Brief Summary of Prescribing Information for XARELTO® (rivaroxaban)
XARELTO® (rivaroxaban) tablets, for oral use
See package insert for full Prescribing Information
XARELTO® (rivaroxaban) tablets
To reduce the potential risk of bleeding associated with the concurrent
use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO
puncture, consider the pharmacokinetic profile of rivaroxaban [see
INCREASES THE RISK OF THROMBOTIC EVENTS,
Clinical Pharmacology (12.3) in full Prescribing Information]. Placement
(B) SPINAL/EPIDURAL HEMATOMA
or removal of an epidural catheter or lumbar puncture is best performed
A. PREMATURE DISCONTINUATION OF XARELTO INCREASES THE
when the anticoagulant effect of rivaroxaban is low; however, the exact
RISK OF THROMBOTIC EVENTS
timing to reach a sufficiently low anticoagulant effect in each patient is
Premature discontinuation of any oral anticoagulant, including
not known.
XARELTO, increases the risk of thrombotic events. If anticoagulation
An epidural catheter should not be removed earlier than 18 hours after
with XARELTO is discontinued for a reason other than pathological
the last administration of XARELTO. The next XARELTO dose is not to be
bleeding or completion of a course of therapy, consider coverage
administered earlier than 6 hours after the removal of the catheter. If
with another anticoagulant [see Dosage and Administration (2.2, 2.6)
traumatic puncture occurs, the administration of XARELTO is to be
in full Prescribing Information, Warnings and Precautions, and
delayed for 24 hours.
Clinical Studies (14.1) in full Prescribing Information].
Should the physician decide to administer anticoagulation in the context
B. SPINAL/EPIDURAL HEMATOMA
of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor
Epidural or spinal hematomas have occurred in patients treated with
frequently to detect any signs or symptoms of neurological impairment,
XARELTO who are receiving neuraxial anesthesia or undergoing
such as midline back pain, sensory and motor deficits (numbness,
tingling, or weakness in lower limbs), bowel and/or bladder dysfunction.
spinal puncture. These hematomas may result in long-term or
Instruct patients to immediately report if they experience any of the
permanent paralysis. Consider these risks when scheduling patients
above signs or symptoms. If signs or symptoms of spinal hematoma are
for spinal procedures. Factors that can increase the risk of
suspected, initiate urgent diagnosis and treatment including
developing epidural or spinal hematomas in these patients include:
consideration for spinal cord decompression even though such
• use of indwelling epidural catheters
treatment may not prevent or reverse neurological sequelae.
• concomitant use of other drugs that affect hemostasis, such as
non-steroidal anti-inflammatory drugs (NSAIDs), platelet
Use in Patients with Renal Impairment: Nonvalvular Atrial Fibrillation:
inhibitors, other anticoagulants
Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug
• a history of traumatic or repeated epidural or spinal punctures
exposure is increased. Periodically assess renal function as clinically
• a history of spinal deformity or spinal surgery
indicated (i.e., more frequently in situations in which renal function may
• optimal timing between the administration of XARELTO and
decline) and adjust therapy accordingly. Discontinue XARELTO in
neuraxial procedures is not known
patients who develop acute renal failure while on XARELTO [see Use in
[see Warnings and Precautions and Adverse Reactions].
Specific Populations]
Monitor patients frequently for signs and symptoms of neurological
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE),
and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use
impairment. If neurological compromise is noted, urgent treatment is
of XARELTO in patients with CrCl <30 mL/min due to an expected
necessary [see Warnings and Precautions].
increase in rivaroxaban exposure and pharmacodynamic effects in this
Consider the benefits and risks before neuraxial intervention in
patient population [see Use in Specific Populations].
patients anticoagulated or to be anticoagulated for thromboProphylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
prophylaxis [see Warnings and Precautions].
Surgery: Avoid the use of XARELTO in patients with CrCl <30 mL/min due
to an expected increase in rivaroxaban exposure and pharmacodynamic
INDICATIONS AND USAGE
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular effects in this patient population. Observe closely and promptly evaluate
Atrial Fibrillation: XARELTO is indicated to reduce the risk of stroke and 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
systemic embolism in patients with nonvalvular atrial fibrillation.
