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Xarelto

Xarelto(rivaroxaban) – Janssen

BOXED WARNING

May increase the risk of thrombotic events and stroke after d/c of therapy in atrial fibrillation patients. If therapy must be d/c for a reason other than pathological bleeding, consider administering another anticoagulant. Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture; long-term or permanent paralysis may result. Increased risk of developing epidural or spinal hematomas in patients using indwelling epidural catheters, concomitant use of other drugs that affect hemostasis (eg, NSAIDs, platelet inhibitors, other anticoagulants), history of traumatic or repeated epidural or spinal puncture, and a history of spinal deformity or spinal surgery. Monitor frequently for signs/symptoms of neurologic impairment; urgent treatment is necessary if neurologic compromise occurs. Consider benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

View FDA-Approved Full Prescribing Information for Xarelto

THERAPEUTIC CLASS

Specific factor Xa inhibitor

INDICATIONS

Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Reduction in the risk of recurrence of DVT and PE following initial 6 months treatment for DVT and/or PE. Prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

ADULT DOSAGE

Adults: Reduction In Risk Of Stroke In Nonvalvular Atrial Fibrillation: CrCl >50mL/min: 20mg qd with pm meal. CrCl 15-50mL/min: 15mg qd with pm meal. Refer to PI for information when switching from or to warfarin or other anticoagulants. Treatment of DVT/PE: Initial: 15mg bid for the first 21 days, then 20mg qd, at approximately the same time each day. Reduction in Risk of Recurrence of DVT/PE: 20mg qd at approximately the same time each day. Prophylaxis of DVT: 10mg qd. Give initial dose at least 6-10 hrs after surgery once hemostasis is established. Treatment Duration: Hip Replacement Surgery: 35 days. Knee Replacement Surgery: 12 days. Surgery/Intervention: If anticoagulation must be d/c with surgery or other procedures, d/c therapy at least 24 hrs before procedure to reduce the risk of bleeding. Weigh risk of bleeding against urgency of intervention to decide whether procedure should be delayed until 24 hrs after last dose. After procedure, restart therapy as soon as adequate hemostasis has been established. Missed Dose: Refer to PI.

HOW SUPPLIED

Tab: 10mg, 15mg, 20mg

CONTRAINDICATIONS

Active pathological bleeding.

WARNINGS/PRECAUTIONS

May increase risk of bleeding and cause serious or fatal bleeding; risk of thrombotic events should be weighed against risk of bleeding before initiation of treatment. Promptly evaluate any signs/symptoms of blood loss and consider the need for blood replacement; d/c in patients with active pathological hemorrhage. An epidural catheter should not be removed earlier than 18 hrs after last administration of therapy. The next dose should not be administered earlier than 6 hrs after catheter removal. If traumatic puncture occurs, delay administration for 24 hrs. May increase risk of pregnancy related hemorrhage. Avoid use for prophylaxis of DVT, treatment of DVT/PE, and reduction in risk of recurrence of DVT/PE in patients with CrCl<30mL/min or for nonvalvular atrial fibrillation in patients with CrCl <15mL/min. Avoid with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, or any hepatic disease associated with coagulopathy. Monitor for signs/symptoms of blood loss in patients with CrCl 30-50mL/min in prophylaxis of DVT. D/C therapy if acute renal failure develops.

ADVERSE REACTIONS

Spinal/epidural hematomas, neurological impairment, bleeding events, back pain, wound secretion, pain in extremity.

DRUG INTERACTIONS

See Boxed Warning. May result in changes in exposure with inhibitors/inducers of CYP3A4/5, CYP2J2, and P-glycoprotein (P-gp) and ATP-binding cassette G2 transporters. Avoid with combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John's wort); may decrease exposure and efficacy. Increased exposure with combined P-gp and CYP3A4 inhibitors (eg, clarithromycin, erythromycin, and fluconazole) may increase bleeding risk; avoid with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Renally impaired patients may have increases in exposure with combined P-gp and weak or moderate CYP3A4 inhibitors (eg, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine). Single dose of enoxaparin resulted in an additive effect on anti-factor Xa activity. Concomitant use of other drugs affecting hemostasis (eg, platelet aggregation inhibitors, other antithrombotic agents, fibrinolytic therapy, NSAIDs/aspirin) increases the risk of bleeding. Single dose of warfarin resulted in an additive effect on factor Xa inhibition and PT. May increase bleeding time with clopidogrel. Avoid concurrent use with other anticoagulants due to increased bleeding risk unless benefit outweighs risk.

PREGNANCY

Category C, not for use in nursing.

MECHANISM OF ACTION

Specific factor Xa inhibitor; selectively blocks the active site of factor Xa and does not require a cofactor for activity. Activation of factor X to factor Xa via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.

PHARMACOKINETICS

Absorption: Absolute bioavailability (80-100% [10mg], 66% [20mg, fasted]); Tmax=2-4 hrs. Distribution: Vd=50L; plasma protein binding (92-95%). Metabolism: Oxidative degradation via CYP3A4/5 and CYP2J2; hydrolysis. Elimination: Urine (66%, 36% unchanged), feces (28%, 7% unchanged); T1/2=5-9 hrs (20-45 yrs), 11-13 hrs (elderly).

ASSESSMENT

Assess for known hypersensitivity, active pathological bleeding, risk factors for developing epidural or spinal hematomas, conditions that may increase risk of bleeding, renal/hepatic impairment, hepatic disease, pregnancy/nursing status, and possible drug interactions.

MONITORING

Monitor for signs/symptoms of bleeding, stroke, thrombotic events, and other adverse reactions. In patients undergoing neuraxial anesthesia or spinal puncture, monitor for epidural or spinal hematomas and neurologic impairment. Monitor renal function (eg, CrCl) periodically.

PATIENT COUNSELING

Instruct to take ud. Advise to follow missed dosing instructions. Advise not to d/c without consulting physician. Advise to report any unusual bleeding or bruising. Inform that it may take longer than usual to stop bleeding, and that they may bruise and/or bleed more easily. Advise patients who had neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal/epidural hematoma (eg, tingling, numbness, and muscular weakness), especially if concomitantly taking NSAIDs or platelet inhibitors; contact physician if symptoms occur. Inform physician about therapy before any invasive procedure. Instruct to inform their physicians and dentists if they are taking, or plan to take, any prescription or OTC drugs or herbals. Inform physician immediately if nursing/pregnant or intend to nurse or become pregnant. Advise pregnant women receiving therapy to immediately report to the physician any bleeding or symptoms of blood loss.

ADMINISTRATION/STORAGE

Administration: Oral route. 15mg and 20mg should be taken with food, while 10mg can be taken with or without food. Storage: 25°C (77°F); excursions permitted to 15-30°C (59-86°F).


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    Xarelto

    Xarelto

    Generic Name: rivaroxaban

    Dosage Form: tablet, film coated

    For ProfessionalsSide EffectsDosageInteractionsMore…

    WARNING: (A) DISCONTINUING Xarelto IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING Xarelto IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION

    Discontinuing Xarelto places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following Xarelto discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with Xarelto must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Clinical Studies (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. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

    • use of indwelling epidural catheters
    • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
    • a history of traumatic or repeated epidural or spinal punctures
    • a history of spinal deformity or spinal surgery

    [see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].

    Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].

    Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].

    Indications and Usage for Xarelto

    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)].

    Treatment of Deep Vein Thrombosis

    Xarelto is indicated for the treatment of deep vein thrombosis (DVT).

    Treatment of Pulmonary Embolism

    Xarelto is indicated for the treatment of pulmonary embolism (PE).

    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.

    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.

    Xarelto 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  

    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.

    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.

    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)].

    Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

    The 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)].

    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 at least 6 to 10 hours after surgery once 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.

    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.

    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, 15 or 10 mg once daily: The patient should take the missed Xarelto dose immediately.

    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

    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)]

    Warnings and Precautions

    Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation

    Discontinuing 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 must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.3) and Clinical Studies (14.1)].

    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.

    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. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical trials.

    Concomitant use of other drugs affecting 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)].

    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].

    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.

    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)].

    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)].

    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/ritonavir, 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)].

    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).

    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)]

    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 study.

    Table 1: Bleeding Events in ROCKET AF*
    Parameter Xarelto

    N = 7111

    n (%)

    Event Rate

    (per 100 Pt-yrs)

    Warfarin

    N = 7125

    n (%)

    Event Rate

    (per 100 Pt-yrs)

    *
    For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event.
    Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for Xarelto vs. 2.9 per 100 Pt-yrs for warfarin.
    The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.
    Major bleeding† 395 (5.6) 3.6 386 (5.4) 3.5
      Bleeding into a critical organ‡ 91 (1.3) 0.8 133 (1.9) 1.2
      Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5
      Bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 183 (2.6) 1.7 149 (2.1) 1.3
    Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2

    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 (%)

    *
    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
    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)

    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 (%)

    *
    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.
    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)

    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†
    *
    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
    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)

    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 (%)

    *
    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.
    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)

    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 (%)

    *
    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)
    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)

    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.

    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

    Gastrointestinal disorders: retroperitoneal hemorrhage

    Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis

    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

    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.

    Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

    In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin and 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)].

    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)].

    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 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)].

    Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

    Patients with renal impairment receiving full dose Xarelto in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

    Xarelto should be used in patients with CrCl 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Clinical Pharmacology (12.3)].

    USE IN SPECIFIC POPULATIONS

    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.

