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利伐沙班片Xarelto(Rivaroxaban Tablets)

2012-01-08 04:12:32  作者:新特药房  来源:中国新特药网天津分站  浏览次数:1675  文字大小:【】【】【
简介: 英文药名: 利伐沙班片|Xarelto(Rivaroxaban Tablets) 中文药名: 拜瑞妥(利伐沙班片) 生产厂家: Bayer Corporation 药品说明 拜瑞妥 薄膜衣片 [Xarelto®] 成份: 利伐沙班 Rivaroxaban 适应 ...

Xarelto(利伐沙班 rivaroxaban)是每天用药1次的口服抗凝药,获美国FDA扩展使用治疗减低血液凝固复发
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的用量及用法为:20mg,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15mg、每日1次的用药方案。


Xarelto由位于新泽西州Janssen Pharmaceuticals Inc.的Raritan上市
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XARELTO ® (rivaroxaban) safely and effectively. See full prescribing information for XARELTO.
XARELTO (rivaroxaban) tablets, for oral use
Initial U.S. Approval: 2011
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS,
(B) SPINAL/EPIDURAL HEMATOMASee full prescribing information for complete boxed warning
(A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy (2.2, 2.6, 5.1, 14.1).
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis (5.2, 5.3, 6.2).
Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated (5.3).
RECENT MAJOR CHANGES
Dosage and Administration (2.8) 01/2015
INDICATIONS AND USAGE
XARELTO is a factor Xa inhibitor indicated:
to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (1.1)
for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction in the risk of recurrence of DVT and of PE (1.2, 1.3, 1.4)
for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (1.5)
DOSAGE AND ADMINISTRATION
Take 15 mg and 20 mg tablets with food; take 10 mg tablets with or without food (2.1)
Nonvalvular Atrial Fibrillation:
For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal (2.3)
For patients with CrCl 15 – 50 mL/min: 15 mg orally, once daily with the evening meal (2.3)
Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE: 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and of PE. (2.4)
Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally, once daily with or without food (2.5)
DOSAGE FORMS AND STRENGTHS
Tablets: 10 mg, 15 mg, and 20 mg (3)
CONTRAINDICATIONS
Active pathological bleeding (4)
Severe hypersensitivity reaction to XARELTO (4)
WARNINGS AND PRECAUTIONS
Risk of bleeding: XARELTO can cause serious and fatal bleeding. Promptly evaluate signs and symptoms of blood loss. (5.2)
Pregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. Promptly evaluate signs and symptoms of blood loss. (5.7)
Prosthetic heart valves: XARELTO use not recommended (5.8)
ADVERSE REACTIONS
The most common adverse reaction (>5%) was bleeding. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid concomitant use (7.1, 7.2)
Anticoagulants: Avoid concomitant use (7.3)
USE IN SPECIFIC POPULATIONS
Nursing mothers: discontinue drug or discontinue nursing (8.3)
Renal impairment: Avoid or adjust dose based on CrCl (8.7)
Hepatic impairment: Avoid use in patients with Child-Pugh B and C hepatic impairment or with any degree of hepatic disease associated with coagulopathy (8.8)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1)].
1.2 Treatment of Deep Vein Thrombosis
XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
1.3 Treatment of Pulmonary Embolism
XARELTO is indicated for the treatment of pulmonary embolism (PE).
1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism
XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE.
1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.
2 DOSAGE AND ADMINISTRATION

