福霉素
活性成分（补）：
利福昔明550mg;标签。
指示（补）：
在公开的肝性脑病（HE）的复发风险降低≥18岁患者。
药理作用：
肝性脑病是由一对血液中的有毒物质时可能出现肝功能降低（如氨）的积累。利福昔明，非氨基糖甙类半合成利福霉素SV抗菌来源于，通过具有约束力的行为β-细菌的DNA -依赖的RNA聚合酶亚基的抑制细菌RNA的合成产生的。利福昔明被认为是对胃肠道菌群的效果，从而减少是肠道细菌产生氨。
临床试验：
一个多中心，随机，安慰剂对照，双盲，6个月进行审判，以评估在减少明显肝性脑病发作Xifaxan 550mg复发的疗效。该研究纳入299例成人≥2谁经历与慢性肝病相关的过去6个月肝性脑病发作，谁是被作为缓解（康恩评分0或1）条界定。
Xifaxan 550mg的疗效进行了评估，首先突破了明显的肝性脑病发作时间（如神经功能显着恶化和康恩评分≥2定义）。在6个月治疗期间，肝性脑病发作明显的突破经历了22年的Xifaxan 550mg治疗的患者相比，46％患者接受安慰剂谁％。对事件的自由曲线的Kaplan - Meier估计的比较表明，Xifaxan 550mg显着降低了58％，在6个月的治疗期肝性脑病的突破的危险。
法律分类：
接收
成人：
≥18yrs：550mg，每日两次。
儿童：
“18yrs：不推荐。
警告/注意事项：
没有研究与MELD评分> 25例，仅有8.6％的患者在控制范围内的审判已经MELD评分> 19。加强与更严重的肝功能不全患者的全身暴露;应小心治疗重度肝功能不全（Child - Pugh分级丙）。老人。妊娠（Cat.C）。哺乳母亲：不推荐。
不良反应（补）：
周边水肿，恶心，头晕，乏力，腹水。
如何提供：
制表- 60
最后更新：
2010年5月20日

Xifaxan
Generic Name: rifaximin (rif AX i min)
Brand Names: Xifaxan
What is Xifaxan?
Xifaxan (rifaximin) is an antibiotic that fights bacterial infection only in the intestines.
Xifaxan is used to treat travelers' diarrhea caused by E. coli in adults and children who are at least 12 years old. Most people get this infection by eating food or drinking fluids that have been contaminated with the bacteria.
Xifaxan is also used to lower the risk of worsened brain function, or hepatic encephalopathy, in adults with liver failure. Brain function can be affected when the liver stops working and cannot remove toxic substances from the body.
Xifaxan may also be used for other purposes not listed in this medication guide.
Important information about Xifaxan
You should not use take Xifaxan if you are allergic to rifaximin or medications such as rifabutin (Mycobutin), rifampin (Rifater, Rifadin, Rifamate), or rifapentine (Priftin).
Before you take Xifaxan, tell your doctor if you have severe liver disease, diarrhea with fever, or diarrhea that is watery or has blood in it.
Take Xifaxan for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Xifaxan will not treat a viral infection such as the common cold or flu, or any form of diarrhea that is caused by a virus. Call your doctor if your symptoms do not improve after 24 hours, or if they get worse while taking rifaximin. Xifaxan does not treat all bacterial forms of traveler's diarrhea.
Before taking Xifaxan
You should not use take Xifaxan if you are allergic to rifaximin or medications such as rifabutin (Mycobutin), rifampin (Rifater, Rifadin, Rifamate), or rifapentine (Priftin).
If you have any of these other conditions, you may need a Xifaxan dose adjustment or special tests:
severe liver disease;
diarrhea with a fever; or
watery or bloody diarrhea.
FDA pregnancy category C. It is not known whether Xifaxan will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using Xifaxan. It is not known whether rifaximin passes into breast milk or if it could harm a nursing baby. Do not use Xifaxan without telling your doctor if you are breast-feeding a baby.
How should I take Xifaxan?
Take Xifaxan exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Xifaxan can be taken with or without food.
Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Xifaxan will not treat a viral infection such as the common cold or flu, or any form of diarrhea that is caused by a virus. Call your doctor if your symptoms do not improve after 24 hours, or if they get worse while taking rifaximin. Xifaxan does not treat all bacterial forms of traveler's diarrhea.
Store at room temperature away from moisture and heat.
What happens if I miss a dose?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
What should I avoid while taking Xifaxan?
Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking Xifaxan and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.