    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).

    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.

    Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    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)].

    Females of Reproductive Potential

    Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

    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.

    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.

    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)].

    Xarelto Description

    Rivaroxaban, a factor Xa 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 Xarelto 15 mg tablets is Opadry® Red, 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.

    Xarelto – Clinical Pharmacology

    Mechanism of Action

    Xarelto is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.

    Pharmacodynamics

    Dose-dependent inhibition of factor Xa 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.

    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.

    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 via a method that could deposit drug directly into the proximal small intestine (e.g., feeding tube) which can result in reduced absorption and related drug exposure.

    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 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 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.

    Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

    In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors the following increases in rivaroxaban exposure were observed. Similar increases in pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were also observed. Significant increases in rivaroxaban exposure may increase bleeding risk.

    • Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.
    • Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.
    • Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.
    • Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.
    • Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

    Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems

    In a drug interaction study, coadministration of Xarelto (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.

    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. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and Xarelto (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.

    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. In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with Xarelto.

    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

    Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose Xarelto in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

    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 combined P-gp and 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)].

    Drugs that are Substrates of CYP3A4 and/or Drug Transport Systems

    In addition, there were no significant pharmacokinetic interactions observed in studies comparing concomitant rivaroxaban 20 mg and 7.5 mg single dose of midazolam (substrate of CYP3A4), 0.375 mg once-daily dose of digoxin (substrate of P-gp), or 20 mg once daily dose of atorvastatin (substrate of CYP3A4 and P-gp) in healthy volunteers.

    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).

    NON-CLINICAL TOXICOLOGY

    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.

    Clinical Studies

    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
    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)

    *
    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.
    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

    Figure 1 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.

    Figure 1: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group

    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.

    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)

    *
    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)]
    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)

    Figures 2 and 3 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 2: 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 3: 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)

    *
    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.
    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)

    Figure 4 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.

    Figure 4: 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

    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

    *
    Relative Risk Reduction; CI=confidence interval
    Includes the placebo-controlled period of RECORD 2
    Proximal DVT, nonfatal PE or VTE-related death
    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%)

    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

    *
    Relative Risk Reduction; CI=confidence interval
    Proximal DVT, nonfatal PE or VTE-related death
    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%)

    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 an “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)

    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.

    Patient Counseling Information

    See FDA-approved patient labeling (Medication Guide).

    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)].
    • 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.

    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 tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].

    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.

    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)].

    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)].

    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)].

    Females of Reproductive Potential

    Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use in Specific Populations (8.6)].

    Active Ingredient Made in Germany

    Finished Product Manufactured by:

    Janssen Ortho, LLC

    Gurabo, PR 00778

    Manufactured for:

    Janssen Pharmaceuticals, Inc.

    Titusville, NJ 08560

    Licensed from:

    Bayer HealthCare AG

    51368 Leverkusen, Germany

    © Janssen Pharmaceuticals, Inc. 2011

    MEDICATION GUIDE

    Xarelto® (zah-REL-toe)

    (rivaroxaban)

    Tablets

    Read this Medication Guide before you start taking Xarelto and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

    What is the most important information I should know about Xarelto?

    • For people taking Xarelto for atrial fibrillation: People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. Xarelto lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking Xarelto, you may have increased risk of forming a clot in your blood.

      Do not stop taking Xarelto without talking to the doctor who prescribes it for you. Stopping Xarelto increases your risk of having a stroke.

      If you have to stop taking Xarelto, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

    • Xarelto can cause bleeding which can be serious, and rarely may lead to death. This is because Xarelto is a blood thinner medicine that reduces blood clotting. While you take Xarelto you are likely to bruise more easily and it may take longer for bleeding to stop. You may have a higher risk of bleeding if you take Xarelto and take other medicines that increase your risk of bleeding, including:
      • aspirin or aspirin containing products
      • non-steroidal anti-inflammatory drugs (NSAIDs)
      • warfarin sodium (Coumadin®, Jantoven®)
      • any medicine that contains heparin
      • clopidogrel (Plavix®)
      • other medicines to prevent or treat blood clots

      Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

      Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

      • unexpected bleeding or bleeding that lasts a long time, such as:
        • nose bleeds that happen often
        • unusual bleeding from the gums
        • menstrual bleeding that is heavier than normal or vaginal bleeding
      • bleeding that is severe or you cannot control
      • red, pink or brown urine
      • bright red or black stools (looks like tar)
      • cough up blood or blood clots
      • vomit blood or your vomit looks like “coffee grounds”
      • headaches, feeling dizzy or weak
      • pain, swelling, or new drainage at wound sites
    • Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like Xarelto, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot than can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:
      • a thin tube called an epidural catheter is placed in your back to give you certain medicine.
      • you take NSAIDs or a medicine to prevent blood from clotting
      • you have a history of difficult or repeated epidural or spinal punctures
      • you have a history of problems with your spine or have had surgery on your spine.

    If you take Xarelto and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.

    See “What are the possible side effects of Xarelto?” for more information about side effects.

    What is Xarelto?

    • Xarelto is a prescription medicine used to:
      • reduce the risk of stroke and blood clots in people who have a medical condition called atrial fibrillation. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing a stroke, or to other parts of the body.
      • treat blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism) and reduce the risk of them occurring again.
      • reduce the risk of forming a blood clot in the legs and lungs of people who have just had hip or knee replacement surgery.

    It is not known if Xarelto is safe and effective in children.

    Who should not take Xarelto?

    Do not take Xarelto if you:

    • currently have certain types of abnormal bleeding. Talk to your doctor before taking Xarelto if you currently have unusual bleeding.
    • are allergic to rivaroxaban or any of the ingredients in Xarelto. See the end of this leaflet for a complete list of ingredients in Xarelto.

    What should I tell my doctor before taking Xarelto?

    Before you take Xarelto, tell your doctor if you:

    • have ever had bleeding problems
    • have liver or kidney problems
    • have any other medical condition
    • are pregnant or plan to become pregnant. It is not known if Xarelto will harm your unborn baby. Tell your doctor right away if you become pregnant while taking Xarelto. If you take Xarelto during pregnancy tell your doctor right away if you have any bleeding or symptoms of blood loss.
    • are breastfeeding or plan to breastfeed. It is not known if Xarelto passes into your breast milk. You and your doctor should decide if you will take Xarelto or breastfeed.

    Tell all of your doctors and dentists that you are taking Xarelto. They should talk to the doctor who prescribed Xarelto for you before you have any surgery, medical or dental procedure.

    Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way Xarelto works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about Xarelto?”

    Especially tell your doctor if you take:

    • ketoconazole (Nizoral®)
    • itraconazole (Onmel, Sporanox®)
    • ritonavir (Norvir®)
    • lopinavir/ritonavir (Kaletra®)
    • indinavir (Crixivan®)
    • carbamazepine (Carbatrol®, Equetro®, Tegretol®, Tegretol®-XR, Teril, Epitol®)
    • phenytoin (Dilantin-125®, Dilantin®)
    • phenobarbital (Solfoton)
    • rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®)
    • St. John’s wort (Hypericum perforatum)

    Ask your doctor if you are not sure if your medicine is one listed above.

    Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

    How should I take Xarelto?

    • Take Xarelto exactly as prescribed by your doctor.
    • Do not change your dose or stop taking Xarelto unless your doctor tells you to.
    • Your doctor will tell you how much Xarelto to take and when to take it.
    • Your doctor may change your dose if needed.
    • For people who have:
      • atrial fibrillation: Take Xarelto 1 time a day with your evening meal. Stopping Xarelto may increase your risk of having a stroke or forming blood clots in other parts of your body.
      • blood clots in the veins of your legs or lungs: To treat blood clots, take Xarelto once or twice a day according to your doctor’s instructions. Xarelto is usually taken with food. Take Xarelto at the same time each day.
      • hip or knee replacement surgery: Take Xarelto 1 time a day with or without food.
    • Your doctor will decide how long you should take Xarelto. Do not stop taking Xarelto without talking with your doctor first.
    • Your doctor may stop Xarelto for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking Xarelto again after your surgery or procedure.
    • Do not run out of Xarelto. Refill your prescription of Xarelto before you run out. When leaving the hospital following a hip or knee replacement, be sure that you will have Xarelto available to avoid missing any doses.
    • If you miss a dose of Xarelto, take it as soon as you remember on the same day and continue with your next regularly scheduled dose.
    • If you take too much Xarelto, go to the nearest hospital emergency room or call your doctor right away.

    What are the possible side effects of Xarelto?

    • See “What is the most important information I should know about Xarelto?”

    Tell your doctor if you have any side effect that bothers you or that does not go away.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Xarelto?

    • Store Xarelto at room temperature between 68°F to 77°F (20° to 25° C).

    Keep Xarelto and all medicines out of the reach of children.

    General information about Xarelto.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Xarelto for a condition for which it was not prescribed. Do not give Xarelto to other people, even if they have the same condition. It may harm them.

    This Medication Guide summarizes the most important information about Xarelto. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Xarelto that is written for health professionals.

    For more information call 1-800-526-7736 or go to www.Xarelto-US.com.

    What are the ingredients in Xarelto?