Indication Dosage
Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation (2.3) CrCl >50 mL/min: 20 mg once daily with the evening meal
CrCl 15 to 50 mL/min: 15 mg once daily with the evening meal
Treatment of DVT (2.4)
Treatment of PE (2.4)
15 mg twice daily with food, for first 21 days
  ▼after 21 days, transition to ▼
20 mg once daily with food, for remaining treatment
Reduction in the Risk of Recurrence of DVT and of PE (2.4) 20 mg once daily with food
Prophylaxis of DVT Following Hip or Knee Replacement Surgery (2.5) Hip replacement: 10 mg once daily for 35 days
Knee replacement: 10 mg once daily for 12 days
2.1 Important Food Effect Information
The 15 mg and 20 mg XARELTO tablets should be taken with food, while the 10 mg tablet can be taken with or without food [see Clinical Pharmacology (12.3)].
In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.
2.2 Switching to and from XARELTO
Switching from Warfarin to XARELTO - When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.
Switching from XARELTO to Warfarin - No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.
Switching from XARELTO to Anticoagulants other than Warfarin - For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken [see Drug Interactions (7.3)].
Switching from Anticoagulants other than Warfarin to XARELTO - For patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.
2.3 Nonvalvular Atrial Fibrillation
For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal [see Use in Specific Populations (8.7)].
2.4 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
of Recurrence of DVT and of PEThe recommended dose of XARELTO for the initial treatment of acute DVT and/or PE is 15 mg taken orally twice daily with food for the first 21 days. After this initial treatment period, the recommended dose of XARELTO is 20 mg taken orally once daily with food, at approximately the same time each day. The recommended dose of XARELTO for reduction in the risk of recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same time each day [see Clinical Studies (14.2)].
2.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
The recommended dose of XARELTO is 10 mg taken orally once daily with or without food. The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established [see Dosage and Administration (2.6)].
For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.
2.6 Discontinuation for Surgery and other Interventions
If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions (5.2)]. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions (5.1)]. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
2.7 Missed Dose
If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day as follows:
For patients receiving 15 mg twice daily: The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. In this particular instance, two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed XARELTO dose immediately.
2.8 Administration Options
For patients who are unable to swallow whole tablets, 10 mg, 15 mg or 20 mg XARELTO tablets may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food [see Dosage and Administration (2.1, 2.3, 2.4) and Clinical Pharmacology (12.3)].
Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, 10 mg, 15 mg or 20 mg XARELTO tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding [see Clinical Pharmacology (12.3)].
Crushed 10 mg, 15 mg or 20 mg XARELTO tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing. 
3 DOSAGE FORMS AND STRENGTHS
10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a "10" marked on one side and "Xa" on the other side
15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a "15" marked on one side and "Xa" on the other side
20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a "20" marked on one side and "Xa" on the other side
4 CONTRAINDICATIONS
XARELTO is contraindicated in patients with:
active pathological bleeding [see Warnings and Precautions (5.2)]
severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions (6.2)]
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.6) and Clinical Studies (14.1)].
5.2 Risk of Bleeding
XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.
Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3)].
Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.1)].
Reversal of Anticoagulant Effect
A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.
5.3 Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.
Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
5.4 Use in Patients with Renal Impairment
Nonvalvular Atrial Fibrillation
Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug exposure is increased. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.7)].
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations (8.7)].
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations (8.7)].
5.5 Use in Patients with Hepatic Impairment
No clinical data are available for patients with severe hepatic impairment.
Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations (8.8)].
5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan) [see Drug Interactions (7.1)].
Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Drug Interactions (7.2)].
5.7 Risk of Pregnancy-Related Hemorrhage
In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
5.8 Patients with Prosthetic Heart Valves
The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.
5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy
Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
6 ADVERSE REACTIONS
The following adverse reactions are also discussed in other sections of the labeling:
Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see Boxed Warning and Warnings and Precautions (5.1)]
Bleeding risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
During clinical development for the approved indications, 16326 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 patients who received either XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1–3).
Hemorrhage
The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions (5.2)].
Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days 

