非布索坦属片剂，是抗痛风药。非布索坦对氧化型和还原型的XOR均有显著的抑制作用，因而其降低尿酸的作用更强大、持久，因此本品可用于治疗痛风的慢性高尿酸血症。
日本帝人制药株式会社于5月17日在日本推出高尿酸血症治疗药非布索坦(Febuxostat，TMX- 67，商品名Feburic)。

该药能有效降低高尿酸血症患者血中尿酸的含量至低于6.0mg/dL的推荐含量，而且罹患轻度至中度肾功能损伤的患者在未调整剂量的情况下，耐受性良好。据估计，日本罹患高尿酸血症的人数在1600万左右。

帝人制药早在1991年发现非布索坦，该药是第一个非嘌呤类黄嘌呤氧化酶选择性抑制剂，其化学结构不同于别嘌呤醇，别嘌呤醇作为高尿酸血症的标准治疗已使用超过40年。

非布索坦以商品名Uloric在美国和加拿大获得批准上市，以商品名Adenuric在欧洲上市
PHARMACOLOGY

Febuxostat is a selective inhibitor of xanthine oxidase, the enzyme that catalyses the metabolism of purines to uric acid.1

Accumulation of uric acid in the blood, leading to the precipitation of urate crystals in joints and tendons, is responsible for the symptoms of gout.

CLINICAL STUDIES

Febuxostat was studied in 2 randomised, double-blind, pivotal trials involving 1834 patients with hyperuricaemia (serum uric acid level ≥480 micromoles per litre) and gout. Both studies showed the drug to be more effective than a fixed dose of 300mg allopurinol once daily at lowering blood uric acid levels.2

The first study (APEX), which enrolled 1072 patients, compared 3 once daily doses of febuxostat (80mg, 120mg and a safety dose of 240mg) with placebo and allopurinol over a 6-month period.3 The second study (FACT) compared 2 doses of febuxostat (80mg and 120mg once daily) with allopurinol over 1 year in 762 patients.4

Allopurinol was administered at a dose of 300mg once daily in both studies, except in patients with mild or moderately impaired renal function, who received 100mg daily in the APEX study and were excluded from the FACT study.

Febuxostat has not been studied in patients with severe renal impairment. All participants also received either colchicine or naproxen for the first 8 weeks, to prevent gout flares.

The primary efficacy endpoint was the number of patients whose final three monthly blood uric acid measurements were below 357 micromoles per litre.

In the APEX study, 48 per cent of patients taking febuxostat 80mg and 65 per cent of patients taking febuxostat 120mg had uric acid levels below 357 micromoles per litre on the final three occasions. This was compared with 22 per cent of the patients taking allopurinol and none of the patients taking placebo (p<0.05 for all comparisons). After the 8 eight weeks of treatment, the proportions of patients who required treatment for gout flares were similar in all the groups.

Median tophus area decreased by a comparable amount in each group.3

Similar results were seen in the FACT study. After 1 year, the proportion of patients who achieved the target uric acid level was 53 per cent in the febuxostat 80mg group and 62 per cent in the febuxostat 120mg group, compared with 21 per cent of the patients in the allopurinol group (p<0.001 for both comparisons). There were no significant differences between any of the groups in the rate of gout flare or the median reduction in tophus area.4

The most common adverse effects associated with febuxostat are liver function abnormalities, diarrhoea, headache, nausea and rash. There may also be an increased risk of cardiovascular effects; therefore, febuxostat is not recommended in patients with ischaemic heart disease or congestive heart failure.1

The recommended dose of febuxostat is 80mg once daily, increasing to 120mg once daily if uric acid levels remain elevated after 2–4 weeks. As with allopurinol, gout flares can still occur during initial treatment as a result of urate mobilisation from tissue deposits. Consequently, concomitant use of colchicine or an NSAID is recommended for at least the first six months of treatment. Febuxostat should not be initiated during an acute attack of gout.1