    Active ingredient: rivaroxaban

    Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

    The proprietary film coating mixture for Xarelto 10 mg tablets is Opadry® Pink contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

    The proprietary film coating mixture for Xarelto 15 mg tablets is Opadry® Red, contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

    The proprietary film coating mixture for Xarelto 20 mg tablets is Opadry® II Dark Red, contains: ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Finished Product Manufactured by:

    Janssen Ortho, LLC

    Gurabo, PR 00778

    Manufactured for:

    Janssen Pharmaceuticals, Inc.

    Titusville, NJ 08560

    Licensed from:

    Bayer HealthCare AG

    51368 Leverkusen, Germany

    Revised: November 2012

    © Janssen Pharmaceuticals, Inc. 2011

    Trademarks are property of their respective owners.

    PRINCIPAL DISPLAY PANEL – 10 mg Tablet Bottle Label

    NDC 50458-580-30

    30 Tablets

    Xarelto®

    (rivaroxaban)

    Tablets

    10 mg

    Rx only

    janssen

    PRINCIPAL DISPLAY PANEL – 15 mg Tablet Bottle Label

    NDC 50458-578-30

    30 Tablets

    Xarelto®

    (rivaroxaban)

    Tablets

    15 mg

    Dispense the accompanying

    Medication Guide to each patient.

    janssen

    Rx only

    PRINCIPAL DISPLAY PANEL – 20 mg Tablet Bottle Label

    NDC 50458-579-30

    30 Tablets

    Xarelto®

    (rivaroxaban)

    Tablets

    20 mg

    Dispense the accompanying

    Medication Guide to each patient.

    janssen

    Rx only

    Xarelto 

    rivaroxaban tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50458-580
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    rivaroxaban (rivaroxaban) rivaroxaban 10 mg
    Inactive Ingredients
    Ingredient Name Strength
    cellulose, microcrystalline  
    croscarmellose sodium  
    hypromelloses  
    lactose monohydrate  
    magnesium stearate  
    sodium lauryl sulfate  
    polyethylene glycol 3350  
    titanium dioxide  
    ferric oxide red  
    Product Characteristics
    Color RED (light red) Score no score
    Shape ROUND (biconvex) Size 6mm
    Flavor Imprint Code 10;Xa
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:50458-580-10 10 BLISTER PACK in 1 CARTON
    1 10 TABLET, FILM COATED in 1 BLISTER PACK
    2 NDC:50458-580-30 30 TABLET, FILM COATED in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022406 07/01/2011
    Xarelto 

    rivaroxaban tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50458-578
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    rivaroxaban (rivaroxaban) rivaroxaban 15 mg
    Inactive Ingredients
    Ingredient Name Strength
    cellulose, microcrystalline  
    croscarmellose sodium  
    hypromelloses  
    lactose monohydrate  
    magnesium stearate  
    sodium lauryl sulfate  
    polyethylene glycol 3350  
    titanium dioxide  
    ferric oxide red  
    Product Characteristics
    Color RED Score no score
    Shape ROUND (biconvex) Size 6mm
    Flavor Imprint Code 15;Xa
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:50458-578-10 10 BLISTER PACK in 1 CARTON
    1 10 TABLET, FILM COATED in 1 BLISTER PACK
    2 NDC:50458-578-30 30 TABLET, FILM COATED in 1 BOTTLE
    3 NDC:50458-578-90 90 TABLET, FILM COATED in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202439 11/04/2011
    Xarelto 

    rivaroxaban tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50458-579
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    rivaroxaban (rivaroxaban) rivaroxaban 20 mg
    Inactive Ingredients
    Ingredient Name Strength
    cellulose, microcrystalline  
    croscarmellose sodium  
    hypromelloses  
    lactose monohydrate  
    magnesium stearate  
    sodium lauryl sulfate  
    polyethylene glycol 3350  
    titanium dioxide  
    ferric oxide red  
    Product Characteristics
    Color RED (dark red) Score no score
    Shape TRIANGLE Size 7mm
    Flavor Imprint Code 20;Xa
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:50458-579-10 10 BLISTER PACK in 1 CARTON
    1 10 TABLET, FILM COATED in 1 BLISTER PACK
    2 NDC:50458-579-30 30 TABLET, FILM COATED in 1 BOTTLE
    3 NDC:50458-579-90 90 TABLET, FILM COATED in 1 BOTTLE
    4 NDC:50458-579-99 1 BOTTLE in 1 CARTON
    4 5 TABLET, FILM COATED in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202439 11/05/2011
    Labeler - Janssen Pharmaceuticals, Inc. (063137772)
    Establishment
    Name Address ID/FEI Operations
    Bayer Schering Pharma AG 341081414 MANUFACTURE(50458-580, 50458-578, 50458-579)
    Establishment
    Name Address ID/FEI Operations
    Janssen Ortho LLC 805887986 MANUFACTURE(50458-580, 50458-578, 50458-579), ANALYSIS(50458-580, 50458-578, 50458-579)

    Revised: 11/2012   Janssen Pharmaceuticals, Inc.

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    Xarelto

    Xarelto

    Generic Name: rivaroxaban (RIV-a-ROX-a-ban)

    Brand Name: Xarelto

    Do not stop taking Xarelto without checking with your doctor. This may increase the risk of developing a blood clot, including stroke in certain patients. If you need to stop taking Xarelto, follow your doctor’s directions carefully.

    Tell your doctor you use Xarelto before you have any type of spinal or epidural procedure. Patients who have these procedures while they use Xarelto are at risk of serious bleeding problems on or near the spine. This could result in long-term or permanent paralysis.

    The risk is increased in patients who have a certain type of epidural catheter. It is also increased in patients with a history of traumatic or repeated epidural or spinal puncture, a deformed spine, or spinal surgery. It is also increased in patients who use medicines that may affect blood clotting, such as other anticoagulants (eg, warfarin), aspirin, platelet inhibitors (eg, clopidogrel), and nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen).

    If you have a spinal or epidural procedure while you use Xarelto, tell your doctor at once if you notice any symptoms of nerve problems (eg, numbness [especially in the legs and feet], tingling, muscle weakness, paralysis).

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    Xarelto is used for:

    Preventing and treating blood clots in certain patients. It is also used to reduce the risk of stroke and serious blood clots in certain patients with atrial fibrillation. Xarelto is also used to treat and prevent deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism).

    Xarelto is a direct factor Xa inhibitor. It works by blocking the formation of blood clots.

    Do NOT use Xarelto if:

    • you are allergic to any ingredient in Xarelto
    • you have certain types of abnormal bleeding (eg, active major bleeding)
    • you have severe kidney problems, moderate to severe liver problems, or bleeding problems caused by liver disease
    • you are taking abciximab, alteplase, other anticoagulants (eg, enoxaparin, heparin, warfarin), bivalirudin, boceprevir, carbamazepine, cobicistat, conivaptan, dabigatran, desirudin, enzalutamide, eptifibatide, hydantoins (eg, phenytoin), indinavir, itraconazole, ketoconazole, lopinavir, nelfinavir, phenobarbital, posaconazole, rifamycins (eg, rifampin), ritonavir, saquinavir, St. John’s wort, telaprevir, tirofiban, or voriconazole

    Contact your doctor or health care provider right away if any of these apply to you.

    Before using Xarelto:

    Some medical conditions may interact with Xarelto. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

    • if you are pregnant, planning to become pregnant, or are breast-feeding
    • if you are able to become pregnant
    • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
    • if you have allergies to medicines, foods, or other substances
    • if you have a history of bleeding or clotting problems, high blood pressure, blood vessel problems (especially in the eyes, brain, or spinal column), anemia or other blood problems, low blood platelet levels or other platelet problems, or kidney or liver problems
    • if you have a history of a stroke, especially if it occurred within the last 6 months
    • if you have an active or recent stomach or bowel ulcer, or certain rare hereditary problems (galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption)
    • if you are at increased risk of bleeding
    • if you have recently had or are scheduled to have certain procedures (eg, surgery, including brain, spine, or eye surgery; dental procedures; a spinal or epidural procedure)
    • if you have kidney problems and are taking amiodarone, azithromycin, chloramphenicol, cimetidine, diltiazem, dronedarone, erythromycin, felodipine, quinidine, ranolazine, or verapamil

    Some MEDICINES MAY INTERACT with Xarelto. Tell your health care provider if you are taking any other medicines, especially any of the following:

    • Abciximab, alteplase, other anticoagulants (eg, enoxaparin, heparin, warfarin), aspirin, bivalirudin, dabigatran, desirudin, eptifibatide, NSAIDs (eg, ibuprofen, ketorolac), platelet inhibitors (eg, clopidogrel, prasugrel, ticlopidine), or tirofiban because the risk of bleeding may be increased
    • Boceprevir, clarithromycin, cobicistat, conivaptan, erythromycin, fluconazole, indinavir, itraconazole, ketoconazole, lopinavir, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, or voriconazole because they may increase the risk of Xarelto’s side effects, such as bleeding
    • Carbamazepine, enzalutamide, hydantoins (eg, phenytoin), phenobarbital, rifamycins (eg, rifampin), or St. John’s wort because they may decrease Xarelto’s effectiveness

    This may not be a complete list of all interactions that may occur. Ask your health care provider if Xarelto may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

    How to use Xarelto:

    Use Xarelto as directed by your doctor. Check the label on the medicine for exact dosing instructions.