Xifaxan side effects
Get emergency medical help if you have any of these signs of an allergic reaction to Xifaxan: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using Xifaxan and call your doctor at once if you have a fever or diarrhea that is watery or bloody.
Less serious Xifaxan side effects are more likely, and may include:
bloating, gas, stomach pain;
feeling like you need to empty your bowel urgently;
feeling like your bowel is not completely empty;
nausea, vomiting, constipation;
headache, dizziness;
tired feeling; or
swelling in your hands, feet, or torso.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What other drugs will affect Xifaxan?
There may be other drugs that can interact with Xifaxan. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.
Where can I get more information?
Your pharmacist can provide more information about Xifaxan.
Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Xifaxan only for the indication prescribed.
Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects.
XIFAXAN 550mg
Manufacturer:Salix Pharmaceuticals, Inc.
Pharmacological Class:Rifamycin
Active Ingredient(s):Rifaximin 550mg; tabs.
Indication(s):Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age.
Pharmacology:Hepatic encephalopathy is caused by an accumulation of toxic substances (eg, ammonia) in the blood that may occur when liver function is reduced. Rifaximin, a non-aminoglycoside semi-synthetic antibacterial derived from rifamycin SV, acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis. Rifaximin is believed to have an effect on gastrointestinal flora, thereby reducing the intestinal bacteria that is producing the ammonia.
Clinical Trials:A multicenter, randomized, placebo-controlled, double-blind, 6-month trial was conducted to assess the efficacy of Xifaxan 550mg in reducing the recurrence of overt hepatic encephalopathy episodes. The study enrolled 299 adult patients who experienced ≥2 episodes of hepatic encephalopathy associated with chronic liver disease in the previous 6 months and who were defined as being in remission (Conn score 0 or 1).
Efficacy of Xifaxan 550mg was assessed by the time to first breakthrough overt hepatic encephalopathy episode (defined as marked deterioration in neurological function and Conn score ≥2). During the 6-month treatment period, breakthrough overt hepatic encephalopathy episodes were experienced by 22% of patients treated with Xifaxan 550mg compared to 46% of patients who received placebo. Comparison of Kaplan-Meier estimates of event-free curves showed that Xifaxan 550mg significantly reduced the risk of hepatic encephalopathy breakthrough by 58% during the 6-month treatment period.
Legal Classification:Rx
