2011年11月4日，美国食品药品管理局(FDA)和杨森制药公司宣布Xarelto(利伐沙班)已获准用于非瓣膜性房颤(AF)患者以降低其卒中和全身性栓塞的风险。Xarelto是一种口服抗凝药，每天用药1次，无需进行常规的实验室监测。

Xarelto此前已获准用于进行膝关节或髋关节置换术的患者，预防深静脉血栓形成，这种血栓可能会导致肺栓塞。

Xarelto的这项新适应证获准是基于一项关键性、全球性、双盲、3期试验，试验名为“利伐沙班每日1次口服用药直接抑制Ⅹa因子与维生素K拮抗作用预防房颤患者发生卒中和栓塞效果之比较”(ROCKET AF)。在该研究中，对非瓣膜性房颤患者每日给予1次利伐沙班有效降低了卒中和全身性栓塞的风险，其大出血发生率可与华法林相媲美。就最令人担忧的出血类型而言，比如血液流入重要器官及致死性出血，利伐沙班治疗组的事件较少；而对于可引起输液和胃肠道出血的出血类型，利伐沙班治疗组的发生率较高。ROCKET AF试验的具体细节发表于《新英格兰医学杂志》(The New England Journal of Medicine)。

与其他抗凝药一样，Xarelto也可引起出血，严重时也可能会导致死亡。出血是ROCKET AF试验中接受Xarelto治疗的患者报告最多的不良事件。Xarelto的说明书中有一个须向患者澄清的黑框警告，即在咨询医务人员之前不得停药，否则会增加卒中风险。

Xarelto的用量及用法为20 mg，每日1次，与晚餐同服，而对于有中重度肾损害的患者则采用15 mg、每日1次的用药方案。

Xarelto(利伐沙班rivaroxaban)批准日期：2011年7月1日；公司：杨森Janssen Pharmaceuticals, Inc.

适应证和用途
XARELTO一种因子Xa抑制剂适用于在正在膝或髋关节置换手术患者中预防深部静脉血栓形成(DVT)，后者可能导致肺栓塞(PE)。

剂量和给药方法
10 mg口服，每天1次

剂型和规格
片：10 mg

禁忌证
（1）对XARELTO超敏性
（2）活动性重要出血

警告和注意事项
（1）出血的风险：XARELTO可引起严重和致命性出血。及时评价失血的征象和症状。 
（2）妊娠相关出血：在妊娠妇女中由于潜在的产科出血和/或紧急剖宫产慎用XARELTO。及时评价失血征象和症状。

不良反应
最常见不良反应 (>5%)是出血。

为报道怀疑不良反应，联系Janssen Pharmaceuticals, Inc.电话1-800-526-7736或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.

药物相互作用
（1）P-gp和强CYP3A4抑制剂联用：避免同时使用除非证明缺乏明显相互作用。
（2）P-gp和弱或中度CYP3A4抑制剂联用：避免同时使用除非在有肾受损患者权衡效益胜于出血风险。
（3）P-gp和强CYP3A4诱导剂联用：避免同时使用或考虑增加剂量
（4）抗凝剂：避免同时使用
（5）氯吡格雷[Clopidogrel]：避免同时使用除非权衡获益胜于出血风险。

特殊人群中使用
（1）哺乳母亲：终止药物或终止哺乳
（2）肾受损：避免在有严重受损(CrCl <30 mL/min)患者中使用。在中度受损(CrCl 30至<50 mL/min)慎用
（3）肝受损：避免在有中度(Child-Pugh B)或严重(Child-Pugh C)肝受损患者或伴有凝血病有任何程度肝病患者中使用。
 
如何供应/贮存和处置

XARELTO(利伐沙班)10 mg片是 圆形，淡红色，双凸膜衣片标志有一个指向下的三角形在一侧上面一个“10”，和另侧一个“Xa”。被供应在包装内列出：
NDC 50458-580-30瓶含30片
NDC 50458-580-10 泡包装含100片(10泡卡各含10片)
贮存在25°C(77° F)或室温；外出时允许至15°-30° C (59°-86° F)[见USP控制室温]。
保存在儿童不能取到处。