    • Xarelto comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Xarelto refilled.
    • Take Xarelto by mouth with or without food, as directed by your doctor.
    • Taking Xarelto at the same time each day will help you remember to take it.
    • Be sure to take Xarelto for the full course of treatment. If you do not, you may be at increased risk of developing blood clots. Keep taking it even if you feel well.
    • If you miss a dose of Xarelto, take it as soon as possible on the same day you missed the dose then go back to your regular dosing schedule. Do not take 2 doses at once.

    Ask your health care provider any questions you may have about how to use Xarelto.

    Important safety information:

    • Do not change your dose or stop taking Xarelto without checking with your doctor. Stopping Xarelto may increase the risk of developing a blood clot, including stroke in patients with atrial fibrillation. If you need to stop taking Xarelto, follow your doctor’s directions carefully.
    • When your medicine supply is low, get more from your doctor or pharmacist as soon as you can.
    • Tell your doctor or dentist that you take Xarelto before you receive any medical or dental care, emergency care, or surgery. Xarelto may need to be stopped before certain types of surgery, as directed by your doctor. If Xarelto is stopped, your doctor will tell you when to start taking Xarelto again after your surgery or procedure.
    • If you have any type of spinal or epidural procedure while you are taking Xarelto, you may be at risk of serious bleeding problems on or near the spine, especially if you are also taking aspirin, NSAIDs (eg, ibuprofen), or platelet inhibitors (eg, clopidogrel). This could result in long-term or permanent paralysis. Tell your doctor at once if you notice any symptoms of nerve problems (eg, numbness [especially in the legs and feet], tingling, muscle weakness, paralysis).
    • Lab tests, including kidney function, hemoglobin, hematocrit, and blood pressure, may be performed while you use Xarelto. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
    • Use Xarelto with caution in the ELDERLY; they may be more sensitive to its effects.
    • Xarelto should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.
    • PREGNANCY and BREAST-FEEDING: It is not known if Xarelto can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Xarelto while you are pregnant. It is not known if Xarelto is found in breast milk. Do not breast-feed while taking Xarelto.

    Possible side effects of Xarelto:

    All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

    Mild bleeding.

    Seek medical attention right away if any of these SEVERE side effects occur:

    Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); bloody or black, tarry stools; change in the amount of urine produced; coughing up blood; dark urine; fever, chills, or persistent sore throat; pain, swelling, or new drainage at wound sites; pink or red urine; red, swollen, blistered, or peeling skin; stiff, sore, hot, or painful joints; symptoms of anemia (eg, unusual paleness, severe or persistent headache, shortness of breath, fast heartbeat, chest pain, unusual tiredness or weakness); symptoms of bleeding in the brain (eg, sudden, severe headache; one-sided weakness; vision problems; slurred speech; confusion); symptoms of low blood pressure (eg, fainting, dizziness or light-headedness); unexplained swelling; unusual or prolonged bruising or bleeding (eg, abnormal menstrual periods, frequent nosebleeds, unusual bleeding from the gums, vaginal bleeding); vomit that looks like coffee grounds; yellowing of the skin or eyes.

    This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

    If OVERDOSE is suspected:

    Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include unusual bruising or bleeding.

    Proper storage of Xarelto: Store Xarelto at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Xarelto out of the reach of children and away from pets.

    General information:

    • If you have any questions about Xarelto, please talk with your doctor, pharmacist, or other health care provider.
    • Xarelto is to be used only by the patient for whom it is prescribed. Do not share it with other people.
    • If your symptoms do not improve or if they become worse, check with your doctor.
    • Check with your pharmacist about how to dispose of unused medicine.

    This information should not be used to decide whether or not to take Xarelto or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Xarelto. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Xarelto. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Xarelto.

    Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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    Xarelto

    Xarelto

    Generic Name: rivaroxaban (Oral route)

    riv-a-ROX-a-ban

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore… Oral route(Tablet) Discontinuing rivaroxaban places patients at an increased risk of thrombotic events such as stroke. If anticoagulation with rivaroxaban must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Epidural or spinal hematomas, which may result in long-term or permanent paralysis, have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. Factors that can increase the risk of developing these hematomas include: use of indwelling epidural catheters, concomitant use of drugs affecting hemostasis such as NSAIDs, platelet inhibitors, or other anticoagulants, or history of traumatic or repeated epidural or spinal puncture, spinal deformity, or spinal surgery. Monitor patients frequently for neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider risks/benefits before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis .

    Commonly used brand name(s)

    In the U.S.

    • Xarelto

    Available Dosage Forms:

    • Tablet

    Therapeutic Class: Anticoagulant

    Pharmacologic Class: Factor Xa Inhibitor

    Uses For Xarelto

    Rivaroxaban is used to prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. This medicine is used for several days after hip or knee replacement surgery while you are unable to walk. It is during this time that blood clots are most likely to form.

    Rivaroxaban is also used to prevent stroke and blood clots in patients with certain heart rhythm problem (e.g., nonvalvular atrial fibrillation).

    Rivaroxaban is a factor Xa inhibitor, an anticoagulant. It works by decreasing the clotting ability of the blood and helps preventing harmful clots from forming in the blood vessels.

    This medicine is available only with your doctor’s prescription.

    Before Using Xarelto

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Appropriate studies have not been performed on the relationship of age to the effects of rivaroxaban in the pediatric population. Safety and efficacy have not been established.

    Geriatric

    Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of rivaroxaban in the elderly. However, elderly patients are more likely to have bleeding and blood clotting problems and age-related kidney disease, which may require caution and an adjustment in the dose for patients receiving rivaroxaban.

    Pregnancy

    Pregnancy Category Explanation
    All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

    Breast Feeding

    There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Abciximab
    • Acenocoumarol
    • Alteplase, Recombinant
    • Anistreplase
    • Argatroban
    • Aspirin
    • Bivalirudin
    • Bromfenac
    • Carbamazepine
    • Celecoxib
    • Cilostazol
    • Clarithromycin
    • Clopidogrel
    • Conivaptan
    • Dabigatran Etexilate
    • Dalteparin
    • Danaparoid
    • Desirudin
    • Dexamethasone
    • Diclofenac
    • Diflunisal
    • Dipyridamole
    • Drotrecogin Alfa
    • Enoxaparin
    • Eptifibatide
    • Etodolac
    • Flurbiprofen
    • Fondaparinux
    • Heparin
    • Ibuprofen
    • Ibuprofen Lysine
    • Indinavir
    • Indomethacin
    • Itraconazole
    • Ketoconazole
    • Ketoprofen
    • Ketorolac
    • Lepirudin
    • Lopinavir
    • Magnesium Salicylate
    • Mefenamic Acid
    • Meloxicam
    • Nabumetone
    • Naproxen
    • Nelfinavir
    • Nepafenac
    • Oxaprozin
    • Phenindione
    • Phenobarbital
    • Phenprocoumon
    • Phenytoin
    • Piroxicam
    • Posaconazole
    • Prasugrel
    • Protein C, Human
    • Reteplase, Recombinant
    • Rifampin
    • Rifapentine
    • Ritonavir
    • Salsalate
    • Saquinavir
    • St John’s Wort
    • Streptokinase
    • Sulfinpyrazone
    • Sulindac
    • Tenecteplase
    • Ticagrelor
    • Ticlopidine
    • Tinzaparin
    • Tirofiban
    • Tolmetin
    • Urokinase
    • Voriconazole
    • Warfarin

    Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Erythromycin

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Bleeding problems or
    • Blood vessel problems or
    • Catheter insertion in the spine or
    • Stomach or intestinal ulcer or bleeding or
    • Stroke, recent or history of or
    • Surgery (e.g., eye, brain, or spine), recent or history of—Use with caution. The risk of bleeding may be increased.
    • Kidney disease or
    • Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
    • Major bleeding, active—Should not be used in patients with this condition.

    Proper Use of Xarelto

    Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

    You may take this medicine with or without food.

    This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

    Dosing

    The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    • For oral dosage form (tablets):
      • For prevention of deep venous thrombosis (hip replacement surgery):
        • Adults—10 milligrams (mg) once a day for 35 days. The starting dose should be taken at least 6 to 10 hours after surgery.
        • Children—Use and dose must be determined by your doctor.
      • For prevention of deep venous thrombosis (knee replacement surgery):
        • Adults—10 milligrams (mg) once a day for 12 days. The starting dose should be taken at least 6 to 10 hours after surgery.
        • Children—Use and dose must be determined by your doctor.
      • For prevention of stroke and blood clots in patients with nonvalvular atrial fibrillation:
        • Adults—15 or 20 milligrams (mg) once a day, taken with the evening meal.
        • Children—Use and dose must be determined by your doctor.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    Storage

    Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

    Keep out of the reach of children.

    Do not keep outdated medicine or medicine no longer needed.

    Ask your healthcare professional how you should dispose of any medicine you do not use.

    Precautions While Using Xarelto

    It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests will be needed to check for unwanted effects. Be sure to keep all appointments.

    You may bleed or bruise more easily while you are using this medicine. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Be careful when using sharp objects, including razors and fingernail clippers. Avoid nose picking and forceful nose blowing.

    Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery or medical tests.

    This medicine may cause bleeding problems. This risk is higher if you have a catheter in your back for pain medicine or anesthesia (sometimes called an “epidural”), or if you have kidney problems. The risk of bleeding increases if your kidney problems get worse. Check with your doctor right away if you have any unusual bleeding or bruising; black, tarry stools; bleeding gums; blood in the urine or stools; tingling, numbness, or weakness of the lower legs; or pinpoint red spots on your skin.

    Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.

