美国食品药品管理局批准第一个盐酸罗匹尼罗仿制药

近期，美国食品药品管理局（FDA）批准盐酸罗匹尼罗(ropinirole hydrochloride)仿制，盐酸罗匹尼罗由GlaxoSmithKline(GSK)开发，商品名Requip，1997年首次被批准用于帕金森病，后被批准用于治疗中度到重度的不宁腿（多动腿）综合症（Restless Legs Syndrome，RLS)。
本次美国食品药品管理局批准第一个盐酸罗匹尼罗仿制药，用于治疗中度到重度的多动腿综合症（Restless Legs Syndrome，RLS)。盐酸罗匹尼罗已经被批准的规格有：0.25mg，0.5mg,1mg,2mg,3mg和4mg。盐酸罗匹尼罗除治疗多动腿综合症外FDA还曾批准此该治疗帕金森氏症。因为治疗帕金森氏症用途受到了专利保护，本次盐酸罗匹尼罗仿制药仅能获准治疗多动腿综合症。一旦原发厂治疗帕金森氏症的用途专利期满后，仿制药生产商才可能寻求获准该药治疗帕金森氏症的可能。因此本次批准的说明书不同于原发厂药品说明书的治疗范围。
多动腿或不宁腿综合征（restless legs syndrome，RLS）是一种常见的神经病变，人群中的发病率为5％～10％。并且随着年龄的增长有明显的上升趋势。
多动腿综合征的主要特点是患者的小腿有难以形容的不适感、蚁走感、酸痛胀感、夜晚或休息时加重，运动后可短暂缓解，严重者可侵及上肢并引发夜间睡眠障碍，白天疲乏倦怠，昏昏欲睡，更严重者可以出现焦虑、抑郁等精神症状。FDA官员认为，盐酸罗匹尼罗仿制药的批准再次表明，FDA在法律的许可下，在努力为消费者提供并增加安全有效的仿制药的可获得性。
盐酸罗匹尼罗片原研药Requip的安全性警告信息同样适用于仿制药，提醒患者该药具有镇静作用，会出现嗜睡症状，以及可能在从事驾驶作业等日常生活活动时入睡。服药后，患者出现上述症状的时间不同，有的患者会在用药后立即出现，有的患者则在治疗一年后出现。
目前， Roxane Laboratories Inc.,以色列泰华美国公司（Teva Pharmaceuticals USA）,Par Pharmaceuticals Inc和美兰制药公司（Mylan Pharmaceuticals Inc）获得了盐酸罗匹尼罗仿制药上市许可。

Requip® XL™

REQUIP

Requip Information

Requip triggers the same effects as a natural chemical that is known to naturally occur in the human body that is called dopamine. A low level of this chemical has been linked to Parkinson’s disease. This medicine is prescribed to patients who are suffering from this medical condition as it is known to ease some of its symptoms (stiffness, muscle spasms, tremors, and poor muscular control).

Requip Indications

Requip is a popular medicine that is regularly prescribed to patients who are suffering from Parkinson’s disease or from RLS (restless legs syndrome). However, this medicine may also be used to treat some other medical disorders that have not been listed here.

Requip Warnings

Several patients who have been following a treatment with Requip have fallen asleep while performing their regular daily activities (while talking, working, driving or eating). If you experience any problems with drowsiness or day time sleepiness you should alert your personal health care provider at once. During your treatment with this medicine you should avoid performing any activities that are known to require physical or mental awakeness or alertness.

Drowsiness or dizziness are known to especially occur when the patients rises from a lying or sitting position. This is why it is highly recommended to rise slowly, in order to prevent falling. During your treatment with this medicine you should avoid taking other medicines or drugs that cause sleepiness. It is not recommended to consume any products that contain alcohol during your intake of Requip. A prolonged treatment with this medicine can also cause hallucinations, especially in the case of elderly patients.

Before you start a treatment with this drug you should alert your personal health care provider if you are suffering from kidney disease, heart disease, or liver disorders. Patients who have any of these medical conditions should be prescribed a lower dose of Requip. They should also undergo several medical exams during their treatment with this medicine.

Requip is a category C FDA pregnancy medicine. Therefore, a treatment with this product during pregnancy could harm a growing fetus (it could cause severe birth defects). Therefore, if you are pregnant you should ask your personal doctor if it is safe to start taking this medicine. It has not been determined whether this drug’s components can pass into the patient’s breast milk flow. If you are nursing an infant, you should ask your personal health care provider if it is safe (both for you and for the nursing infant) to start a treatment with Requip. It has been established that taking this medicine affects the patient’s breast milk production.