Parameter XARELTO
N = 7111
n (%/year)
Warfarin
N = 7125
n (%/year)
XARELTO vs. Warfarin
HR
(95% CI)
Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major.
Major Bleeding 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20)
  Intracranial Hemorrhage (ICH) 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93)
    Hemorrhagic Stroke§ 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96)
    Other ICH 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34)
  Gastrointestinal (GI) 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99)
  Fatal Bleeding 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79)
    ICH 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96)
    Non-intracranial 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82)
Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment.
Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma.
Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days.
Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding.
Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 
Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE
EINSTEIN DVT and EINSTEIN PE Studies
In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.
Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies 

Parameter XARELTO
N = 4130
n (%)
Enoxaparin/
VKA
N = 4116
n (%)
Major bleeding event 40 (1.0) 72 (1.7)
  Fatal bleeding 3 (<0.1) 8 (0.2)
    Intracranial 2 (<0.1) 4 (<0.1)
  Non-fatal critical organ bleeding 10 (0.2) 29 (0.7)
    Intracranial 3 (<0.1) 10 (0.2)
    Retroperitoneal 1 (<0.1) 8 (0.2)
    Intraocular 3 (<0.1) 2 (<0.1)
    Intra-articular 0 4 (<0.1)
  Non-fatal non-critical organ bleeding 27 (0.7) 37 (0.9)
  Decrease in Hb ≥ 2g/dL 28 (0.7) 42 (1.0)
  Transfusion of ≥2 units of whole blood or packed red blood cells 18 (0.4) 25 (0.6)
Clinically relevant non-major bleeding 357 (8.6) 357 (8.7)
Any bleeding 1169 (28.3) 1153 (28.0)
Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.
Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0–3.0)]
Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group
Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells
EINSTEIN Extension Study
In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO and placebo treatment groups.
Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study.
Table 3: Bleeding Events* in EINSTEIN Extension Study 

Parameter XARELTO
20 mg
N = 598
n (%)
Placebo
N = 590
n (%)
Major bleeding event‡ 4 (0.7) 0
  Decrease in Hb ≥2 g/dL 4 (0.7) 0
  Transfusion of ≥2 units of whole blood or packed red blood cells 2 (0.3) 0
  Gastrointestinal 3 (0.5) 0
  Menorrhagia 1 (0.2) 0
Clinically relevant non-major bleeding 32 (5.4) 7 (1.2)
Any bleeding 104 (17.4) 63 (10.7)
Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category.
Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily
There were no fatal or critical organ bleeding events.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO.
The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.
Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1–3) 

XARELTO 10 mg Enoxaparin
Total treated patients N = 4487
n (%)
N = 4524
n (%)
  Major bleeding event 14 (0.3) 9 (0.2)
    Fatal bleeding 1 (<0.1) 0
    Bleeding into a critical organ 2 (<0.1) 3 (0.1)
    Bleeding that required re-operation 7 (0.2) 5 (0.1)
    Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 (0.1) 1 (<0.1)
  Any bleeding event‡ 261 (5.8) 251 (5.6)
Hip Surgery Studies N = 3281
n (%)
N = 3298
n (%)
  Major bleeding event 7 (0.2) 3 (0.1)
    Fatal bleeding 1 (<0.1) 0
    Bleeding into a critical organ 1 (<0.1) 1 (<0.1)
    Bleeding that required re-operation 2 (0.1) 1 (<0.1)
    Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 (0.1) 1 (<0.1)
  Any bleeding event‡ 201 (6.1) 191 (5.8)
Knee Surgery Study N = 1206
n (%)
N = 1226
n (%)
  Major bleeding event 7 (0.6) 6 (0.5)
    Fatal bleeding 0 0
    Bleeding into a critical organ 1 (0.1) 2 (0.2)
    Bleeding that required re-operation 5 (0.4) 4 (0.3)
    Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 (0.1) 0
  Any bleeding event 60 (5.0) 60 (4.9)
Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event.
Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3)
Includes major bleeding events
Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.
Other Adverse Reactions
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN Extension study are shown in Table 5.
Table 5: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN Extension Study 

System Organ Class
  Preferred Term
XARELTO
N = 598
n (%)
Placebo
N = 590
n (%)