Febuxostat is approved by NICE as an option for the management of chronic hyperuricaemia in gout if allopurinol is not tolerated or contraindicated.5

英文药名: Uloric(Febuxostat Tablets)

中文药名: 非布索坦片

【原产地英文商品名】ULORIC 40mg/tablet x 30tablets
【原产地英文药品名】FEBUXOSTAT
【原产地英文化合物名称】FEBUXOSTAT
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·ULORIC/优络瑞克 80毫克/粒，30粒/瓶（美国包装）
·ULORIC/优络瑞克40毫克/粒，30粒/瓶
【中文参考药品译名】非布索坦
【生产厂家中文参考译名】武田制药北美公司/帝人制药
【生产厂家英文名】Takeda Pharmaceuticals America, Inc

药品介绍

美国FDA批准了近40年来的第一个用于治疗高尿酸症的痛风药物——武田制药的非布索坦（febuxostat；ULORIC）。非布索坦通过降低患者血液中的尿酸水平改善来痛风患者的症状。此外，武田制药北美公司还是该产品在美国市场中的独立开发商与销售商。 　　
根据武田公司的一项声明：该产品的结构与40年前开发的黄嘌呤氧化酶抑制剂药物完全不同，它是一种全新的高效的非嘌呤类黄嘌呤氧化酶选择性抑制剂。黄嘌呤氧化酶则是促进尿酸生成的关键酶。 　　
非布索坦可以降低高尿酸血症痛风患者血液中的尿酸水平，在临床研究中已经证明了非布索坦的安全性和有效性，而且在中、重度肝肾功能不全的患者中也不需要进行剂量调整。该产品的服用剂量为每日一次，一次40 毫克或者80毫克，但是该产品不推荐用于无高尿酸血症的痛风患者。 　　
非布索坦的原研厂家为日本的另一家公司，日本帝人制药（TeijinPharma）。在帝人制药公司总裁最近的一份声明中，我们可以了解到该公司对该产品采取的全球战略。他说，在本品获得FDA的许可之前，Ipsen公司的产品也获得了欧盟的上市许可。Ipsen公司是帝人制药关于该产品在欧盟的许可公司，而武田北美制药是本品在美国的许可公司。所以公司在全球已经取得了里程碑式的战略意义。同时他还指出，在亚洲市场，帝人制药将采取自主开发或联合开发的形式。 　　
据专家介绍，痛风是一组异质性疾病，是遗传性和（或）获得性引起的尿酸排泄减少和（或）嘌呤代谢障碍。临床特点：高尿酸血症，以及尿酸盐结晶，沉积所致的特征性急性关节炎、痛风石、间质性肾炎、严重者呈关节畸形及功能障碍；常伴尿酸性尿路结石。假性痛风常常与痛风混淆，因为其症状非常相似，假性痛风是由磷酸钙的代谢障碍引起，而不是尿酸代谢障碍引起。 　　　
根据美国国家关节肌肉骨骼疾病与皮肤病研究所（NIAMS）的研究数据表明，在美国有600万20岁及其以上的人生平有患痛风的经历。通常40~50岁的男性患者较为常见，而绝经前的女性患者少见。经历过器官移植的患者也容易患痛风。

通用名：非布索坦 　　
英文名：Febuxostat 　　
商品名：Adenuric&reg;（Ipsen公司） 　　
类 别：抗痛风药 　　

适应症：用于治疗痛风的慢性高尿酸血证。 　　
剂型：片剂 　　
规格：80mg、120mg

【原产地英文商品名】:ADENURIC 80mg/tablet x 30tablets
【原产地英文药品名】FEBUXOSTAT
【原产地英文化合物名称】FEBUXOSTAT
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·Adenuric/优络瑞克 80毫克/粒，30粒/瓶（欧洲包装）
·Adenuric/优络瑞克 40毫克/粒，30粒/瓶
【中文参考药品译名】非布索坦
【生产厂家中文参考译名】武田制药北美公司/帝人制药
【生产厂家英文名】Takeda Pharmaceuticals America, Inc