一般描述
利伐沙班，一种因子Xa抑制剂，是在XARELTO片活性成分有化学名5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-
thiophenecarboxamide。利伐沙班的分子式为C19H18ClN3O5S和分子量435.89。结构式为：

Xarelto (rivaroxaban) is the first oral factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), following knee or hip replacement surgery. According to the American Academy of Orthopedic Surgeons, more than 800,000 Americans undergo knee or hip replacement surgery each year, and these procedures are associated with an increased risk for blood clots that form in a deep vein, usually in the leg.

If all or part of a DVT detaches, it can travel to the lungs and become a PE, where it may impact the flow of oxygenated blood and lead to potentially life-threatening consequences. The American College of Chest Physicians recommends the use of anticoagulants immediately following major orthopedic replacement surgery and extends its use post-discharge, as DVT and PE are the leading causes of rehospitalizations following joint replacement surgery.

In November 2011, Xarelto also gained FDA approval to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (AF). AF increases the risk of stroke approximately 4 to 5 times across all age groups and is the cause of 15% of all strokes. The American College of Chest Physicians recommends long-term anticoagulation in most patients with AF.

Mechanism of Action

Xarelto is an oral, highly selective direct factor Xa inhibitor that blocks the active site of factor Xa without the need of a cofactor for activity. Inhibition of factor Xa interrupts both the intrinsic and extrinsic pathways of the blood coagulation cascade, thus inhibiting both thrombin formation and the development of thrombi.

Clinical Trials

Pivotal data from the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) Phase III trials compared the efficacy and safety of Xarelto 10 mg/day with subcutaneous enoxaparin 40 mg/day for prevention of VTE after total hip or knee arthroplasty. RECORD1 and RECORD2 involved hip replacement and RECORD3 and RECORD4 involved knee replacement surgeries. These studies, which enrolled more than 12,000 patients, showed that Xarelto had noninferior and possibly superior efficacy compared with enoxaparin. In RECORD1, 1.1% of patients who received Xarelto had a VTE compared with 3.9% of those who received enoxaparin.

In RECORD2, 2.0% of those treated with Xarelto had VTE compared with 8.4% of those who received enoxaparin. RECORD3 proved noninferiority, whereas RECORD4 demonstrated that Xarelto was significantly more effective in reducing the occurrence of VTE than enoxaparin. In regard to safety, the risk of bleeding was greater in patients receiving Xarelto than enoxaparin.

ROCKET AF (The Rivaboxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) provided pivotal data to support FDA approval for the stroke prevention in nonvalvular AF indication. The study enrolled 14,264 patients with nonvalvular AF who were at a moderate-to-high risk for stroke. It compared Xarelto 20 mg/day for patients with normal kidney function and Xarelto 15 mg/day for patients with a creatinine clearance (CrCl) less than 50 mL/min to adjusted-dose warfarin.

Xarelto was shown to be noninferior to warfarin; stroke or systemic embolism occurred in 1.7% of those who received Xarelto compared with 2.2% of those who received warfarin. Overall rates of major and clinically relevant nonmajor bleeding were similar between groups.

Dosing

The dosing of Xarelto for postoperative thromboprophylaxis is 10 mg orally once daily for 12 to 14 days for knee replacement and 35 days for hip replacement. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established. For prevention of stroke in patients with nonvalvular AF, the dosing is 20 mg orally once daily with the evening meal. If CrCl is less than 50 mL/min, the dose must be reduced to 15 mg orally once daily.

Contraindications, Warnings, And Precautions3,4

Common side effects of Xarelto include bleeding (5%), wound secretion (2.8%), extremity pain (1.7%), muscle spasms (1.2%), pruritis (2.1%) and blister formation (1.4%). Caution should be used when spinal/epidural anesthesia or puncture is being employed, in conditions with increased risk of hemorrhage or with concomitant use of drugs affecting hemostasis, and in pregnant women.