 

Gastrointestinal disorders
  Abdominal pain upper 10 (1.7) 1 (0.2)
  Dyspepsia 8 (1.3) 4 (0.7)
  Toothache 6 (1.0) 0
General disorders and administration site conditions
  Fatigue 6 (1.0) 3 (0.5)
Infections and infestations
  Sinusitis 7 (1.2) 3 (0.5)
  Urinary tract infection 7 (1.2) 3 (0.5)
Musculoskeletal and connective tissue disorders
  Back pain 22 (3.7) 7 (1.2)
  Osteoarthritis 10 (1.7) 5 (0.8)
Respiratory, thoracic and mediastinal disorders
  Oropharyngeal pain 6 (1.0) 2 (0.3)

Adverse reaction (with Relative Risk >1.5 for XARELTO versus placebo) occurred after the first dose and up to 2 days after the last dose of study drug. Incidences are based on the number of patients, not the number of events. Although a patient may have had 2 or more clinical adverse reactions, the patient is counted only once in a category. The same patient may appear in different categories.
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 6.
Table 6: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD 1–3 Studies

System/Organ Class
  Adverse Reaction
XARELTO
10 mg
Enoxaparin†
N = 4487
n (%)
N = 4524
n (%)
Injury, poisoning and procedural complications
  Wound secretion 125 (2.8) 89 (2.0)
Musculoskeletal and connective tissue disorders
  Pain in extremity 74 (1.7) 55 (1.2)
  Muscle spasm 52 (1.2) 32 (0.7)
Nervous system disorders
  Syncope 55 (1.2) 32 (0.7)
Skin and subcutaneous tissue disorders
  Pruritus 96 (2.1) 79 (1.8)
  Blister 63 (1.4) 40 (0.9)
Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication
Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) 
Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia
Gastrointestinal disorders: retroperitoneal hemorrhage
Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)
Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema
Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
7 DRUG INTERACTIONS
Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.
7.1 Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
In drug interaction studies, conducted in subjects with normal renal function, evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, and erythromycin) or a moderate CYP3A4 inhibitor (fluconazole), increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. The increases in exposure ranged from 30% to 160%. Significant increases in rivaroxaban exposure may increase bleeding risk [see Clinical Pharmacology (12.3)].
When data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors.
Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors [see Warnings and Precautions (5.6)].
7.2 Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems
Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of XARELTO with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 50%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy [see Clinical Pharmacology (12.3)].
Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Warnings and Precautions (5.6)].
7.3 Anticoagulants and NSAIDs/Aspirin
Single doses of enoxaparin and XARELTO given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO resulted in an additive effect on factor Xa (FXa) inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Coadministration of the platelet aggregation inhibitor clopidogrel and XARELTO resulted in an increase in bleeding time for some subjects [see Clinical Pharmacology (12.3)].
Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)].
7.4 Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
Results from a pharmacokinetic trial with erythromycin indicated that patients with renal impairment coadministered XARELTO with drugs classified as combined P-gp and moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, dronedarone, and erythromycin) have increased exposure compared with patients with normal renal function and no inhibitor use. Significant increases in rivaroxaban exposure may increase bleeding risk.
While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with either combined P-gp and/or weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)] [see Use in Specific Populations (8.7)].
XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, dronedarone, and erythromycin) unless the potential benefit justifies the potential risk [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions (5.7)].
Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post‑implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.
8.2 Labor and Delivery
Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).
8.3 Nursing Mothers
It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in the RECORD 1–3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
8.6 Females of Reproductive Potential
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
8.7 Renal Impairment
In a pharmacokinetic study, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)].
Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.3)].
Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE
In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.
Prophylaxis of DVT Following Hip or Knee Replacement Surgery
The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.
8.8 Hepatic Impairment
In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).
The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)].
Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.
10 OVERDOSAGE
Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.
11 DESCRIPTION
Rivaroxaban, a FXa inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:


Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
XARELTO is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.
12.2 Pharmacodynamics
Dose-dependent inhibition of FXa activity was observed in humans and the Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban.
12.3 Pharmacokinetics
Absorption
The absolute bioavailability of rivaroxaban is dose-dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food [see Dosage and Administration (2.1)].
The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 2).
Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.
Distribution
Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.
Metabolism
Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.
Excretion
Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a [14C]-rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.
Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
Specific Populations
Gender
Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.
Race
Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.
Elderly
In clinical studies, elderly subjects exhibited higher rivaroxaban plasma concentrations than younger subjects with mean AUC values being approximately 50% higher, mainly due to reduced (apparent) total body and renal clearance. Age related changes in renal function may play a role in this age effect. The terminal elimination half-life is 11 to 13 hours in the elderly [see Use in Specific Populations (8.5)].
Body Weight
Extremes in body weight (<50 kg or >120 kg) did not influence (less than 25%) rivaroxaban exposure.
Renal Impairment
The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 7). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.
Table 7: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study 

CrCl (mL/min)
Parameter 50 to 79
N = 8
30 to 49
N = 8
15 to 29
N =
8
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance
Exposure AUC 44 52 64
(% increase relative to normal) Cmax 28 12 26
FXa Inhibition AUC 50 86 100
(% increase relative to normal) Emax 9 10 12
PT Prolongation AUC 33 116 144
(% increase relative to normal) Emax 4 17 20
Hepatic Impairment
The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 8). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.
Table 8: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study 

Hepatic Impairment Class
(Child-Pugh Class)
Parameter Mild
(Child-Pugh A)
N = 8
Moderate
(Child-Pugh B)
N = 8
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect
Exposure AUC 15 127
(% increase relative to normal) Cmax 0 27
FXa Inhibition AUC 8 159
(% increase relative to normal) Emax 0 24
PT Prolongation AUC 6 114
(% increase relative to normal) Emax 2 41
Drug Interactions
In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induces CYP1A2, 2B6, 2C19, or 3A4. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.
The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure 2 [see Drug Interactions (7) for dosing recommendations].
Figure 2: Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban

Anticoagulants
In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 2).
NSAIDs/Aspirin
In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 2).
Clopidogrel
In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.
Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A4 inhibitor). Compared to XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.
12.6 QT/QTc Prolongation
In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, single-dose).
13 NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.
Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.
No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.
14 CLINICAL STUDIES
14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation
The evidence for the efficacy and safety of XARELTO was derived from ROCKET AF, a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to <50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:
a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non‑CNS systemic embolism, or
2 or more of the following risk factors:
age ≥75 years,
hypertension,
heart failure or left ventricular ejection fraction ≤35%, or
diabetes mellitus
ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin's effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.
Table 9 displays the overall results for the primary composite endpoint and its components.
Table 9: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population) 

XARELTO Warfarin XARELTO vs. Warfarin
Event N = 7081
n (%)
Event Rate
(per 100 Pt-yrs)
N = 7090
n (%)
Event Rate
(per 100 Pt-yrs)
Hazard Ratio
(95% CI)

 

Primary Composite Endpoint* 269 (3.8) 2.1 306 (4.3) 2.4 0.88 (0.74, 1.03)
Stroke 253 (3.6) 2.0 281 (4.0) 2.2
  Hemorrhagic Stroke† 33 (0.5) 0.3 57 (0.8) 0.4
  Ischemic Stroke 206 (2.9) 1.6 208 (2.9) 1.6
  Unknown Stroke Type 19 (0.3) 0.2 18 (0.3) 0.1
Non-CNS Systemic Embolism 20 (0.3) 0.2 27 (0.4) 0.2
The primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic embolism. Data are shown for all randomized patients followed to site notification that the study would end.
Defined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification
Figure 3 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
Figure 3: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population)