药理作用特点

痛风的发生是由于体内产生尿酸过多及肾脏清除能力下降，尿酸体内蓄积，导致尿酸盐结晶在关节及各脏器沉积。因此，痛风的治疗通常采取的手段是：促进尿酸排泄和抑制尿酸生成，并采用适当措施改善相关症状。 　　

体内尿酸的生成与嘌呤代谢有关，在嘌呤代谢的最后步骤中，次黄嘌呤在黄嘌呤氧化还原酶（XOR）的作用下生成黄嘌呤，再进一步生成尿酸，抑制该酶的活性可以有效的减少尿酸的生成。非布索坦为目前世界上最新研制的XOR抑制剂，其通过高度选择性地作用于该氧化酶，减少体内尿酸合成，降低尿酸浓度，从而有效治疗通风疾病。 　　
30年来，别嘌呤醇是临床上唯一一个用于抑制尿酸生成的药物，并作为痛风的黄金治疗药物广泛用于临床，在抗痛风的治疗中取得了不俗的成绩。

与别嘌呤相比，非布索坦具有明显优势：
　　
（1）别嘌呤醇只对还原型的XOR有抑制作用，而非布索坦对氧化型和还原型的XOR均有显著的抑制作用，因而其降低尿酸的作用更强大、持久； 　　
（2）由于别嘌呤醇为嘌呤类似物，不可避免的造成涉及嘌呤及吡啶代谢其他酶活性的影响。因此别嘌呤醇治疗中，需要重复大剂量给药来维持较高的药物水平。由此也带来由于药物蓄积所致的严重甚至致命的不良反应。而非布索坦为非嘌呤类XOR抑制剂，因此具有更好的安全性。

临床评价

一项多中心、双盲、随机Ⅱ期临床研究评价了非布索坦的安全性和对痛风的疗效。总共有136名男性和17名女性痛风病人随机接受安慰剂或本品(40、80或120mg/d),4周后检测发现,本品各剂量组病人血清尿酸浓度较治疗前均显著降低,按剂量由低至高各组分别平均降低37%、44%和59%,而安慰剂组病人仅降低了2%；绝大多数病人坚持完成了试验,本品和安慰剂组不良反应发生率相近，并且这些不良反应大多轻微,具有自限性,常见的有腹泻、疼痛、背痛、头痛和关节痛。 　　
一项Ⅲ期临床试验平行比较了本品(80和120mg/d)和别嘌醇(300mg/d)的疗效。对760名病人进行的为期1年的研究显示,与别嘌醇组相比,本品组中有更多的病人达到主要试验疗效指标－最后3个月均测得sUA浓度低于60mg/L(所有受试者均为痛风病人,且试验前sUA浓度均在80mg/L以上)；在治疗52周后,本品未能显著减少痛风石面积(痛风石是痛风特有的尿酸盐结晶的聚集体),但在试验早期的高剂量组,该作用较明显；各治疗组中,sUA浓度达标(<60mg/L)的病人较少再突发痛风，且其痛风石面积有更明显的减少；各治疗组的不良反应及其发生率相似,不良反应包括肝功能异常、腹泻、头痛、关节相关征和症状及肌骨骼/结缔组织症状。