    Do not suddenly stop taking this medicine without first checking with your doctor. Doing so, may increase risk of having a stroke.

    Make sure your doctor knows if you are pregnant or planning to become pregnant during treatment with this medicine.

    Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John’s wort) or vitamin supplements.

    Xarelto Side Effects

    Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor immediately if any of the following side effects occur:

    More common

    • Back pain
    • bleeding gums
    • bloody stools
    • bowel or bladder dysfunction
    • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
    • coughing up blood
    • difficulty with breathing or swallowing
    • dizziness
    • headache
    • increased menstrual flow or vaginal bleeding
    • leg weakness
    • nosebleeds
    • numbness
    • paralysis
    • prolonged bleeding from cuts
    • red or black, tarry stools
    • red or dark brown urine
    • shortness of breath
    • vomiting of blood or material that looks like coffee grounds

    Less common

    • Fainting
    • pain in the arms or legs
    • wound secretion

    Rare

    • Burning while urinating
    • difficult or painful urination

    Incidence not known

    • Abdominal or stomach pain or swelling
    • blistering, peeling, or loosening of the skin
    • blurred vision
    • chills
    • clay-colored stools
    • cough or hoarseness
    • dark urine
    • diarrhea
    • fast or irregular heartbeat
    • fever with or without chills
    • general feeling of tiredness or weakness
    • hives
    • itching
    • joint or muscle pain
    • loss of appetite
    • lower back or side pain
    • nausea or vomiting
    • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
    • red skin lesions, often with a purple center
    • red, irritated eyes
    • severe headache
    • skin rash
    • sore throat
    • sores, ulcers, or white spots in the mouth or on the lips
    • tightness in the chest
    • unpleasant breath odor
    • unusual bleeding or bruising
    • unusual tiredness or weakness
    • wheezing
    • yellow eyes or skin

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    Less common

    • Blisters
    • muscle spasm

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    See also: Xarelto side effects (in more detail)

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    Xarelto

    Xarelto

    Generic Name: Rivaroxaban
    Class: Direct Factor Xa Inhibitors

    Chemical Name: 5 – Chloro – N – [[(5S) - 2 - oxo - 3 - [4 - (3 - oxo - 4 - morpholinyl)phenyl] – 5 – oxazolidinyl]methyl] – 2 – thiophenecarboxamide

    Molecular Formula: C19H18ClN3O5S

    CAS Number: 366789-02-8

    Warning(s)

    • Risks of Discontinuing Rivaroxaban in Patients with Nonvalvular Atrial Fibrillation
    • Increased risk of thrombotic events following rivaroxaban discontinuance.1 35 If discontinuance required for reasons other than pathologic bleeding (e.g., prior to surgery), consider use of an alternative anticoagulant.1 (See Risks of Discontinuing Rivaroxaban in Atrial Fibrillation Patients under Cautions.)
    • Spinal/Epidural Hematoma Risk
    • Risk of epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, in patients who are anticoagulated and also receiving neuraxial (spinal/epidural) anesthesia or spinal puncture.1
    • Risk increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet inhibitors, other anticoagulants).1
    • Risk also increased by history of traumatic or repeated epidural or spinal puncture or history of spinal deformity or spinal surgery.1
    • Monitor frequently for signs and symptoms of neurologic impairment and treat urgently if neurologic compromise noted.1
    • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.1 (See Spinal/Epidural Hematoma under Cautions and also see Interactions.)

    REMS:

    FDA approved a REMS for rivaroxaban to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of rivaroxaban and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

    Introduction

    Anticoagulant; an oral, direct, activated factor X (Xa) inhibitor.1 2 3 4 5 7 8 9 12 16 17 18 20 32 33

    Uses for Xarelto

    Embolism Associated with Atrial Fibrillation

    Reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 32

    Appears to be no less effective than warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; risk of major bleeding similar with rivaroxaban or warfarin.1 32 However, limited data exist on relative efficacy of rivaroxaban and warfarin when warfarin anticoagulation well controlled.1 11 32 40

    Many clinicians recommend long-term oral anticoagulation (usually with warfarin) for patients with paroxysmal or permanent atrial fibrillation at increased risk of stroke, unless contraindicated.35 36 1007

    Rivaroxaban suggested as alternative therapy in selected patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or do not achieve consistent therapeutic response to warfarin.32 37 38 49

    When selecting appropriate anticoagulant, consider factors such as individual patient’s risks of stroke and bleeding, compliance, preference, and comorbidities; cost; and availability of agents to reverse anticoagulant effects in case of bleeding complications.36 37 45 49 50 1007

    Efficacy of rivaroxaban for prevention of post-cardioversion stroke and systemic embolism in patients with atrial fibrillation not established.1

    Thromboprophylaxis in Hip- or Knee-Replacement Surgery

    Prevention of postoperative DVT and associated PE in patients undergoing hip- or knee-replacement surgery.1 2 3 4 5 6

    More effective than enoxaparin in preventing DVT and associated PE in patients undergoing elective total hip- or knee-replacement surgery; bleeding rates similar with rivaroxaban or enoxaparin.1 2 3 4 5 6 11 12 29 30 37

    ACCP and other clinicians consider rivaroxaban an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery;12 29 37 1003 however, a low molecular weight heparin (LMWH) generally is preferred.1003 Rivaroxaban may be a reasonable choice when an LMWH is not available or cannot be used.1003 Consider factors such as relative efficacy, bleeding risk, logistics, and compliance issues when selecting an appropriate thromboprophylaxis regimen.1003

    Treatment and Secondary Prevention of Acute DVT and PE

    Has been used for treatment and secondary prevention of acute DVT with or without PE†.59 60 1005 Recommended by ACCP as an acceptable option for initial and long-term anticoagulant therapy in patients with DVT of the leg and/or PE; pending additional data, ACCP suggests using warfarin or LMWH over rivaroxaban in such patients.1005

    Xarelto Dosage and Administration

    General

    • Routine monitoring of coagulation tests not required.10 12 14 20 28 46 54 55 56 57

    • May be possible to use PT test to assess rivaroxaban plasma concentration; however, PT test results may vary depending on reagent used and may not reliably predict degree of anticoagulation.11 28 54 55 56 57 58

    Administration

    Oral Administration

    Administer orally once daily.1 Administer 15- or 20-mg dose with the evening meal; 10-mg dose may be taken with or without food.1

    If a dose is missed, take as soon as possible on the same day, then resume regular schedule the following day.1

    Do not administer through a feeding tube (may reduce absorption).1

    Dosage

    Adults

    Embolism Associated with Atrial Fibrillation
    Oral

    Patients with normal renal function (Clcr >50 mL/minute): 20 mg once daily with the evening meal.1

    Transferring to Rivaroxaban from Warfarin

    Discontinue warfarin and initiate rivaroxaban as soon as INR < 3.1

    Transferring to Rivaroxaban from Other Anticoagulants

    Administer initial dose of rivaroxaban within 2 hours of the next scheduled evening dose of the other anticoagulant (e.g., LMWH, non-warfarin oral anticoagulant) and discontinue other anticoagulant.1

    When transferring to rivaroxaban from continuous IV heparin infusion, discontinue infusion and initiate rivaroxaban at same time.1

    Transferring from Rivaroxaban to Warfarin

    Data from clinical trials not available to guide conversion from rivaroxaban to warfarin.1 Discontinuance of rivaroxaban and simultaneous initiation of a parenteral anticoagulant and warfarin at the time of the next scheduled dose of rivaroxaban is suggested.1 INR measurements may not be useful in determining appropriate dosage of warfarin during conversion.1

    Transferring from Rivaroxaban to Other Anticoagulants

    When transferring from rivaroxaban to an anticoagulant (oral or parenteral) with a rapid onset of action, discontinue rivaroxaban and administer first dose of the other anticoagulant at the time of the next scheduled dose of rivaroxaban.1

    Thromboprophylaxis in Hip- or Knee-Replacement Surgery
    Oral

    10 mg once daily.1

    Administer first dose at least 6–10 hours after surgery, provided hemostasis has been established.1

    Duration of therapy: Manufacturer recommends 35 days for patients undergoing hip-replacement surgery, 12 days for patients undergoing knee-replacement surgery.1

    ACCP recommends at least 10–14 days, possibly up to 35 days, for patients undergoing major orthopedic surgery (e.g., hip-replacement, knee-replacement surgery).

    Managing Anticoagulation in Patients Requiring Invasive Procedures

    If temporary discontinuance of anticoagulation required prior to surgery or other invasive procedures, discontinue rivaroxaban ≥24 hours prior to procedure.1 In deciding whether a procedure should be delayed, weigh increased risk of bleeding against urgency of intervention.1 Resume therapy after procedure once adequate hemostasis established; if oral anticoagulation not possible, consider use of a parenteral anticoagulant.1 (See Risks of Discontinuing Rivaroxaban in Atrial Fibrillation Patients under Cautions.)

    Special Populations

    Hepatic Impairment

    Avoid use in patients with moderate or severe hepatic impairment or any hepatic disease associated with coagulopathy.1 (See Hepatic Impairment under Cautions.)

    Renal Impairment

    Embolism Associated with Atrial Fibrillation
    Oral

    Patients with Clcr15–50 mL/minute: Reduce dosage to 15 mg once daily with the evening meal.1 (See Renal Impairment under Cautions.)