Figure 4 shows the risk of stroke or non-CNS systemic embolism across major subgroups.
* Data are shown for all randomized patients followed to site notification that the study would end. 
Figure 4: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF* (Intent-to-Treat Population)


Data are shown for all randomized patients followed to site notification that the study would
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
The efficacy of XARELTO was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.
14.2 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies
XARELTO for the treatment of DVT and/or PE and for the reduction in the risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.
Table 10 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Table 10: Primary Composite Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population 

Event XARELTO 20 mg† Enoxaparin/VKA† XARELTO vs. Enoxaparin/VKA Hazard Ratio
(95% CI)
EINSTEIN DVT Study N = 1731
n (%)
N = 1718
n (%)
Primary Composite Endpoint 36 (2.1) 51 (3.0) 0.68 (0.44, 1.04)
  Death (PE) 1 (<0.1) 0
  Death (PE cannot be excluded) 3 (0.2) 6 (0.3)
  Symptomatic PE and DVT 1 (<0.1) 0
  Symptomatic recurrent PE only 20 (1.2) 18 (1.0)
  Symptomatic recurrent DVT only 14 (0.8) 28 (1.6)
EINSTEIN PE Study N = 2419
n (%)
N = 2413
n (%)
Primary Composite Endpoint 50 (2.1) 44 (1.8) 1.12 (0.75, 1.68)
  Death (PE) 3 (0.1) 1 (<0.1)
  Death (PE cannot be excluded) 8 (0.3) 6 (0.2)
  Symptomatic PE and DVT 0 2 (<0.1)
  Symptomatic recurrent PE only 23 (1.0) 20 (0.8)
  Symptomatic recurrent DVT only 18 (0.7) 17 (0.7)
For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (3, 6 or 12 months) irrespective of the actual treatment duration. If the same patient had several events, the patient may have been counted for several components.
Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0–3.0)]
Figures 5 and 6 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.
Figure 5: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study


Figure 6: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study

EINSTEIN Extension Study
XARELTO for reduction in the risk of recurrence of DVT and of PE was studied in the EINSTEIN Extension study, a multi-national, double-blind, superiority study comparing XARELTO (20 mg once daily with food) to placebo in patients who had completed 6 to 14 months of treatment for DVT and/or PE following the acute event. The intended treatment duration was 6 or 12 months based on investigator's assessment prior to randomization.
A total of 1196 patients were randomized and followed on study treatment for a mean of 190 days for both XARELTO and placebo treatment groups. The mean age was approximately 58 years. The population was 58% male, 78% Caucasian, 8% Asian and about 2% Black. Aspirin was taken as on-treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. In the EINSTEIN Extension study about 60% of patients had a history of proximal index DVT without PE event and 29% of patients had a PE without symptomatic DVT event. About 59% of patients had an idiopathic DVT/PE. Other risk factors included previous episode of DVT/PE (16%), immobilization (14%), known thrombophilic conditions (8%), or active cancer (5%).
In the EINSTEIN Extension study XARELTO was demonstrated to be superior to placebo for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [HR (95% CI): 0.18 (0.09, 0.39)].
Table 11 displays the overall results for the primary composite endpoint and its components.
Table 11: Primary Composite Endpoint Results* in EINSTEIN Extension Study – Intent-to-Treat Population 

Event XARELTO 20 mg
N = 602
n (%)
Placebo
N = 594
n (%)
XARELTO vs. Placebo
Hazard Ratio
(95% CI)
Primary Composite Endpoint 8 (1.3) 42 (7.1) 0.18 (0.09, 0.39)
p-value = <0.0001
  Death (PE) 0 1 (0.2)
  Death (PE cannot be excluded) 1 (0.2) 0
  Symptomatic recurrent PE 2 (0.3) 13 (2.2)
  Symptomatic recurrent DVT 5 (0.8) 31 (5.2)
For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (6 or 12 months) irrespective of the actual treatment duration.
Figure 7 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN Extension Study