Adults:≥18yrs: 550mg twice daily.
Children:<18yrs: not recommended.
Warnings/Precautions:Not studied in patients with MELD scores >25; only 8.6% of patients in the controlled trial had MELD >19. Increased systemic exposure in patients with more severe hepatic dysfunction; caution should be exercised in patients with severe hepatic impairment (Child-Pugh C). Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.
Adverse Reaction(s):Peripheral edema, nausea, dizziness, fatigue, ascites.
How Supplied:Tabs—60
Last Updated:5/20/2010
【利福昔明:简介】
利福昔明是一种肠道抗生素，是一种利福霉素的衍生物。最大特点为口服后在胃肠道内不被吸收，抗菌作用强，抗菌谱广。与氨基糖甙类抗生素相比，本品对革兰氏阳性需氧菌中金黄色化脓性葡萄球菌，对表皮葡萄球菌和肠球菌，对革兰氏阳性厌氧菌中的艰难梭状杆菌有高度活性，而氨基糖甙类抗生素抗上述菌种的活性很低或极低。利福昔明对拟杆菌亦具有高度活性，而氨基糖甙类则无。利福昔明的不良反应远远低于氨基糖甙类，它不损伤听觉功能，不引起肾脏功能不全，且可避免二重感染。与环丙沙星等喹诺酮类抗生素相比，虽然疗效相似或略高于后者，但前者抗菌谱较后者高（对链球菌较后者敏感），安全性也较后者大（前者不产生中枢神经系统副作用）。因而，利福昔明是一种高效低毒的肠道抗生素。
本品由意大利Alfa Wassermann公司研制开发，1987年作为抗感染性腹泻药以商品名Normix在意大利上市。Alfa Wassermann公司还开发了外用的5%利福昔明霜剂，用于化脓性细菌引起的皮肤感染。
本品在国外有着15年临床应用的历史，至今仍广泛使用。有关Rifaximin的药理作用、毒理作用和临床研究已有报道，现将有关内容简要总结如下：
1．药理作用
（1）药效学研究
本品系利福霉素衍生物，是第一个非氨基糖甙类肠道抗生素。本品作用强，抗菌谱广。本品对革兰氏阳性需氧菌中金黄色化脓性葡萄球菌；对革兰氏阴性不规则需氧菌中的沙门氏菌属、大肠杆菌、志贺氏菌属、小肠结肠炎耶尔森氏菌、球菌；革兰氏阴性厌氧菌中的拟杆菌属有高度活性。 使用本品不需使用肠解道痉药（如咯哌丁胺等），也不需要肠道吸附药（如白陶土、果胶等）。 本品作用迅速，2天后即不再腹泻，腹部痉挛性疼痛、头痛及恶心呕吐症状均很快消失。本品不被吸收，在肠道内极高浓度，不存在于其他器官中。 本品优于新霉素、链霉素及其他氨基糖甙类抗生素的特点尚有：本品不损伤听觉功能；不会引起肾功能不全；寄生的正常菌群，特别是肠道非致病性大肠杆菌很快即重新定居于肠道而避免了重复感染；肠道粘膜炎症趋于消失。
（2）药代动力学研究
大鼠单次口服利福昔明100mg/kg后，在血清及肝脏中仅存在少量药物（0.2μg/ml，9.6μg/ml）。大鼠单次口服利福昔明25mg/kg后72小时，在粪便中的回收率为53.4%，尿中的回收率为0.29%。
犬单次口服利福昔明25mg/kg或多次连续使用利福昔明8天（10mg/kg/天）后均未在血清中检出利福昔明。
健康志愿者禁食9小时后口服利福昔明400mg，在血浆标本中未检出该药；在给药48小时内，尿中可见极少量的原形药物（低于给药剂量的0.01%）。
2．毒理学研究
（1）急性毒性研究
利福昔明毒性小。小鼠口服本品的LD50大于5000mg/kg；小鼠腹腔注射本品的LD50大于5000mg/kg。
（2）长期毒性研究
SD大鼠每天灌胃给予利福昔明25、50、100mg/kg，连续给药180天，除雌性大鼠血清总胆固醇出现剂量相关性增高外，其它血液学、血清生化及病理组织学检查均未见异常改变。
（3）三致毒性研究
体内外研究表明，利福昔明无致突变、致生殖毒性、致癌作用。
3．临床疗效
墨西哥旅行者腹泻患者，给予利福昔明200-600mg，一天三次或甲氧苄啶/磺胺甲异恶唑（TMP/SMX）160/180mg,一天二次,连续使用5天,结果显示利福昔明200mg组疗程最短,利福昔明无效者为6/55(11%),TMP/SMX无效者为5/17（29%）。利福昔明治疗24小时可减少未成形大便次数，大便恢复正常天数两者分别为3.3及5.1天。
细菌性腹泻儿童患者分别口服利福昔明（100mg，每6h一次）或巴龙霉素（125mg，每6h一次），连续服用4天，结果显示两药细菌清除率、治愈率、粪便正常化和临床症状的消失率等指标相似，但利福昔明治疗组更好更快，治愈率为21/24，3人无效；巴龙霉素组治愈率为20/25，5人无效。
30名急性复发性腹泻儿童患者口服利福昔明后，在治疗第一天有24人（80%）粪便形态及次数正常化，对照组在4天后有7人（43.8%）正常化。利福昔明治疗5天后有15人治愈（50%），13人显效（43.3%），2人无效（6.7%）；对照组上述数据分别为5人（31.2%），4人（37.5%），7人（31.2%）。
急性感染性腹泻患者口服利福昔明800mg/day，治疗5天后，临床有效率为100%，细菌清除率为85%，其作用与新霉素（1000mg/day×5天）相似（临床有效率为100%，细菌清除率为89%）。
肝性脑病患者口服利福昔明1200mg/day，连续用药15天后，血氨下降，神经症状减轻，意识状态改善，其作用较乳果糖（60g/d）或新霉素（3000mg/d）更迅速。在大肠外科手术前3天开始口服给予利福昔明600mg-800mg/d，结果患者大便中某些需氧菌和厌氧菌明显减少（P＜0.05）。在手术前3天给予利福昔明800mg/d的19名患者中有1例发生了并发症，而巴龙霉素组19人中有5人发生了术后并发症。
利福昔明在意大利已取得专利权，专利号为IL 54655。该药在治疗由隐孢子虫病引起的腹泻中的用途已在我国获得专利，专利号为CN 1214244。该药未在中国申请行政保护，因此该药目前申报的适应症在中国不受专利和行政保护的限制。