There are limited data on the relative effectiveness of XARELTO and discontinue the treatment [see Use in Specific Populations].
warfarin in reducing the risk of stroke and systemic embolism when Use in Patients with Hepatic Impairment: No clinical data are available
warfarin therapy is well-controlled [see Clinical Studies (14.1) in full for patients with severe hepatic impairment.
Prescribing Information].
Avoid use of XARELTO in patients with moderate (Child-Pugh B) and
Treatment of Deep Vein Thrombosis: XARELTO is indicated for the severe (Child-Pugh C) hepatic impairment or with any hepatic disease
associated with coagulopathy since drug exposure and bleeding risk
treatment of deep vein thrombosis (DVT).
Treatment of Pulmonary Embolism: XARELTO is indicated for the may be increased [see Use in Specific Populations].
Use with P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid
treatment of pulmonary embolism (PE).
Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of concomitant use of XARELTO with combined P-gp and strong CYP3A4
Pulmonary Embolism: XARELTO is indicated for the reduction in the risk inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir,
of recurrence of deep vein thrombosis and of pulmonary embolism indinavir, and conivaptan) [see Drug Interactions].
Avoid concomitant use of XARELTO with drugs that are combined P-gp
following initial 6 months treatment for DVT and/or PE.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin,
Replacement Surgery: XARELTO is indicated for the prophylaxis of DVT, St. John’s wort) [see Drug Interactions].
which may lead to PE in patients undergoing knee or hip replacement Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO
should be used only if the potential benefit justifies the potential risk to
surgery.
the mother and fetus. XARELTO dosing in pregnancy has not been
CONTRAINDICATIONS
studied. The anticoagulant effect of XARELTO cannot be monitored with
XARELTO is contraindicated in patients with:
standard laboratory testing nor readily reversed. Promptly evaluate
• active pathological bleeding [see Warnings and Precautions]
any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin
• severe hypersensitivity reaction to XARELTO (e.g., anaphylactic and/or hematocrit, hypotension, or fetal distress).
reactions) [see Adverse Reactions]
Patients with Prosthetic Heart Valves: The safety and efficacy of
WARNINGS AND PRECAUTIONS
XARELTO have not been studied in patients with prosthetic heart valves.
Increased Risk of Thrombotic Events after Premature Discontinuation: Therefore, use of XARELTO is not recommended in these patients.
Premature discontinuation of any oral anticoagulant, including XARELTO,
in the absence of adequate alternative anticoagulation increases the Acute PE in Hemodynamically Unstable Patients or Patients Who
risk of thrombotic events. An increased rate of stroke was observed Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO
during the transition from XARELTO to warfarin in clinical trials in atrial is not recommended acutely as an alternative to unfractionated heparin
fibrillation patients. If XARELTO is discontinued for a reason other than in patients with pulmonary embolism who present with hemodynamic
pathological bleeding or completion of a course of therapy, consider instability or who may receive thrombolysis or pulmonary embolectomy.
coverage with another anticoagulant [see Dosage and Administration ADVERSE REACTIONS
(2.2, 2.6) and Clinical Studies (14.1) in full Prescribing Information].
The following adverse reactions are also discussed in other sections of
Risk of Bleeding: XARELTO increases the risk of bleeding and can cause the labeling:
serious or fatal bleeding. In deciding whether to prescribe XARELTO to • Increased risk of stroke after discontinuation in nonvalvular atrial
fibrillation [see Boxed Warning and Warnings and Precautions]
patients at increased risk of bleeding, the risk of thrombotic events
should be weighed against the risk of bleeding.