14.3 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 12.
Table 12: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery - Modified Intent-to-Treat Population 

RECORD 1 RECORD 2
Treatment Dosage and Duration XARELTO
10 mg once daily
Enoxaparin
40 mg once daily
RRR,
p-value
XARELTO
10 mg once daily
Enoxaparin†
40 mg once daily
RRR*,
p-value

 

Number of Patients N = 1513 N = 1473 N = 834 N = 835
Total VTE 17 (1.1%) 57 (3.9%) 71%
(95% CI: 50, 83),
p<0.001
17 (2.0%) 70 (8.4%) 76%
(95% CI: 59, 86),
p<0.001
Components of Total VTE
  Proximal DVT 1 (0.1%) 31 (2.1%) 5 (0.6%) 40 (4.8%)
  Distal DVT 12 (0.8%) 26 (1.8%) 11 (1.3%) 43 (5.2%)
  Non-fatal PE 3 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%)
  Death (any cause) 4 (0.3%) 4 (0.3%) 2 (0.2%) 4 (0.5%)
Number of Patients N = 1600 N = 1587 N = 928 N = 929
Major VTE 3 (0.2%) 33 (2.1%) 91% (95% CI: 71, 97), p<0.001 6 (0.7%) 45 (4.8%) 87% (95% CI: 69, 94), p<0.001
Number of Patients N = 2103 N = 2119 N = 1178 N = 1179
Symptomatic VTE 5 (0.2%) 11 (0.5%) 3 (0.3%) 15 (1.3%)
Relative Risk Reduction; CI = confidence interval
Includes the placebo-controlled period of RECORD 2
Proximal DVT, nonfatal PE or VTE-related death
One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 13.
Table 13: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery - Modified Intent-to-Treat Population 

RECORD 3
Treatment Dosage and Duration XARELTO
10 mg once daily
Enoxaparin
40 mg once daily
RRR*,
p-value

 

Number of Patients N = 813 N = 871
Total VTE 79 (9.7%) 164 (18.8%) 48%
(95% CI: 34, 60),
p<0.001
Components of events contributing to Total VTE
  Proximal DVT 9 (1.1%) 19 (2.2%)
  Distal DVT 74 (9.1%) 154 (17.7%)
  Non-fatal PE 0 4 (0.5%)
  Death (any cause) 0 2 (0.2%)
Number of Patients N = 895 N = 917
Major VTE 9 (1.0%) 23 (2.5%) 60% (95% CI: 14, 81), p = 0.024
Number of Patients N = 1206 N = 1226
Symptomatic VTE 8 (0.7%) 24 (2.0%)
Relative Risk Reduction; CI = confidence interval
Proximal DVT, nonfatal PE or VTE-related death
16 HOW SUPPLIED/STORAGE AND HANDLING
XARELTO (rivaroxaban) Tablets are available in the strengths and packages listed below:
10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a "10" on one side, and "Xa" on the other side. The tablets are supplied in the packages listed: NDC 50458-580-30 Bottle containing 30 tablets
NDC 50458-580-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)
15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a "15" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed: NDC 50458-578-30 Bottle containing 30 tablets
NDC 50458-578-90 Bottle containing 90 tablets
NDC 50458-578-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)
20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a "20" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed: NDC 50458-579-30 Bottle containing 30 tablets
NDC 50458-579-90 Bottle containing 90 tablets
NDC 50458-579-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)
Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism: NDC 50458-584-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg
Store at 25°C (77°F) or room temperature; excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].
Keep out of the reach of children.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
17.1 Instructions for Patient Use
Advise patients to take XARELTO only as directed.
Remind patients to not discontinue XARELTO without first talking to their healthcare professional.
Advise patients with atrial fibrillation to take XARELTO once daily with the evening meal.
Advise patients with DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day [see Dosage and Administration (2.4)].
Advise patients who cannot swallow the tablet whole to crush XARELTO and combine with a small amount of applesauce followed by food [see Dosage and Administration (2.8)].
For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the XARELTO tablet and mix it with a small amount of water before administering via the tube [see Dosage and Administration (2.8)].
If a dose is missed, advise the patient to take XARELTO as soon as possible on the same day and continue on the following day with their recommended daily dose regimen.
17.2 Bleeding Risks
Advise patients to report any unusual bleeding or bruising to their physician. Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with XARELTO [see Warnings and Precautions (5.2)].
If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].
17.3 Invasive or Surgical Procedures
Instruct patients to inform their healthcare professional that they are taking XARELTO before any invasive procedure (including dental procedures) is scheduled.
17.4 Concomitant Medication and Herbals
Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions [see Drug Interactions (7)].
17.5 Pregnancy and Pregnancy-Related Hemorrhage
Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with XARELTO [see Use in Specific Populations (8.1)].
Advise pregnant women receiving XARELTO to immediately report to their physician any bleeding or symptoms of blood loss [see Warnings and Precautions (5.7)].
17.6 Nursing
Advise patients to discuss with their physician if they are nursing or intend to nurse during anticoagulant treatment [see Use in Specific Populations (8.3)].
17.7 Females of Reproductive Potential
Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use in Specific Populations (8.6)].
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10db92f9-2300-4a80-836b-673e1ae91610