Requip Intake Guidelines

Ask your personal physician to tell you exactly how to use this medicine. Do not deviate from your physician’s directions. If you did not understand some of them, please refer to a pharmacist or to a nurse and ask them to properly explain them to you. In case you want to know more about Requip you should read the drug’s label.

Some patients are given Requip in a special starting kit (each tablet is marked with the day in which it is supposed to be taken in). Avoid mixing these pills, as they are known to contain various amounts of Requip’s components. This medicine can be taken either on a full or on an empty stomach, as it is not supposed to cause stomach upset. However, taking this drug without food could trigger nausea. If you are disturbed by this particular side effect you should take your doses of Requip with milk or food.
 
Do not stop your treatment with Requip without your physician’s approval. This medicine should be kept in a cool and dry place, away from the reach of pets and children.

Requip Dosage

Ask your personal health care provider to tell you the proper dose of this medicine that you should take in during your treatment with Requip. From time to time, your doctor might want to change your dose of this medicine. Do not alter the dose that you have been prescribed by your doctor without his or her approval.

Requip Overdose

If you suspect that you are suffering from an overdose with this product you should seek immediate medical care. The average symptoms of an overdose with Requip could include tingly feeling, weakness, nausea, hallucinations, vomiting, agitation, muscle twitching, fainting, confusion, and chest pain.

Requip Missed Dose

If you miss one of your doses of this product, you should take it in as soon as you can. If it is already time for another dose, skip the one that you have missed and proceed with your regular treatment. Do not take double doses of Requip without your doctor’s consent.

Requip Side Effects

If you develop any symptoms of an allergic reaction to this drug’s ingredients you should seek emergency medical care. Alert your personal physician at once if you develop any of these severe side effects during your treatment with Requip:

• muscle stiffness, fever, light-headedness;
• fainting, slow heartbeat.

Alert your doctor at once if you develop any of these less severe, but more common side effects:

• vomiting, mild nausea, loss of appetite, upset stomach;
• worsened symptoms of  RLS especially in the morning;
• constipation or diarrhea;
• sweating, dry mouth;
• headache;
• confusion or drowsiness.

Requip Drug Reactions

During your treatment with Requip you should avoid taking:

• levodopa;
• ciprofloxacin;
• estrogens.

Buy Requip

Buy Requip through our Online Pharmacy Escrow Service or at any Canada Pharmacy where it is sold. In some countries REQUIP may also be known as: Ropinirole, Repreve, Adartrel

盐酸罗匹尼罗及片剂、胶囊 
特点：
1、 本品用于治疗帕金森病，属三类新药。由SmithKline-Beechem（史克-必成）公司率先开发，1996年首先在英国上市，后又在美国、法国等多个国家上市，已成为治疗帕金森病的一线药物；
2. 本品作用时间长于左旋多巴，所以单独应用可给多巴胺受体更稳定持久的刺激，副作用小于左旋多巴；与左旋多巴共同使用可增加疗效、减少副作用；
3. 与目前国内常用的多巴胺受体激动剂溴隐亭相比，单独使用时疗效更优，与左旋多巴合用时疗效与之类似，但在减轻左旋多巴的不良反应和疗效衰退方面有明显优势；
4. 不象左旋多巴那样发生氧化代谢，因此不产生可加速神经元变性的氧化增强，还可清除自由基和抗氧化，从而起神经元保护作用；
5. 轻、中度肾功能不全患者无需调整剂量，食物不影响其生物利用度。

