2012年11月2日美国食品和药品监督管理局(FDA)扩展Xarelto(利伐沙班[rivaroxaban])的被批准使用包括治疗深部静脉血栓(DVT)或肺栓塞(PE)，和减低初始治疗后DVT和PE复发的风险。

当血液粘厚和一团一团在一起发生血凝块。DVT是在身体深部静脉形成血凝块。大多数深部静脉血凝块发生在下肢或大腿，当在深部静脉血凝块折断和移动至肺内动脉和阻断血流，造成一种潜在致死性情况成为肺动脉栓塞PE。

Xarelto早已被FDA-批准减低来自r膝或髋置换手术后发生的DVTs和PEs风险(2011年7月)，和减低有典型异常心节律被称为非瓣膜性心房颤动人们卒中的风险(2011年11月)。

FDA在监管局的优先审评程序下审评了Xarelto的新适应症，这种程序对治疗中提供重大进展或目前没有适当治疗的药物提供加快6个月审评。

FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，M.D.说：“Xarelto是自从接近60年前前批准华法林[warfarin]以来第一个批准的口服治疗和减低血凝块复发的抗凝药物”。

被FDA批准治疗或减低血凝块风险的其他药物包括Lovenox (依诺肝素[enoxaparin])，依诺肝素的仿制药，Arixtra (磺达肝癸钠[fondaparinux])，Fragmin(达肝素钠[dalteparin])，Coumadin (华法林)，和肝素。

在三项临床研究中评价了Xarelto对新适应症的安全性和有效性。总共9,478例DVT或PE患者被随机赋予接受Xarelto，依诺肝素和维生素 K拮抗剂(VKA)联用，或安慰剂。研究被设计测量经受复发DVT，PE症状或接受治疗后死亡患者数。

结果显示Xarelto与依诺肝素和VKA联用对治疗DVT和PE疗效一样。被Xarelto治疗患者经受复发DVT或PE约2.1 %，与之比较用依诺肝素和VKA 联用治疗患者1.8 %至3 %。此外，来自第三研究结果显示扩展Xarelto治疗患者减低DVT和PE复发的风险。用Xarelto治疗患者约3%经受复发DVT或PE 相比较接受安慰剂患者7.1 %。

用Xarelto观察到主要副作用是出血，相似于其他抗凝药物。

Xarelto由位于新泽西州Janssen Pharmaceuticals Inc.的Raritan上市。

美国初始批准：2011
最近主要修改
适应症和用途 (1) 11/2012
剂量和给药方法 (2) 11/2012
禁忌症 (4) 11/2012
警告和注意事项 (5) 11/2012

适应症和用途
XARELTO是凝血因子Xa抑制剂适用于：
● 在非瓣膜性心房颤动患者中减低卒中和全身性栓塞(1.1)。
● 为治疗深部静脉血栓形成(DVT)，肺栓塞(PE)，和为减低DVT和PE复发的风险(1.2，1.3，1.4)。
● 为预防DVT，正在进行膝或髋置换术患者中可能导致PE(1.5)。

剂量和给药方法
● 有食物服用15 mg和20 mg片；有或无食物服用10 mg片。(2.1)
● 非瓣膜性心房颤动:
o 对CrCl >50 mL/min患者：口服20 mg，每天1次随旁晚餐(2.3)
o 对CrCl 15 - 50 mL/min患者：15 mg口服，每天1次随旁晚餐(2.3)。
● DVT，PE治疗，和减低复发性DVT和PE的风险：对急性DVT或PE 初始治疗15 mg有食物口服每天2次共头21天。初始治疗期后，20 mg有食物口服每天1次对维持治疗和长期减低DVT和PE复发的风险。(2.4)
● 髋或膝置换手术后预防DVT：10 mg有或无食物口服，每天1次。(2.5)

剂型和规格-
片：10 mg，15 mg，和20 mg (3)

禁忌症
● 活动性病理性出血。(4)
● 对XARELTO严重超敏性反应。 (4)

警告和注意事项
● 出血风险：XARELTO可致严重和致命性出血。及时评价血液丢失体征和症状。(5.2)
● 妊娠相关出血：由于产科出血潜能和/或紧急分娩在妊娠妇女中谨慎使用XARELTO。及时评价血液丢失体征和症状。(5.7)

不良反应
最常见不良反应(>5%) 是出血。(6.1)
报告怀疑不良反应，联系Janssen Pharmaceuticals，Inc.公司电话1-800-526-7736或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.

药物相互作用
● CP-gp和强CYP3A4抑制剂和诱导剂联用：避免同时使用。(7.1，7.2)
● 抗凝剂：避免同时使用。(7.3)

特殊人群中使用
● 哺乳母亲：终止药物或终止哺乳。 (8.3)
● 肾受损：避免或根据CrCl调整剂量。 (8.7)
● 肝受损：在有Child-Pugh B和C肝受损或有任何程度肝病伴随凝血病患者避免使用。 (8.8)

FDA Approves XARELTO® (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery
XARELTO® is the only new oral anticoagulant with FDA approval in this indication
Raritan, NJ (July 1, 2011) /PRNewswire/ — Janssen Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved XARELTO® (rivaroxaban tablets), a novel, once-daily, oral anticoagulant for the prevention (prophylaxis) of deep vein thrombosis (DVT) which may lead to a pulmonary embolism (PE) in people undergoing knee or hip replacement surgery.