    Patients with Clcr <15 mL/minute: Avoid use.1

    Thromboprophylaxis in Hip- or Knee-Replacement Surgery
    Oral

    No specific dosage recommendations.1

    Avoid use in patients with Clcr <30 mL/minute.1

    Geriatric Patients

    No specific dosage recommendations.1

    Body Weight

    Dosage adjustments not likely to be necessary in patients weighing <50 kg or >120 kg.1 9 21

    Pregnant Women

    Dosing not established.1

    Cautions for Xarelto

    Contraindications

    • Active pathologic bleeding.1

    • Severe hypersensitivity reaction to rivaroxaban.1

    Warnings/Precautions

    Warnings

    Risks of Discontinuing Rivaroxaban in Atrial Fibrillation Patients

    Increased risk of stroke observed in patients with nonvalvular atrial fibrillation who discontinued rivaroxaban in the absence of adequate alternative anticoagulation in principal efficacy study.1 Such patients were generally switched to warfarin without a period of concurrent warfarin and rivaroxaban until a therapeutic INR was obtained.1

    If discontinuance of rivaroxaban required for reasons other than pathologic bleeding, consider use of an alternative anticoagulant.1 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.)

    Spinal/Epidural Hematoma

    Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concomitant use of rivaroxaban and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 42 (See Boxed Warning.) Monitor frequently for manifestations of neurologic impairment.1 (See Advice to Patients.)

    Do not remove epidural catheters <18 hours after a dose of rivaroxaban, and give next dose ≥6 hours after catheter removal.1 If traumatic puncture occurs, delay rivaroxaban administration for 24 hours.1

    Bleeding

    Rivaroxaban increases risk of hemorrhage and can cause serious, sometimes fatal bleeding.1 Weigh risk of bleeding against risk of thrombotic events in patients with increased risk of bleeding (e.g., congenital or acquired bleeding disorders; active ulceration, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic retinopathy; recent brain, spinal, ophthalmic surgery).1 13 Promptly evaluate any manifestations of blood loss during therapy.1 Discontinue if active pathologic hemorrhage occurs.1 (See Contraindications under Cautions.)

    Renal impairment and concomitant use of drugs that affect hemostasis (e.g., aspirin, NSAIAs, fibrinolytics, thienopyridines, other antithrombotic agents) or drugs that are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors (e.g., ketoconazole, ritonavir may increase risk of bleeding).1 5 6 8 30 (See Interactions.)

    Use with caution in pregnant women because of risk of pregnancy-related hemorrhage and/or emergent delivery.1 (See Pregnancy.) Closely monitor for bleeding manifestations (e.g., decline in hemoglobin and/or hematocrit, hypotension, fetal distress).1

    No specific antidote for rivaroxaban; discontinue drug and initiate appropriate treatment if bleeding associated with overdosage occurs.1 7 49 50 Not expected to be dialyzable because of high plasma protein binding.1 May consider use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), anti-inhibitor coagulant complex (activated prothrombin complex concentrate), or factor VIIa (recombinant) for immediate reversal of anticoagulation; however, efficacy not established in clinical studies.1 43 Protamine sulfate and vitamin K not expected to affect anticoagulant activity of rivaroxaban, and no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) or systemic hemostatics (desmopressin, aprotinin).1

    Sensitivity Reactions

    Hypersensitivity Reactions

    Hypersensitivity reactions, including anaphylaxis, reported.1 (See Contraindications under Cautions.)

    Specific Populations

    Pregnancy

    Category C.1

    No adequate data in pregnant women; pronounced maternal bleeding, post-implantation pregnancy loss, and fetotoxic effects observed in animals.1

    Use with caution in pregnant women and only when potential benefits justify potential risks (e.g., hemorrhage, emergent delivery while receiving an anticoagulant that is not readily reversible).1 ACCP recommends avoidance of rivaroxaban in pregnant women.1012 Women of childbearing potential should discuss pregnancy planning with their clinician prior to initiating therapy.1

    Lactation

    Parent drug and metabolites distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1 ACCP recommends alternative anticoagulants to rivaroxaban in nursing women.1012

    Pediatric Use

    Safety and efficacy not established in patients <18 years of age.1 2 3 4

    Geriatric Use

    No substantial differences in efficacy relative to younger adults in clinical studies.1 Although older patients experienced a higher rate of thrombotic and bleeding events, risk-to-benefit profile was favorable in all age groups.1

    Hepatic Impairment

    Possible increased systemic exposure and pharmacodynamic effects (inhibition of factor Xa activity, PT prolongation) in patients with moderate hepatic impairment (Child-Pugh class B); clinically important effects in patients with mild hepatic impairment not observed.1 9 (See Special Populations, under Pharmacokinetics.) Pharmacokinetic profile not established in patients with severe hepatic impairment (Child-Pugh class C).1 9

    Avoid use in patients with moderate or severe hepatic impairment or with any hepatic disease associated with coagulopathy.1

    Renal Impairment

    Possible increased exposure and increased pharmacodynamic effects with decreasing renal function.1 9 12 18 27 (See Special Populations, under Pharmacokinetics.) Discontinue drug if acute renal failure develops.1

    Patients receiving thromboprophylaxis for orthopedic surgery: Closely monitor those with moderate renal impairment (Clcr 30 to <50 mL/minute) and promptly evaluate if any manifestations of bleeding occur.1 Do not use in patients with Clcr <30 mL/minute.1

    Patients with nonvalvular atrial fibrillation: Assess renal function periodically and adjust dosage accordingly.1 (See Renal Impairment under Dosage and Administration.) More frequent monitoring may be necessary in clinical situations in which renal function may decline.1 Do not use in patients with Clcr <15 mL/minute.1

    In patients with renal impairment, concomitant use of drugs that are combined P-gp and weak/moderate CYP3A4 inhibitors may substantially increase rivaroxaban exposure, which may increase risk of bleeding.1 (See Drugs Affecting Both P-glycoprotein and CYP3A4 under Interactions.)

    Common Adverse Effects

    Bleeding.1 2 12 32

    Interactions for Xarelto

    Metabolized by CYP 3A4/5 and 2J2.1 Does not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induce CYP1A2, 2B6, 2C19, and 3A4 in vitro; pharmacokinetic interaction unlikely with drugs metabolized by these enzymes.1 8 9

    Substrate of the efflux transporters P-gp and ABCG2 (breast cancer resistance protein [BCRP]); does not appear to inhibit these transporters.1

    Drugs Affecting Hepatic Microsomal Enzymes

    Inhibitors of CYP3A4/5 or 2J2: Potential pharmacokinetic interaction (increased rivaroxaban exposure).1

    Inducers of CYP3A4/5 or 2J2: Potential pharmacokinetic interaction (decreased rivaroxaban exposure).1

    Drugs Affecting Efflux Transport Systems

    Inhibitors of P-gp or ABCG2: Potential pharmacokinetic interaction (increased rivaroxaban exposure).1

    Inducers of P-gp or ABCG2: Potential pharmacokinetic interaction (decreased rivaroxaban exposure).1

    Drugs Affecting Both P-glycoprotein and CYP3A4

    Combined P-gp and CYP3A4 inhibitors: Possible increased rivaroxaban exposure and pharmacodynamic effects, which may increase risk of bleeding.1 Extent of interaction appears to be related to degree of P-gp or CYP3A4 inhibition.1 No special precautions necessary when clinical data suggest that increased exposure is unlikely to affect bleeding.1 Avoid concomitant use of combined P-gp and potent CYP3A4 inhibitors.1

    Combined P-gp and potent CYP3A4 inducers: Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy.1 Avoid concomitant use.1

    Simulated pharmacokinetic data suggest that exposure to rivaroxaban may be substantially increased in patients with renal impairment receiving full-dose (20 mg) rivaroxaban in conjunction with a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor.1 11 Increased bleeding risk not observed in a clinical study in patients with renal impairment (Clcr 30–49 mL/minute) who received such a combination.1 However, manufacturer advises use of rivaroxaban concomitantly with a combined P-gp and weak or moderate CYP3A4 inhibitor in patients with Clcr 15–50 mL/minute only if potential benefits justify potential risks.1

    Drugs Affecting Hemostasis

    Potential increased risk of hemorrhage.1 8 Promptly evaluate any manifestations of bleeding.1

    Protein-bound Drugs

    Potential interaction with other highly protein-bound drugs.8

    Specific Drugs

    Drug

    Interaction

    Comments

    Antacids (aluminum- or magnesium-containing)

    No effect on rivaroxaban bioavailability or systemic exposure1

    Antiarrhythmic agents, class III (amiodarone, dronedarone)

    Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

    Use concomitantly in patients with renal impairment only when potential benefits justify risks1

    Anticoagulants, other

    Potential increased risk of hemorrhage1

    Promptly evaluate if bleeding manifestations occur1

    Avoid concomitant use in patients receiving rivaroxaban for DVT prophylaxis1

    Antifungals, azole (fluconazole, itraconazole, ketoconazole)

    Fluconazole: Possible increased AUC and peak plasma concentrations of rivaroxaban1

    Itraconazole, ketoconazole: Possible increased rivaroxaban exposure, which may increase risk of bleeding1

    Itraconazole, ketoconazole: Avoid concomitant use1

    Antiretrovirals, HIV protease inhibitors

    Lopinavir/ritonavir, indinavir/ritonavir, ritonavir: Possible increased rivaroxaban exposure, which may increase risk of bleeding1