关于非布司他的的临床问题
非布司他（Febuxostat）为是非嘌呤型的黄嘌呤氧化酶/黄嘌呤脱氢酶的选择性抑制剂，临床用于降低痛风患者的血尿酸。
2008年4月EMEA批准非布司他片上市，规格为80mg和120mg，商品名为“Adenuric”， 推荐起始剂量为80mg，每日一次。如果2－4周后，血浆尿酸仍大于6mg/dl（357umol/L），建议剂量增至120mg，每日一次。
2009年2月FDA批准非布司他片上市，规格为40mg和80mg，商品名为“ULORIC”，推荐起始剂量为40mg，每日一次。如果两周后，血浆尿酸仍大于6mg/dl，建议剂量增至80mg，每日一次。
EMEA和FDA批准的剂量、规格不同。基于以上情况我们查阅了大量的国外临床研究及其评价报告文献：
国外申请者在向FDA递交NDA申请时，FDA要求提供额外的新的临床试验数据以更加清楚地描述80mg非布司他潜在的心血管风险，同时评价低剂量的情况。基于以上要求，进行了一项新的，大规模（病例数2269例）的、阳性药对照的Ⅲ期临床试验，非布司他40mg和80mg与别嘌呤醇进行对照研究，此项试验结果表明40mg是有效的，80mg是安全的。申请者主动提出不再申请120mg剂量上市。
EMEA要求上市后进行剂量滴定试验，从40mg或更低开始，考察其效益。同时认为进行上市后的非布司他的心血管风险研究是非常必要的。
根据国外研究情况，建议国内的申办者，从权衡风险效益的角度，谨慎研发非布司他的规格，谨慎考虑给药剂量以及如何进行临床试验。我们建议同时研发40mg、80mg两个规格，临床试验需要进行40mg、80mg两个规格及剂量的疗效以及安全性研究，并与阳性药别嘌呤醇作对照。

Important Safety and Other Information

ULORIC is a prescription medicine used to lower blood uric acid levels in adults with gout. Individual results may vary.

Do not take ULORIC if you are taking Azathioprine (Imuran®, Azasan®), Mercaptopurine (Purinethol®), or Theophylline (Theo-24®, Elixophyllin®, Theochron®, Theolair®, Uniphyl®).

For some people, gout may flare up when starting certain gout medicines, including ULORIC. If you have a flare while taking ULORIC, do not stop taking your medicine. Your healthcare provider may give you other medicines to help prevent your gout flares.

Heart Problems. A small number of heart attacks, strokes and heart-related deaths were seen in clinical studies. It is not certain that ULORIC caused these events.

Your healthcare professional may do blood tests to check your liver function while you are taking ULORIC.

The most common side effects are liver problems, nausea, gout flares, joint pain, and rash. 

Uloric - What You Need to Know
Uloric, generic name febuxostat, has been approved by the FDA for the chronic management of hyperuricemia in gout. Uloric is the first new treatment option for gout in over 40 years.

Uloric Recommended for FDA Approval
The FDA arthritis advisory committee has recommended the approval of Uloric for the treatment of gout. Uloric, the name that has been given to generic Febuxostat, was recommended by a 12-0 vote (one member of the committee abstained).

Febuxostat: More Effective Than Standard Drug
Febuxostat, a new treatment for gout, is at least twice as effective at lowering uric acid levels than allopurinol. Study results about febuxostat came from the largest and longest trial of gout drugs ever conducted.

Mismanagement of Gouty Arthritis Not Uncommon
Although gouty arthritis is not considered a difficult disease to diagnose and gout treatments are very effective in most cases, errors in the management of gout are common.

Gout - 10 Things You Should Know
Gout is an intensely painful type of arthritis. There are 10 important facts you should know about gout.

Fast Facts About Gout
Gout is one of the most painful types of arthritis. Gout is caused by uric acid crystals deposited in the body's tissues which lead to recurrent attacks of joint inflammation.

Gout Screening Quiz
Gout is one of the most painful types of arthritis. Do you have symptoms which are associated with gout? Do you have a lifestyle which increases the risk factors associated with gout? Take our Gout Screening Quiz.

Gout Risk Factor Quiz
A risk factor increases your chances of developing gout but it is not certain that you will develop the disease. What factors increase the risk of developing gout?

How to Recognize the Signs and Symptoms of Gout
Gout symptoms are very painful and are caused by monosodium urate crystals in joints and surrounding tissues. Gout symptoms can occur with more frequency if untreated.