背景资料
概述 帕金森病是一种较常见的锥体外系疾病，以运动减少、肌张力强直和震颤为主要症状。它的的药物治疗主要致力于加强症候控制、改善和减轻治疗副反应。一直以来，左旋多巴是控制本病最有效、应用最普遍的药物，但长期应用会引起一系列严重不良反应，最常见的为运动症状波动和运动障碍，而且都会逐渐发生药效衰减。研究认为，服用左旋多巴者的血浆药物浓度波动直接作用于脑内多巴胺受体，引起运动症状波动和运动障碍，所以持续稳定的多巴胺类药物刺激能防止或减轻这类不良反应。但是，目前生产的左旋多巴缓释片尚不能提供连续稳定的多巴胺受体刺激。
多巴胺受体激动剂都可给多巴胺受体更稳定持久的刺激，减轻左旋多巴所致症状波动和运动障碍等不良反应。第一代多巴胺受体激动剂是麦角类，包括溴隐亭、培高利特（pergolide）等，此类药物的不良反应较多，包括胸膜肺、腹膜纤维化、冠状动脉收缩、红斑性肢痛病、指血管痉挛、恶心、呕吐等；罗吡尼洛属第二代非麦角多巴胺受体激动剂，与第一代药物相比，其优越性主要在于：可避免麦角相关的不良反应，且可选择性刺激多巴胺D2、D3类受体，不刺激a和b肾上腺素受体、GABA受体、5-HT1、5-HT2受体，激动受体范围小，激动目的受体的作用更为理想，从而提高疗效，减少不良反应。
临床研究
1.单独用药 多项多中心、双盲、随机、平行的临床研究中，比较了罗吡尼洛与左旋多巴、溴隐亭的疗效。两项长期研究中，以帕金森病统一量表（UPDRS）评价临床效果，特别是运动评分和日常生活行为（ADL）评分，结果见表1。可见单用罗匹尼罗的疗效显著高于左旋多巴，但不良反应明显轻；与溴隐亭相比，疗效更好，需要补充左旋多巴治疗的病例数较少而且所需剂量较小。

表 1 早期帕金森病人单独用罗匹尼罗左旋多巴、溴隐亭的疗效比较

研究时限（年）	药物 [ 最大(平均) 剂量 mg/d]	病例数	需要补充左旋多巴的病例（ % ）	UPDRS 运动评分	UPDRS ADL 评分	运动障碍 （ % ）
5	R[24 (16.5)]	179	66	-4.8±8.3**	1.6±5.4	20***
	L [1200(753)]	89	36	-0.8±10.1	0±4.7	45
3	R[24 (12)]	168	34	-7.7	-2.7*	7.7
	B [40(24.1)]	167	42	-6.3	-0.86	7.2

注：评分中负数表明临床有改善

R：罗匹尼罗 L：左旋多巴，剂量中包括补充的量 B：溴隐亭
*与溴隐亭比比p=0.009, ** 与左旋多巴比p=0.008
***与左旋多巴比p<.0.001,

2．合并左旋多巴 在合并使用左旋多巴的总体疗效上，罗匹尼罗与麦角类药相似，但它可使左旋多巴剂量减少得更多，从而减轻治疗的副作用。一项包括368个病例的对照研究中，加用罗匹尼罗和溴隐亭分别使左旋多巴用量减少19%和9%，且许多研究中这种差别在高剂量左旋多巴导致了运动症状波动的病人中更明显。安慰剂对照的研究中，罗匹尼罗可使左旋多巴的剂量减少20%以上，而且可减少运动症状波动病人处于"开-关"状态中"关"的时间，改善临床总体印象评分。观察期达5年的临床研究中，早期帕金森病患者约有1/3可一直只用罗匹尼罗，这意味着本品可以推迟患者对左旋多巴的需要，将发生运动障碍的危险性降到最低。

效益分析

帕金森病是一种主要发生于中、老年人的慢性神经元变性疾病，严重影响生活质量，并给社会和家庭带来巨大心理压力和经济负担。近年的几项研究提示我国发病率并不像过去认为的那样低，而是与发病率较高的欧美国家处在同一水平，即患者数量约占 60 岁以上人群的 1% 。我国目前正步入老龄化社会， 60 岁以上人口已占总人口的 15% ，而且这个比例还在升高，所以估计目前患者近 200 万，今后将会越来越多。由于我国过去对该病不够重视，因此这方面药物的开发一直大大落后于发达国家，目前可用药物较少，只有左旋多巴、溴隐亭、卡比多巴、抗胆碱药（如安坦）等，其中卡比多巴单独使用无活性，仅用于减轻左旋多巴的不良反应；抗胆碱类药的副作用多而且严重，不作为首选药。对于左旋多巴治疗导致的严重副作用和疗效衰退，除加用或改用溴隐亭外没有好的办法，而这两种药都存在疗效衰退的问题。

罗匹尼罗既可单独应用，又可与左旋多巴合用以解决其严重不良反应和疗效衰减现象，效果强于包括溴隐亭在内的现有药物，不仅将填补帕金森病治疗药物品种的的缺乏，而且以其疗效好、安全性高的优点将会很快如其他国家一样成为首选药物。目前包括帕金森病在内的一些老年病日益受到重视，本品临床使用剂量小（不超过 24mg/day ），治疗成本低，必将占领帕金森病治疗药的主要份额，从而带来良好的社会和经济效益。