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Xarelto

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Xarelto uses


WARNING: PREMATURE DISCONTINUATION OF Xarelto INCREASES THE RISK OF THROMBOTIC EVENTS,

(B) SPINAL/EPIDURAL HEMATOMA

WARNING: (A) PREMATURE DISCONTINUATION OF Xarelto INCREASES THE RISK OF THROMBOTIC EVENTS,

(B) SPINAL/EPIDURAL HEMATOMA

See full prescribing information for complete boxed warning

(A) Premature discontinuation of Xarelto increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including Xarelto, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy (2.3, 2.7, 5.1, 14.1).

(B) Spinal/epidural hematoma

Epidural or spinal hematomas have occurred in patients treated with Xarelto who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis (5.2, 5.3, 6.2).

Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated (5.3).

A. Premature discontinuation of Xarelto increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including Xarelto, increases the risk of thrombotic events. If anticoagulation with Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant .

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:


.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary .

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis .

Warnings and Precautions (5.2, 5.4) 05/2016
Warnings and Precautions (5.3) 08/2016

1 INDICATIONS AND USAGE

Xarelto is a factor Xa inhibitor indicated:

1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Xarelto is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of Xarelto and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled.

1.2 Treatment of Deep Vein Thrombosis

Xarelto is indicated for the treatment of deep vein thrombosis.

1.3 Treatment of Pulmonary Embolism

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

1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism

Xarelto is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE.

1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Xarelto is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Indication Dosage
Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation (2.4) 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 (2.5)

Treatment of PE (2.5)

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 (2.5) 20 mg once daily with food
Prophylaxis of DVT Following Hip or Knee Replacement Surgery (2.6) Hip replacement: 10 mg once daily for 35 days
Knee replacement: 10 mg once daily for 12 days

2.2 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 .

In the nonvalvular atrial fibrillation efficacy study Xarelto was taken with the evening meal.

2.3 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 .

Switching from Anticoagulants other than Warfarin to Xarelto - For patients currently receiving an anticoagulant other than warfarin, start Xarelto 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start Xarelto at the same time.

2.4 Nonvalvular Atrial Fibrillation

For patients with creatinine clearance >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 .

2.5 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 .

2.6 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The recommended dose of Xarelto is 10 mg taken orally once daily with or without food. The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established .

2.7 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 . 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 . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

2.8 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:

2.9 Administration Options

For patients who are unable to swallow whole tablets, 10 mg, 15 mg or 20 mg Xarelto tablets may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed Xarelto 15 mg or 20 mg tablet, the dose should be immediately followed by food .

Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, 10 mg, 15 mg or 20 mg Xarelto tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since Xarelto absorption is dependent on the site of drug release, avoid administration of Xarelto distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed Xarelto 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding .

Crushed 10 mg, 15 mg or 20 mg Xarelto tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of Xarelto from a water suspension of a crushed Xarelto tablet to PVC or silicone nasogastric (NG) tubing.

3 DOSAGE FORMS AND STRENGTHS


Tablets: 10 mg, 15 mg, and 20 mg (3)

4 CONTRAINDICATIONS

Xarelto is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including Xarelto, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Xarelto to warfarin in clinical trials in atrial fibrillation patients. If Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant .

5.2 Risk of Bleeding

Xarelto increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe Xarelto to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue Xarelto in patients with active pathological hemorrhage. The terminal elimination half-life of Xarelto is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A4 inhibitors increases Xarelto exposure and may increase bleeding risk .

Reversal of Anticoagulant Effect

A specific antidote for Xarelto is not available. Because of high plasma protein binding, Xarelto is not expected to be dialyzable . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of Xarelto. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.

5.3 Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis .

To reduce the potential risk of bleeding associated with the concurrent use of Xarelto and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of Xarelto . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of Xarelto is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of Xarelto . The next Xarelto dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of Xarelto for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

5.4 Use in Patients with Renal Impairment

Nonvalvular Atrial Fibrillation

Periodically assess renal function as clinically indicated and adjust therapy accordingly . Consider dose adjustment or discontinuation of Xarelto in patients who develop acute renal failure while on Xarelto .

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 Xarelto exposure and pharmacodynamic effects in this patient population .

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 Xarelto 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 .

5.5 Use in Patients with Hepatic Impairment

No clinical data are available for patients with severe hepatic impairment.

Avoid use of Xarelto in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased .

5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers

Avoid concomitant use of Xarelto with known combined P-gp and strong CYP3A4 inhibitors .