The Gout Quiz - Test Your Knowledge of Gout
How much do you know about gout? You probably heard of it, but do you know the difference between purines and gout medication probenecid? Do you know what you need to do to prevent gout attacks? Does your lifestyle put you at risk for gout? Take the Gout Quiz and test your knowledge.

How To Treat Gout With Diet And Medication
Gout is one of the most painful types of arthritis. Gout attacks can be controlled or prevented by lifestyle changes and the use of certain medications.

The Gout Guide: Free E-Course Newsletter
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New Gout Drug Gets FDA Panel Nod
Uloric, First New Gout Drug in 40 Years, Recommended for FDA Approval

By Daniel J. DeNoon

WebMD Health NewsReviewed by Louise Chang, MDNov. 24, 2008 -- Uloric should be the first new gout drug to be approved in over 40 years, an FDA expert panel recommends.

Currently, allopurinol (trade name, Zyloprim) is the only FDA-approved drug that prevents formation of the uric acid crystals that cause gout. However, side effects -- including potentially fatal reactions -- limit the amount of allopurinol that can be tolerated. Most gout patients do not receive fully effective doses of allopurinol.

In clinical trials sponsored by Takeda, Uloric's manufacturer, an 80-milligram dose of Uloric worked better than allopurinol; a 40-milligram dose worked at least as well as allopurinol.

Unlike allopurinol, very little Uloric is excreted through the urine, making Uloric safe for patients with kidney problems. Gout patients with impaired kidney function have to take very low doses of allopurinol, making the drug even less effective for these patients.

In 2005, the FDA refused to approve Uloric because there were slightly more deaths and heart problems in patients taking the drug than in patients taking allopurinol. As people with gout problems already are at higher risk of heart disease, the FDA issued an "approvable" letter, noting that Uloric could be approved if this safety question were addressed.

Takeda then performed a large new phase 3 clinical trial that enrolled more gout patients than the two previous phase 3 trials combined. The new study found no more deaths and no more heart problems in patients taking Uloric than in patients taking allopurinol.

Based on the safety and efficacy data, the FDA panel recommended by a 12-0 vote that the FDA approve Uloric at both the 40-milligram and 80-milligram doses. Takeda suggests the higher dose is more effective in subjects with more severe gout.

Takeda has offered to continue studying Uloric after FDA approval. A phase 4 clinical trial would compare Uloric to allopurinol for the reduction of gout flare-ups.

And because drugs with the same mechanism of action as Uloric and allopurinol may affect theophylline bronchodilators, Takeda has agreed to conduct a postmarketing phase 1 study of Uloric's interactions with theophylline.

Gout occurs when blood levels of uric acid rise. At blood levels above 7 mg/dL -- and above 6 mg/dL in the extremities -- crystals can form that lodge in the joints and other body tissues. These crystal deposits provoke an immune response that results in extremely painful swelling and in inflammatory arthritis that can permanently destroy the joints.

(For more on the causes, symptoms, and treatment of gout, see WebMD's Gout Pictures Slideshow.)

About 1.4% of men and 0.6% of women have gout. But prevalence rises with age. After age 80, about 9% of men and 6% of women develop gout.

The body converts a chemical called xanthine into uric acid via an enzyme called xanthine oxidase or XO. Allopurinol and Uloric each inhibit XO and prevent the formation of uric acid.

Allopurinol is approved in doses up to 800 milligrams. However, it's rarely dosed above 300 milligrams per day and is often ineffective. Allopurinol side effects include upset stomach, headache, diarrhea, and rash. Although rare, allopurinol hypersensitivity syndrome can develop. It's fatal 20% to 30% of the time.

The most common side effects seen in patients taking Uloric during clinical trials were upper respiratory tract infections, muscle and connective-tissue symptoms, and diarrhea. The drug was well tolerated, and these side effects did not increase over long-term use.