Discontinuing Xarelto in patients with nonvalvular AF increases the risk for thrombotic events; administration of another anticoagulant is recommended if Xarelto must be discontinued. In patients with renal impairment, Xarelto should be avoided in treating thromboprophylaxis or nonvalvular AF stroke prophylaxis if CrCl is less than 30 mL/min or 15 mL/min, respectively. PT
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Xarelto: two new indications for oral anticoagulant
The direct oral factor Xa inhibitor, rivaroxaban (Xarelto), has been approved for two new indications.
 
Xarelto 15mg and 20mg tablets should be taken with food

In addition to the prevention of venous thromboembolism (VTE) following hip or knee replacement, Xarelto (rivaroxaban) is now licensed for:

prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) and one or more risk factors (including congestive heart failure, hypertension, ≥75 years of age, diabetes mellitus and prior stroke or transient ischaemic attack);
treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT.
Stroke prevention in AF

Rivaroxaban (20mg once daily) was compared with dose-adjusted warfarin (target INR 2.5, range 2.0–3.0) in the pivotal randomised double-blind ROCKET AF study (n=14,264). The primary efficacy endpoint (a composite of stroke and systemic embolism) occurred in 188 patients taking rivaroxaban (1.7% per year) compared with 241 in the warfarin group (2.2% per year); hazard ratio (HR) 0.79 from the per-protocol analysis (95% CI, 0.66–0.96; p<0.001 for non-inferiority). Patients with renal impairment (CrCl 30–49ml/min; n=2950) were given a lower dose of rivaroxaban (15mg once daily) and in a subgroup analysis displayed a similar treatment effect to that found in the overall trial.

DVT
The open-label non-inferiority EINSTEIN DVT study (n=3449) investigated rivaroxaban in the treatment of acute symptomatic DVT. Patients were randomised to receive rivaroxaban 15mg twice daily for 3 weeks then 20mg once daily for 3, 6 or 12 months (n=1731), or subcutaneous enoxaparin plus warfarin or acenocoumarol (n=1718). Rivaroxaban was equally efficacious as the active control in reduction of recurrent VTE (36 events [2.1%] versus 51 events [3.0%], respectively; HR 0.68; 95% CI, 0.44–1.04; p<0.001 for non-inferiority).

The EINSTEIN-Extension trial (n=1197) investigated the efficacy of rivaroxaban (20mg once daily) against placebo in the prevention of VTE recurrence, following treatment for DVT or PE. Rivaroxaban displayed superior efficacy to placebo (8 events [1.3%] versus 42 [7.1%], respectively; HR 0.18; 95% CI, 0.09–0.39; p<0.001).

Safety

Rates of major and non-major clinically relevant bleeding were similar in the two arms of the ROCKET AF study, but fatal bleeding and rates of intracranial haemorrhage were less frequent with rivaroxaban. Additionally, similar rates of all-cause mortality and myocardial infarction were observed but major gastrointestinal bleeding was more common in the rivaroxaban group. In the EINSTEIN trial, similar rates of adverse events occurred in the two groups; however, in the EINSTEIN-Extension study, non-fatal major bleeding occurred in 4 patients in the rivaroxaban group but no patients in the placebo group (p=0.11).

New tablets

To support the new indications, Xarelto is now available as 15mg and 20mg tablets in addition to the existing 10mg tablets licensed for prevention of VTE following hip or knee replacement surgery.

欧洲批准抗凝血药Xarelto

欧盟近日正式批准Xarelto（利伐沙班，rivaroxaban）片剂用于预防臀或膝关节置换术患者发生静脉血栓，这是一种一天一次的一种新型的、一天一次的口服剂型直接凝血因子Xa 抑制剂，Bayer公司表示将很快在欧盟成员国上市该药。

支持此项批准的试验数据来自于3项与依诺肝素对比的3期试验，受试者近1万人，试验表明该药效果优于标准疗法依诺肝素。

在欧盟国家每年有150万的血栓堵塞事件发生，致死54.4万人。riv aroxaban之前已在加拿大获得批准，此外还在其它10个国家申请上市。