    Avoid concomitant use1

    Aspirin

    Potential increased risk of hemorrhage1 5 6 8 30

    Increased bleeding time, but no effect on aspirin’s inhibitory effects on platelet aggregation; no substantial change in pharmacokinetics or pharmacodynamics of rivaroxaban1 8 9 23

    Promptly evaluate if bleeding manifestations occur1

    Atorvastatin

    Pharmacokinetic interaction unlikely1

    Calcium-channel blocking agents (diltiazem, felodipine, verapamil)

    Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

    Use concomitantly in patients with renal impairment only when potential benefits justify risks1

    Carbamazepine

    Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy1

    Avoid concomitant use1

    Clopidogrel

    Increased bleeding time; no change in pharmacokinetics of either drug1

    Promptly evaluate if bleeding manifestations occur1

    Conivaptan

    Possible increased rivaroxaban exposure and pharmacodynamic effects, which may increase risk of bleeding1

    Avoid concomitant use1

    Digoxin

    Pharmacokinetic interaction unlikely1

    Enoxaparin

    Additive effects on anti-factor Xa activity; pharmacokinetics of rivaroxaban not affected1 9 39

    Promptly evaluate if bleeding manifestations occur1

    Avoid concurrent use in patients receiving rivaroxaban for DVT prophylaxis1

    Fibrinolytics

    Potential increased risk of hemorrhage1

    Macrolides (azithromycin, clarithromycin, erythromycin)

    Clarithromycin, erythromycin: Increased rivaroxaban exposure; however, not expected to increase risk of bleeding1

    Azithromycin, erythromycin: Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1 1

    No special precautions necessary in patients with normal renal function1

    Azithromycin, erythromycin: Use concomitantly in patients with renal impairment only when potential benefits justify risks1

    Midazolam

    Pharmacokinetic interaction unlikely1

    NSAIAs (e.g., naproxen)

    Potential increased risk of hemorrhage1 5 6 8 30

    Naproxen: Bleeding time increased slightly, but no substantial pharmacokinetic or pharmacodynamic interaction1 8 9 24 39

    Promptly evaluate if bleeding manifestations occur1

    Omeprazole

    Pharmacokinetics of rivaroxaban not affected1 44

    Phenytoin

    Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy1

    Avoid concomitant use1

    Platelet-aggregation inhibitors

    Potential increased risk of hemorrhage1

    Promptly evaluate if bleeding manifestations occur1

    Quinidine

    Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

    Use concomitantly in patients with renal impairment only when potential benefits justify risks1

    Ranitidine

    No effect on rivaroxaban bioavailability or systemic exposure1

    Ranolazine

    Substantial increases in rivaroxaban exposure may occur in patients with renal impairment1

    Use concomitantly in patients with renal impairment only when potential benefits justify risks1

    Rifampin

    Decreased rivaroxaban exposure and pharmacodynamic effects; possible decreased efficacy1

    Avoid concomitant use1

    St. John’s wort (Hypericum perforatum)

    Possible decreased rivaroxaban exposure and pharmacodynamic effects, which may decrease efficacy1

    Avoid concomitant use1

    Warfarin

    Additive effects on factor Xa inhibition and PT prolongation; pharmacokinetics of rivaroxaban not affected1

    Promptly evaluate if bleeding manifestations occur1

    Avoid concurrent use in patients receiving rivaroxaban for DVT prophylaxis1

    Xarelto Pharmacokinetics

    Absorption

    Bioavailability

    Rapidly and well absorbed following oral administration; bioavailability approximately 80–100% (10-mg dose).1 8 9 12 15 16 20

    Following oral administration, peak plasma concentrations occur within 2–4 hours.1 8 9 12 15 16 46

    Absorption dependent on site of release in the GI tract; exposure reduced when drug released into the proximal small intestine and further reduced when released in distal small intestine or ascending colon.1

    Food

    Food increases peak plasma concentrations and systemic exposure to 20-mg dose; effects of food on 10-mg dose not expected to be clinically important.1 22 39

    Distribution

    Extent

    Parent drug and metabolites distributed into milk in rats; not known whether distributed into human milk.1

    Crosses the placenta in animals.1

    Plasma Protein Binding

    Approximately 92–95% (mainly to albumin).1 9

    Elimination

    Metabolism

    Undergoes oxidative degradation (by CYP3A4/5 and 2J) and hydrolysis.1 26 No major circulating metabolites identified.1 8 26

    Elimination Route

    Approximately 66% of administered dose eliminated renally (36% unchanged drug) and 28% eliminated in feces (7% unchanged drug).1 8 26

    No substantial accumulation with multiple dosing.8 9

    Not expected to be removed by dialysis due to high plasma protein binding.1

    Half-life

    5–9 hours in healthy individuals 20–45 years of age.1 8

    Special Populations

    Exposure to rivaroxaban increased by 44, 52, or 64% in patients with mild, moderate, or severe renal impairment, respectively, compared with those with normal renal function.1 9 27

    Substantial increased exposure in patients with moderate hepatic impairment (Child-Pugh class B).1 9

    Systemic exposure in geriatric patients increased by approximately 50% compared with younger individuals, likely due to reduced total body and renal clearance; half-life 11–13 hours.1 9 12

    Exposure to rivaroxaban on average 20–40% higher in patients of Japanese ancestry compared with other ethnicities (including Chinese); however, difference reduced after adjustment for body weight.1

    Stability

    Storage

    Oral

    Tablet

    25°C (may be exposed to 15–30°C).1

    Actions

    • Selectively blocks active site of factor Xa; inhibits both free and prothrombinase-bound factor Xa.1 8 9 10 12 17

    • Inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin and subsequent thrombus formation.1 7 8 9 12 15 16 17 23
    • Unlike fondaparinux, unfractionated heparin, and LMWHs, rivaroxaban blocks factor Xa directly and does not require a cofactor (antithrombin III) to exert its anticoagulant activity.1 8 9 15 23
    • Inhibits factor Xa activity, PT, aPTT, and HepTest (an indirect measure of factor Xa activity) in a dose-dependent manner.1 8 12 15 18 20 43

    Advice to Patients

    • Importance of taking drug exactly as prescribed and not discontinuing therapy without first consulting a clinician.1 Patients with atrial fibrillation should take rivaroxaban once daily with the evening meal.1

    • Importance of taking any missed dose as soon as possible and then resuming the once-daily dosing schedule the following day.1
    • Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., tingling or numbness in lower limbs, muscle weakness), particularly if they are receiving concomitant NSAIAs or platelet-aggregation inhibitors (e.g., clopidogrel); importance of immediately contacting a clinician if any of these symptoms occur.1
    • Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking rivaroxaban.1 Importance of informing clinicians about any unusual bleeding or bruising during therapy.1
    • Importance of informing clinicians about rivaroxaban therapy before scheduling any invasive procedures, including dental procedures.1
    • Importance of women immediately informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Women of childbearing potential should discuss pregnancy planning with their clinician prior to receiving rivaroxaban.1 Importance of pregnant women immediately reporting any bleeding or symptoms of blood loss to a clinician.1
    • Importance of informing clinicians (e.g., physicians, dentists) of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.1
    • Importance of informing patients of other important precautionary information.1 (See Cautions.)

    Preparations

    Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

    Rivaroxaban
    Routes

    Dosage Forms

    Strengths

    Brand Names

    Manufacturer

    Oral

    Tablets

    10 mg

    Xarelto

    Janssen

    15 mg

    Xarelto

    Janssen

    20 mg

    Xarelto

    Janssen

    Disclaimer

    This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

    The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug’s actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

    AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions January 16, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

    † Use is not currently included in the labeling approved by the US Food and Drug Administration.

    References

    1. Janssen. Xarelto (rivaroxaban ) oral tablets prescribing information. Titusville, NJ: 2011 Nov.

    2. Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008; 358:2765-75. [PubMed 18579811]

    3. Kakkar AK, Brenner B, Dahl OE et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008; 372:31-9. [PubMed 18582928]

    4. Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008; 358:2776-86. [PubMed 18579812]

    5. Turpie AG, Lassen MR, Davidson BL et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009; 373:1673-80. [PubMed 19411100]

    6. Turpie AG, Lassen MR, Eriksson BI et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011; 105:444-53. [PubMed 21136019]

    7. Van Thiel D, Kalodiki E, Wahi R et al. Interpretation of benefit-risk of enoxaparin as comparator in the RECORD program: rivaroxaban oral tablets (10 milligrams) for use in prophylaxis in deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Clin Appl Thromb Hemost. 2009 Jul-Aug; 15:389-94. [PubMed 19608550]

    8. Abrams PJ, Emerson CR. Rivaroxaban: a novel, oral, direct factor Xa inhibitor. Pharmacotherapy. 2009; 29:167-81. [PubMed 19170587]

    9. Gulseth MP, Michaud J, Nutescu EA. Rivaroxaban: an oral direct inhibitor of factor Xa. Am J Health Syst Pharm. 2008; 65:1520-9. [PubMed 18693206]

    10. Borris LC. Rivaroxaban, a new, oral, direct factor Xa inhibitor for thromboprophylaxis after major joint arthroplasty. Expert Opin Pharmacother. 2009; 10:1083-8. [PubMed 19351271]

    11. Janssen, Titusville, NJ: Personal communication.

    12. Duggan ST, Scott LJ, Plosker GL. Rivaroxaban: a review of its use for the prevention of venous thromboembolism after total hip or knee replacement surgery. Drugs. 2009; 69:1829-51. [PubMed 19719335]

    13. GlaxoSmithKline. Arixtra (fondaparinux sodium) inject ion prescribing information. Research Triangle Park, NC: 2011 Feb.