Avoid concomitant use of Xarelto with drugs that are known combined P-gp and strong CYP3A4 inducers .

5.7 Risk of Pregnancy-Related Hemorrhage

In pregnant women, Xarelto should be used only if the potential benefit justifies the potential risk to the mother and fetus. Xarelto dosing in pregnancy has not been studied. The anticoagulant effect of Xarelto cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

5.8 Patients with Prosthetic Heart Valves

The safety and efficacy of Xarelto have not been studied in patients with prosthetic heart valves. Therefore, use of Xarelto is not recommended in these patients.

5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy

Initiation of Xarelto is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

6 ADVERSE REACTIONS

The following adverse reactions are also discussed in other sections of the labeling:


The most common adverse reaction (>5%) was bleeding. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 16326 patients were exposed to Xarelto. These included 7111 patients who received Xarelto 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728 patients who received either Xarelto 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487 patients who received Xarelto 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1–3).

Hemorrhage

The most common adverse reactions with Xarelto were bleeding complications .

Nonvalvular Atrial Fibrillation

In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for Xarelto vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

Parameter Xarelto

N=7111

n (%/year)

 Warfarin

N=7125

n (%/year)

 Xarelto vs. Warfarin

HR

(95% CI)
Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major.
Major BleedingDefined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20)
Intracranial Hemorrhage (ICH) Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93)
Hemorrhagic StrokeHemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96)
Other ICH 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34)
Gastrointestinal (GI)Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99)
Fatal BleedingFatal bleeding is adjudicated death with the primary cause of death from bleeding. 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79)
ICH 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96)
Non-intracranial 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82)

Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Figure 1

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.

Parameter XareltoTreatment 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)]

N=4130

n (%)

 Enoxaparin/VKA

N=4116

n (%)
Major bleeding event 40 (1.0) 72 (1.7)
Fatal bleeding 3 (<0.1) 8 (0.2)
Intracranial 2 (<0.1) 4 (<0.1)
Non-fatal critical organ bleeding 10 (0.2) 29 (0.7)
IntracranialTreatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group 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 bleedingMajor 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 27 (0.7) 37 (0.9)
Decrease in Hb ≥ 2 g/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.

Parameter XareltoTreatment schedule: Xarelto 20 mg once daily; matched placebo once daily

20 mg

N=598

n (%)

 Placebo

N=590

n (%)
Major bleeding eventThere were no fatal or critical organ bleeding events. 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.

Xarelto 10 mg EnoxaparinIncludes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3)
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 eventIncludes major bleeding events 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.

System Organ Class

Preferred Term

 Xarelto

N=598

n (%)

 Placebo

N=590

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

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 6.

System/Organ Class

Adverse Reaction

 Xarelto

10 mg

N=4487

n (%)

 EnoxaparinIncludes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3)

N=4524

n (%)
Injury, poisoning and procedural complications
Wound secretion 125 (2.8) 89 (2.0)
Musculoskeletal and connective tissue disorders
Pain in extremity 74 (1.7) 55 (1.2)
Muscle spasm 52 (1.2) 32 (0.7)
Nervous system disorders
Syncope 55 (1.2) 32 (0.7)
Skin and subcutaneous tissue disorders
Pruritus 96 (2.1) 79 (1.8)
Blister 63 (1.4) 40 (0.9)

Other clinical trial experience: In an investigational study of acute medically ill patients being treated with Xarelto 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Xarelto. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia

Gastrointestinal disorders: retroperitoneal hemorrhage

Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

7 DRUG INTERACTIONS

7.1 General Inhibition and Induction Properties

Xarelto is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A4 inhibitors increase exposure to Xarelto and may increase the risk of bleeding. Combined P-gp and strong CYP3A4 inducers decrease exposure to Xarelto and may increase the risk of thromboembolic events.

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

Interaction with Combined P-gp and Strong CYP3A4 Inhibitors

Avoid concomitant administration of Xarelto with known combined P-gp and strong CYP3A4 inhibitors .

Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with Xarelto as the change in exposure is unlikely to affect the bleeding risk .

Interaction with Combined P-gp and Moderate CYP3A4 Inhibitors in Patients with Renal Impairment

Xarelto should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk .

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

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) .

7.4 Anticoagulants and NSAIDs/Aspirin

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding .

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 .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate or well-controlled studies of Xarelto in pregnant women, and dosing for pregnant women has not been established. Use Xarelto with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of Xarelto cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. Xarelto should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus .

Xarelto 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. Xarelto 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 Xarelto during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

8.2 Labor and Delivery

Safety and effectiveness of Xarelto during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the Xarelto dose of 40 mg/kg.

8.3 Nursing Mothers

It is not known if Xarelto is excreted in human milk. Xarelto 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 Xarelto, a decision should be made whether to discontinue nursing or discontinue Xarelto, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in the RECORD 1–3 clinical studies evaluating Xarelto, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of Xarelto in the elderly 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 .

8.6 Females of Reproductive Potential

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

8.7 Renal Impairment

In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, Xarelto exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed .

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 Xarelto 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 Xarelto similar to those in patients with normal renal function .

Patients with End-Stage Renal Disease on Dialysis

Clinical efficacy and safety studies with Xarelto did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of Xarelto 15 mg once daily will result in concentrations of Xarelto and pharmacodynamic activity similar to those observed in the ROCKET AF study . It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.

Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE

In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of Xarelto in patients with CrCl <30 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of Xarelto in patients with CrCl <30 mL/min.

8.8 Hepatic Impairment

In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of Xarelto in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated .

Avoid the use of Xarelto in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

10 OVERDOSAGE

Overdose of Xarelto may lead to hemorrhage. Discontinue Xarelto and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for Xarelto is not available. Xarelto 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, Xarelto is not dialyzable . Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.

11 DESCRIPTION

Xarelto, a FXa inhibitor, is the active ingredient in Xarelto Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of Xarelto is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:

Xarelto is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Xarelto 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 Xarelto. The inactive ingredients of Xarelto are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for Xarelto 10 mg tablets is Opadry® Pink and for Xarelto 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for Xarelto 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Xarelto is a selective inhibitor of FXa. It does not require a cofactor for activity. Xarelto inhibits free FXa and prothrombinase activity. Xarelto has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, Xarelto decreases thrombin generation.

12.2 Pharmacodynamics

Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are also prolonged dose-dependently. Anti-factor Xa activity is also influenced by Xarelto.

Specific Populations

Renal Impairment

The relationship between systemic exposure and pharmacodynamic activity of Xarelto was altered in subjects with renal impairment relative to healthy control subjects .

Measure Parameter Creatinine Clearance (mL/min)
50–79 30–49 15–29 ESRD (on dialysis) Separate stand-alone study. ESRD (post-dialysis)
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve
Exposure AUC 44 52 64 47 56
FXa Inhibition AUEC 50 86 100 49 33
PT Prolongation AUEC 33 116 144 112 158

Hepatic Impairment

Anti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A class). There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of Xarelto 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. Xarelto 15 mg and 20 mg tablets should be taken with food .

The maximum concentrations (Cmax) of Xarelto appear 2 to 4 hours after tablet intake. The pharmacokinetics of Xarelto 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 Xarelto.

Absorption of Xarelto 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 Xarelto 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 Xarelto distal to the stomach which can result in reduced absorption and related drug exposure.

In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg Xarelto administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.

Distribution

Plasma protein binding of Xarelto in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.

Metabolism

Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged Xarelto was the predominant moiety in plasma with no major or active circulating metabolites.

Excretion

In a Phase 1 study, following the administration of [14C]-rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Xarelto is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.

Xarelto 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 Xarelto is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Specific Populations

The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of Xarelto are summarized in Figure 2.

Figure 2: Effect of Specific Populations on the Pharmacokinetics of Xarelto

Figure 2

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

The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years .

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. Compared to healthy subjects with normal creatinine clearance, Xarelto exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed .

Hemodialysis in ESRD subjects: Systemic exposure to Xarelto administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (post-dialysis) is 56% higher when compared to subjects with normal renal function. The systemic exposure to Xarelto administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow rate in the range of 320 to 400 mL/min is 47% higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking Xarelto 15 mg. Hemodialysis had no significant impact on Xarelto exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.

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. No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in Xarelto exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed .

Drug Interactions

In vitro studies indicate that Xarelto 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 Xarelto inhibitory potential for P-gp and ABCG2 transporters.

The effects of coadministered drugs on the pharmacokinetics of Xarelto exposure are summarized in Figure 3 .

Figure 3: Effect of Coadministered Drugs on the Pharmacokinetics of Xarelto

Figure 3

Anticoagulants

In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and Xarelto (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and Xarelto (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of Xarelto.

NSAIDs/Aspirin

In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with Xarelto. Neither naproxen nor aspirin affected the pharmacokinetics of 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

In a pharmacokinetic trial, Xarelto was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A4 inhibitor). Compared to Xarelto administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.