“The approval of once-daily XARELTO® tablets will provide a new option to help protect patients from developing venous blood clots following knee or hip replacement surgery,” said Louis M. Kwong, M.D., Professor of Orthopedic Surgery at Harbor-UCLA Medical Center, who was involved with the rivaroxaban clinical trials program in this indication. “XARELTO® has a proven clinical benefit over one of today’s most widely used options in preventing these potentially life-threatening blood clots, and the use of a once-daily pill may play an essential role in helping to simplify clinical practice.”

According to the American Academy of Orthopedic Surgeons, more than 800,000 Americans undergo knee or hip replacement surgery each year. These procedures are associated with an increased risk for DVT, a blood clot that forms in a deep vein, usually in the leg. If all or part of a DVT breaks off, 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 blood thinners (anticoagulants) immediately following major orthopedic replacement surgery and extended use post-discharge (at least 10 days for knee replacement, and up to 35 days for hip replacement) to help reduce such risks; however, full compliance with these guidelines using previously available options has not been widely observed. DVT and PE are the leading causes of re-hospitalization following joint replacement surgery.

“The use of blood thinners has been shown to safely and effectively help keep people from developing preventable blood clots,” said Alan Brownstein, Chief Executive Officer of the National Blood Clot Alliance. “The FDA approval of a new blood thinner, XARELTO®, offers a new option for patients seeking knee or hip replacement surgery, and we encourage people to discuss with their physicians the risk of blood clots and which blood thinner offers optimal protection as part of their pre-surgical consultation.”

Pivotal data from the XARELTO® Phase 3 clinical development program reflected in the approved label showed significantly greater efficacy of rivaroxaban, both in head-to-head comparison with enoxaparin and when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin, followed by placebo. In these trials, rivaroxaban and enoxaparin demonstrated similar safety profiles including low rates of major bleeding.

XARELTO® is approved for use at a 10 mg dose, once-daily for 35 days following hip replacement and for 12 days following knee replacement surgery. To date, XARELTO® is approved in more than 110 countries worldwide and has been successfully launched in more than 80 countries by Bayer HealthCare. Janssen Pharmaceuticals, Inc. holds marketing rights for XARELTO® in the U.S. The U.S. Bayer HealthCare sales force will support the Janssen Pharmaceuticals, Inc. sales force by detailing XARELTO® in designated hospital accounts.

“Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and XARELTO® provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home,” said Paul Chang, M.D., Vice President, Medical Affairs, Internal Medicine, Janssen Pharmaceuticals, Inc. “We’re pleased to make XARELTO® tablets available to physicians to help them better protect their patients from these highly preventable surgical complications.”

About XARELTO® (rivaroxaban tablets)
XARELTO® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in people undergoing knee or hip replacement surgery. XARELTO® belongs to a group of medicines called anticoagulants. It works by blocking the blood clotting Factor Xa and thereby reduces the tendency of the blood to form clots.

XARELTO® is the third New Drug Application the U.S. FDA has approved from the Janssen Pharmaceutical Companies this year.

Additionally, XARELTO® is being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. The extensive program of clinical trials evaluating rivaroxaban makes the compound the most studied oral, Factor Xa inhibitor in the world today. By the time of its completion, more than 65,000 patients will have participated in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare.

Important Safety Information

WHAT IS XARELTO®?

XARELTO®(rivaroxaban tablets) is a prescription medicine used to help prevent blood clots from forming in patients after hip or knee replacement surgery.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO®?

You should take XARELTO® exactly as directed by your doctor
Do not skip a dose or stop taking XARELTO® unless you are advised to do so by your doctor. Stopping may increase your risk of a blood clot
If a dose is missed, take XARELTO® as soon as possible and continue on the following day, taking XARELTO® as directed by your doctor. Do not take two doses at the same time
XARELTO® can cause bleeding, which can sometimes be serious, even life-threatening. You may find you bruise or bleed more easily while you take it. It might take longer than usual to stop bleeding
Alert your doctor right away if you develop any:
Tingling, numbness or muscle weakness, especially in your legs. This is particularly important if you had a procedure called spinal or epidural puncture as part of your anesthesia for your hip or knee replacement surgery
Unusual bleeding or bruising (bruises that develop without an injury or grow in size)
New bleeding (for example, nose bleeds, bleeding gums, red urine, bright red blood in your stool, coughing up or vomiting blood)
Bleeding that is heavier than usual (for example, from cuts or menstruation)
Dizziness, weakness, or tiredness, all of which could indicate a loss of blood
Pain, swelling, or new fluid leakage in or around the surgical incision
WHO SHOULD NOT TAKE XARELTO®?

Tell your doctor if you have:

Unusual bleeding
Ever had an allergic-type (hypersensitivity) reaction to XARELTO®
WHAT SHOULD I TELL MY DOCTOR BEFORE OR WHILE TAKING XARELTO®?

Tell your doctor or dentist about all the medicines you take
This includes XARELTO®, any other prescription and nonprescription medicines, over-the-counter medications, and herbal supplements
Tell your doctor if you:
Have a bleeding disorder or have problems with unusual bleeding
Have any problems with your kidneys or liver
Are pregnant or planning to become pregnant
Are breast-feeding or are planning to breast-feed
WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO®?

XARELTO® may increase your chance of bleeding. This bleeding can sometimes be serious (and even life-threatening)
In studies side effects with XARELTO® included fluid leakage from a wound, itching, pain in arms or legs, blisters, fainting, and muscle spasm
Discuss any side effects with your doctor. You are also encouraged to report side effects to the FDA: visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (526-7736)