FDA批准拜耳Xarelto(拜瑞妥)用于非瓣膜性房颤患者,预防中风及治疗深静脉血栓(DVT)
2015年5月4日,德国制药巨头拜耳(Bayer)近日宣布,每日一次的口服抗凝血剂Xarelto(rivaroxaban,利伐沙班)获中国国家食品药品监督管理总局(CFDA)批准,用于伴有一个或多个风险因素的非瓣膜性房颤患者,预防卒中和全身性栓塞。此外,CFDA已批准Xarelto用于治疗深静脉血栓(DVT)以及预防深静脉血栓(DVT)及肺栓塞(PE)的复发。在中国,Xarelto于2009年上市,用于接受择期髋关节或膝关节置换手术的成人患者,预防静脉血栓栓塞(VTE)。此次批准,使Xarelto在中国静脉和动脉血栓栓塞领域的适应症达到了3个。
FDA批准Xarelto用于房颤患者预防卒中(中风),是基于双盲全球III期研究ROCKET-AF的临床数据,该研究涉及患者总数超过1.4万例,研究中将Xarelto与华法林(warfarin)进行了对比。CFDA批准Xarelto用于急性DVT成人患者,治疗DVT及预防DVT和PE复发,是基于III期EINSTEIN-DVT研究及III其EINSTEIN-Extension研究的数据。
Xarelto(拜瑞妥,通用名:rivaroxaban,利伐沙班)是全球首个口服生物可利用的Xa因子抑制剂,由拜耳和强生合作开发。拜耳负责美国以外地区的商业化销售,强生负责美国的销售。
目前,Xarelto已获全球120多个国家批准。
在全球范围内,Xarelto已获批5个适应症,用于7大治疗领域:
(1)用于伴有一个或多个风险因素的非瓣膜性房颤患者,预防卒中和全身性栓塞;
(2)用于治疗深静脉血栓(DVT);
(3)用于治疗肺栓塞(PE);
(4)用于预防DVT和PE复发;
(5)用于接受择期全膝关节置换术患者,预防静脉血栓栓塞(VTE);
(6)用于接受择期全髋关节置换术患者,预防静脉血栓栓塞(VTE);
(7)联合标准抗血小板疗法,用于心脏生物标志物水平升高及既往无中风或短暂性脑缺血发作(TIA)的成人患者急性冠脉综合征(ACS)发作后动脉粥样硬化事件(心血管死亡、心肌梗死或中风)的预防。

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