12.6 QT/QTc Prolongation

In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for Xarelto (15 mg and 45 mg, single-dose).

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Xarelto was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound Xarelto 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.

Xarelto 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 Xarelto orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg Xarelto daily.

14 CLINICAL STUDIES

14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation

The evidence for the efficacy and safety of Xarelto was derived from ROCKET AF, a multi-national, double-blind study comparing Xarelto 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:


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 8 displays the overall results for the primary composite endpoint and its components.

Xarelto Warfarin Xarelto vs. Warfarin
Event N=7081

n (%)

 Event Rate

(per 100 Pt-yrs)

 N=7090

n (%)

 Event Rate

(per 100 Pt-yrs)

 Hazard Ratio

(95% CI)
Primary Composite EndpointThe 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. 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 StrokeDefined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification 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 4 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.

Figure 4: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population)

Figure 5 shows the risk of stroke or non-CNS systemic embolism across major subgroups.

Figure 5: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AFData are shown for all randomized patients followed to site notification that the study would end.

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. (Intent-to-Treat Population)



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.

Figure 4 Figure 5

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

EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies

Xarelto for the treatment of DVT and/or PE and for the reduction in the risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing Xarelto (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by Xarelto 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.

A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the Xarelto group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.

In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).

In the EINSTEIN DVT and EINSTEIN PE studies, Xarelto was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.

Table 9 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.

Event Xarelto 20 mgTreatment 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)] Enoxaparin/VKA Xarelto vs. Enoxaparin/VKA

Hazard Ratio

(95% CI)
EINSTEIN DVT Study N=1731

n (%)

N=1718

n (%)

Primary Composite Endpoint 36 (2.1) 51 (3.0) 0.68 (0.44, 1.04)
Death (PE) 1 (<0.1) 0
Death (PE cannot be excluded) 3 (0.2) 6 (0.3)
Symptomatic PE and DVT 1 (<0.1) 0
Symptomatic recurrent PE only 20 (1.2) 18 (1.0)
Symptomatic recurrent DVT only 14 (0.8) 28 (1.6)
EINSTEIN PE Study N=2419

n (%)

N=2413

n (%)

Primary Composite Endpoint 50 (2.1) 44 (1.8) 1.12 (0.75, 1.68)
Death (PE) 3 (0.1) 1 (<0.1)
Death (PE cannot be excluded) 8 (0.3) 6 (0.2)
Symptomatic PE and DVT 0 2 (<0.1)
Symptomatic recurrent PE only 23 (1.0) 20 (0.8)
Symptomatic recurrent DVT only 18 (0.7) 17 (0.7)

Figures 6 and 7 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 6: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study

Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study

Figure 6 Figure 7

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 10 displays the overall results for the primary composite endpoint and its components.

Event Xarelto 20 mg

N=602

n (%)

 Placebo

N=594

n (%)

 Xarelto vs. Placebo

Hazard Ratio

(95% CI)
Primary Composite Endpoint 8 (1.3) 42 (7.1) 0.18 (0.09, 0.39)

p-value = <0.0001
Death (PE) 0 1 (0.2)
Death (PE cannot be excluded) 1 (0.2) 0
Symptomatic recurrent PE 2 (0.3) 13 (2.2)
Symptomatic recurrent DVT 5 (0.8) 31 (5.2)

Figure 8 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.

Figure 8: 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

Figure 8

14.3 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Xarelto was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.

The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared Xarelto 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active Xarelto and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active Xarelto and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 11.

RECORD 1 RECORD 2
Treatment Dosage and Duration Xarelto

10 mg once daily

 Enoxaparin

40 mg once daily

 RRRRelative Risk Reduction; CI = confidence interval,

p-value

 Xarelto

10 mg once daily

 EnoxaparinIncludes the placebo-controlled period of RECORD 2

40 mg once daily

 RRR,

p-value
Number of Patients N=1513 N=1473 N=834 N=835
Total VTE 17 (1.1%) 57 (3.9%) 71%

(95% CI: 50, 83),

p<0.001

 17 (2.0%) 70 (8.4%) 76%

(95% CI: 59, 86),

p<0.001
Components of Total VTE
Proximal DVT 1 (0.1%) 31 (2.1%) 5 (0.6%) 40 (4.8%)
Distal DVT 12 (0.8%) 26 (1.8%) 11 (1.3%) 43 (5.2%)
Non-fatal PE 3 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%)
Death (any cause) 4 (0.3%) 4 (0.3%) 2 (0.2%) 4 (0.5%)
Number of Patients N=1600 N=1587 N=928 N=929
Major VTE Proximal DVT, nonfatal PE or VTE-related death 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 12.