    14. Fisher WD, Eriksson BI, Bauer KA et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost. 2007; 97:931-7. [PubMed 17549294]

    15. Kubitza D, Becka M, Roth A et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008; 24:2757-65. [PubMed 18715524]

    16. Jiang J, Hu Y, Zhang J et al. Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban – an oral, direct factor Xa inhibitor – in elderly Chinese subjects. Thromb Haemost. 2010; 103:234-41. [PubMed 20062915]

    17. Graff J, von Hentig N, Misselwitz F et al. Effects of the oral, direct factor xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol. 2007; 47:1398-407. [PubMed 17873238]

    18. Mueck W, Borris LC, Dahl OE et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008; 100:453-61. [PubMed 18766262]

    20. Mueck W, Becka M, Kubitza D et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban–an oral, direct factor xa inhibitor–in healthy subjects. Int J Clin Pharmacol Ther. 2007; 45:335-44. [PubMed 17595891]

    21. Kubitza D, Becka M, Zuehlsdorf M et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007; 47:218-26. [PubMed 17244773]

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    Xarelto

    Xarelto

    Generic Name: rivaroxaban (RIV a ROX a ban)

    Brand Name: Xarelto

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore…

    What is rivaroxaban?

    Rivaroxaban is an anticoagulant (blood thinner) that prevents the formation of blood clots.

    Rivaroxaban is used to prevent a type of blood clot called deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism). A DVT can occur after certain types of surgery.

    Rivaroxaban is also used in people with atrial fibrillation (a heart rhythm disorder) to lower the risk of stroke caused by a blood clot.

    Rivaroxaban may also be used for purposes not listed in this medication guide.

    What is the most important information I should know about rivaroxaban?

    You should not use this medication if you are allergic to rivaroxaban, or if you have active or uncontrolled bleeding.

    Tell any doctor who treats you that you are using rivaroxaban. If you need anesthesia for a medical procedure or surgery, you may need to stop using the medicine for a short time.

    Rivaroxaban can cause a very serious blood clot around your brain or spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural), especially if you have a genetic spinal defect, a history of spinal surgery or repeated spinal taps, or if you are using other medications to treat or prevent blood clots. Symptoms of this type of blood clot include numbness, tingling, muscle weakness, or loss of movement.

    Blood clots around the brain or spinal cord may occur during a spinal tap or epidural if you are using rivaroxaban with other drugs that can affect blood clotting, including aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) such as Advil or Motrin, and any other medications to treat or prevent blood clots.

    Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding or life-threatening blood clots, and it is very important to tell your doctor about all medicines you have recently used.

    Tell your caregivers at once if you have signs of bleeding such as black or bloody stools, coughing up blood, confusion, feeling like you might pass out, or any bleeding that will not stop.

    Do not stop taking this medication without first talking to your doctor. Stopping suddenly can increase your risk of blood clot or stroke.

    What should I discuss with my healthcare provider before taking rivaroxaban?

    You should not use this medication if you are allergic to rivaroxaban, or if you have active or uncontrolled bleeding.

    Rivaroxaban can cause a very serious blood clot around your brain or spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural). This type of blood clot could cause long-term paralysis, and may be more likely to occur if you have:

    • a genetic spinal defect;

    • a history of spinal surgery or repeated spinal taps; or
    • if you are using other medications to treat or prevent blood clots.

    Rivaroxaban may cause you to bleed more easily, especially if you have:

    • a bleeding disorder that is inherited or caused by disease;

    • hemorrhagic stroke;
    • uncontrolled high blood pressure; or
    • stomach or intestinal bleeding or ulcer.

    To make sure you can safely take rivaroxaban, tell your doctor if you have kidney or liver disease.

    FDA pregnancy category C. It is not known whether rivaroxaban will harm an unborn baby. However, this medicine could cause bleeding complications during childbirth. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

    It is not known whether rivaroxaban passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using rivaroxaban.

    How should I take rivaroxaban?

    Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

    Rivaroxaban is usually taken once per day. Follow your doctor’s instructions.

    For hip or knee replacement surgery: You may take rivaroxaban with or without food.

    For atrial fibrillation: Take rivaroxaban with your evening meal.

    Tell any doctor who treats you that you are using rivaroxaban. If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using this medication. If you need anesthesia for a medical procedure or surgery, you may need to stop using rivaroxaban for a short time.

    Use rivaroxaban regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

    Do not stop taking this medication without first talking to your doctor. Stopping suddenly can increase your risk of blood clot or stroke.

    Store at room temperature away from moisture and heat.

    See also: Xarelto dosage (in more detail)

    What happens if I miss a dose?

    Take the missed dose as soon as you remember. Take your next dose the following day and stay on your once-daily schedule. Do not take extra medicine to make up the missed dose.

    What happens if I overdose?

    Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

    Overdose may cause excessive bleeding.

    What should I avoid while taking rivaroxaban?

    Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

    Rivaroxaban side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

    Stop using rivaroxaban and call your doctor at once if you have a serious side effect such as:

    • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;

    • heavy menstrual periods;
    • headache, dizziness, weakness, feeling like you might pass out;
    • red or pink urine;
    • black or bloody stools, coughing up blood or vomit that looks like coffee grounds;
    • numbness, tingling, or muscle weakness (especially in your legs and feet); or
    • loss of movement in any part of your body.

    Less serious side effects may include:

    • muscle pain;

    • itching; or
    • pain in your arms or legs.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Xarelto side effects (in more detail)

    What other drugs will affect rivaroxaban?

    Tell your doctor about all other medicines you use, especially:

    • bosentan (Tracleer);

    • conivaptan (Vaprisol);
    • dexamethasone (Cortastat, Dexasone, Solurex, DexPak);
    • rifabutin (Mycobutin), rifampin (Rifadin, Rifater, Rifamate), or rifapentine (Priftin);
    • St. John’s wort;
    • quinidine (Quin-G);
    • verapamil (Calan, Covera, Isoptin, Verelan);
    • an antibiotic such as azithromycin (Zithromax), clarithromycin (Biaxin) or erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole);
    • antifungal medication such as itraconazole (Sporanox) or ketoconazole (Nizoral);
    • a barbiturate such as butabarbital (Butisol), secobarbital (Seconal), pentobarbital (Nembutal), or phenobarbital (Solfoton);
    • heart or blood pressure medication such as reserpine, amiodarone (Cordarone, Pacerone), diltiazem (Cartia, Cardizem), dronedarone (Multaq), felodipine (Plendil), quinidine (Quin-G), or verapamil (Calan, Covera, Isoptin, Verelan);
    • HIV medication such as efavirenz (Sustiva, Atripla), etravirine (Intelence), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, Kaletra), or saquinavir (Invirase);
    • medicines to treat narcolepsy, such as armodafinil (Nuvigil) or modafinil (Progivil);
    • medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf); or
    • seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenytoin (Dilantin), or primidone (Mysoline).

    Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding, or your risk of developing blood clots around the brain or spinal cord during a spinal tap or epidural. It is very important to tell your doctor about all medicines you have recently used, especially:

    • dextran (Gentran, Hyskon);

    • abciximab (ReoPro), eptifibatide (Integrilin), ticagrelor (Brilinta), tirofiban (Aggrastat);
    • alteplase (Activase), reteplase (Retavase), tenecteplase (TNKase), urokinase (Abbokinase);
    • anagrelide (Agrylin), cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, Aggrenox), eltrombopag (Promacta), oprelvekin (Neumega), prasugrel (Effient), romiplostim (Nplate), ticagrelor (Brilinta), ticlopidine (Ticlid);
    • argatroban (Acova), bivalirudin (Angiomax), dabigatran (Pradaxa), lepirudin (Refludan);
    • dalteparin (Fragmin), enoxaparin (Lovenox), fondaparinux (Arixtra), heparin, tinzaparin (Innohep), warfarin (Coumadin, Jantoven);
    • an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others; or
    • salicylates such as aspirin, Nuprin Backache Caplet, Kaopectate, KneeRelief, Pamprin Cramp Formula, Pepto-Bismol, Tricosal, Trilisate, and others.

    This list is not complete and other drugs may interact with rivaroxaban. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

    Next Page → Side Effects

    More Xarelto resources

    • Side Effects
    • Recommended Dosage
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 5 Reviews - Add your own review/rating
    • Xarelto Prescribing Information (FDA)
    • Xarelto Monograph (AHFS DI)
    • Xarelto Advanced Consumer (Micromedex) – Includes Dosage Information
    • Xarelto Consumer Overview
    • Xarelto MedFacts Consumer Leaflet (Wolters Kluwer)
    • Rivaroxaban Professional Patient Advice (Wolters Kluwer)

    Compare Xarelto with other medications

    • Atrial Fibrillation
    • Deep Vein Thrombosis
    • Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery
    • Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery
    • Deep Vein Thrombosis, Prophylaxis
    • Deep Vein Thrombosis, Recurrent Event
    • Prevention of Thromboembolism in Atrial Fibrillation
    • Pulmonary Embolism
    • Pulmonary Embolism, Recurrent Event

    Where can I get more information?

    • Your pharmacist can provide more information about rivaroxaban.

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