RECORD 3
Treatment Dosage and Duration Xarelto

10 mg once daily

 Enoxaparin

40 mg once daily

 RRRRelative Risk Reduction; CI = confidence interval,

p-value
Number of Patients N=813 N=871
Total VTE 79 (9.7%) 164 (18.8%) 48%

(95% CI: 34, 60),

p<0.001
Components of events contributing to Total VTE
Proximal DVT 9 (1.1%) 19 (2.2%)
Distal DVT 74 (9.1%) 154 (17.7%)
Non-fatal PE 0 4 (0.5%)
Death (any cause) 0 2 (0.2%)
Number of Patients N=895 N=917
Major VTE Proximal DVT, nonfatal PE or VTE-related death 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%)

16 HOW SUPPLIED/STORAGE AND HANDLING

Xarelto (rivaroxaban) Tablets are available in the strengths and packages listed below:


Store at 25°C (77°F) or room temperature; excursions permitted to 15°–30°C (59°–86°F).

Keep out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Instructions for Patient Use


Bleeding Risks


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 .

Pregnancy and Pregnancy-Related Hemorrhage


Nursing

Advise patients to discuss with their physician if they are nursing or intend to nurse during anticoagulant treatment .

Females of Reproductive Potential

Advise patients who can become pregnant to discuss pregnancy planning with their physician .

Active Ingredient Made in Germany

Finished Product Manufactured by:

Janssen Ortho, LLC

Gurabo, PR 00778

or

Bayer Pharma AG

51368 Leverkusen, Germany

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?


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

What is Xarelto?


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

Who should not take Xarelto?

Do not take Xarelto if you:


What should I tell my doctor before taking Xarelto?

Before you take Xarelto, tell your doctor if you:


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:


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?

What are the possible side effects of 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?


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: Xarelto

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 and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.

The proprietary film coating mixture for Xarelto 15 mg tablets is Opadry® Red and 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 and 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

or

Bayer Pharma AG

51368 Leverkusen, Germany

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560

Licensed from:

Bayer HealthCare AG

51368 Leverkusen, Germany

Revised: May 2016

© Janssen Pharmaceuticals, Inc. 2011

Trademarks are property of their respective owners.

NDC 50458-580-30

30 Tablets

Xarelto®

(rivaroxaban)

Tablets

10 mg

Dispense the accompanying

Medication Guide to each patient.

janssen

Rx only

NDC 50458-578-30

30 Tablets

Xarelto®

(rivaroxaban)

Tablets

15 mg

Dispense the accompanying

Medication Guide to each patient.

janssen

Rx only

NDC 50458-579-30

30 Tablets

Xarelto®

(rivaroxaban)

Tablets

20 mg

Dispense the accompanying

Medication Guide to each patient.

janssen

Rx only

Xarelto pharmaceutical active ingredients containing related brand and generic drugs:


Xarelto available forms, composition, doses:


Xarelto destination | category:


Xarelto Anatomical Therapeutic Chemical codes:


Xarelto pharmaceutical companies:


References

  1. Dailymed."XARELTO (RIVAROXABAN) TABLET, FILM COATED XARELTO (RIVAROXABAN) KIT [JANSSEN PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."RIVAROXABAN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Rivaroxaban". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Xarelto?

Depending on the reaction of the Xarelto after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Xarelto not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Xarelto addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Xarelto, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Xarelto consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

One visitor reported frequency of use

How often in a day do you take the medicine?
Are you taking the Xarelto drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Xarelto is mentioned below.
Visitors%
Once in a day1
100.0%

Visitor reported doses

No survey data has been collected yet

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
> 601
100.0%

Visitor reviews

Beverly Jackson14 Mar 2016 22:09
My mother was prescribed this medication for atrial fibrillation. She had only been taking it about 10 days when she awoke in the middle of the night literally laying in a pool of her own blood. She was bleeding from her breasts & what seemed like every pore on her arms. Since this incident she has quit taking this medication. However, her health has deteriorated drastically. She was a very active 90 year old woman who worked every day in her yard & was very alert mentally. She now has problems with her memory, maintaining her balance & at times with her ability to speak. I urge anyone prescribed this mmedication to think long & hard before taking it. I truly believe I lost my best friend due to this medication.


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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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