• Bleeding risk [see Warnings and Precautions]
Promptly evaluate any signs or symptoms of blood loss and consider the • Spinal/epidural hematoma [see Boxed Warning and Warnings and
Precautions]
need for blood replacement. Discontinue XARELTO in patients with
active pathological hemorrhage. The terminal elimination half-life of Clinical Trials Experience: Because clinical trials are conducted under
rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
widely varying conditions, adverse reaction rates observed in the
Concomitant use of other drugs that impair hemostasis increases the clinical trials of a drug cannot be directly compared to rates in the
risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other clinical trials of another drug and may not reflect the rates observed in
antithrombotic agents, fibrinolytic therapy, and non-steroidal anti- clinical practice.
inflammatory drugs (NSAIDs) [see Drug Interactions].
During clinical development for the approved indications, 16326 patients
Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors were exposed to XARELTO. These included 7111 patients who received
(e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558
may increase bleeding risk [see Drug Interactions].
for 12 months and 2512 for 24 months) to reduce the risk of stroke and
systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 4728
Reversal of Anticoagulant Effect:
A specific antidote for rivaroxaban is not available. Because of high patients who received either XARELTO 15 mg orally twice daily for three
plasma protein binding, rivaroxaban is not expected to be dialyzable [see weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE)
Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to
sulfate and vitamin K are not expected to affect the anticoagulant reduce the risk of recurrence of DVT and of PE; and 4487 patients who
activity of rivaroxaban. Partial reversal of prothrombin time prolongation received XARELTO 10 mg orally once daily for prophylaxis of DVT
has been seen after administration of prothrombin complex concentrates following hip or knee replacement surgery (RECORD 1-3).
(PCCs) in healthy volunteers. The use of other procoagulant reversal Hemorrhage: The most common adverse reactions with XARELTO were
agents like activated prothrombin complex concentrate (APCC) or bleeding complications [see Warnings and Precautions].
recombinant factor VIIa (rFVIIa) has not been evaluated.
Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent
Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia adverse reactions associated with permanent drug discontinuation were
(spinal/epidural anesthesia) or spinal puncture is employed, patients bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for
treated with anticoagulant agents for prevention of thromboembolic warfarin. The incidence of discontinuations for non-bleeding adverse
complications are at risk of developing an epidural or spinal hematoma events was similar in both treatment groups.
which can result in long-term or permanent paralysis [see Boxed Table 1 shows the number of patients experiencing various types of
Warning].
bleeding events in the ROCKET AF trial.
XARELTO® (rivaroxaban) tablets
Table 1: Bleeding Events in ROCKET AF*
Parameter
XARELTO Event
N = 7111
Rate
n (%)
(per 100
Pt-yrs)
395 (5.6)
3.6
91 (1.3)
0.8
Warfarin
N = 7125
n (%)
Event
Rate
(per 100
Pt-yrs)
3.5
1.2
386 (5.4)
Major bleeding†
133 (1.9)
Bleeding into a critical
organ‡
Fatal bleeding
27 (0.4)
0.2
55 (0.8)
0.5
Bleeding resulting in
183 (2.6)
1.7
149 (2.1)
1.3
transfusion of ≥2 units of
whole blood or packed
red blood cells
Gastrointestinal bleeding
221 (3.1)
2.0
140 (2.0)
1.2
* 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.
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 dis continuation 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 (%)
Major bleeding event
Fatal bleeding
Intracranial
Non-fatal critical organ bleeding
Intracranial‡
Retroperitoneal‡
Intraocular‡
Intra-articular‡
Non-fatal non-critical organ bleeding§
Decrease in Hb ≥ 2g/dL
Transfusion of ≥2 units of whole blood or
packed red blood cells
Clinically relevant non-major bleeding
Any bleeding
40 (1.0)
3 (<0.1)
2 (<0.1)
10 (0.2)
3 (<0.1)
1 (<0.1)
3 (<0.1)
0
27 (0.7)
28 (0.7)
18 (0.4)
Enoxaparin/
VKA†
N = 4116
n (%)
72 (1.7)
8 (0.2)
4 (<0.1)
29 (0.7)
10 (0.2)
8 (0.2)
2 (<0.1)
4 (<0.1)
37 (0.9)
42 (1.0)
25 (0.6)
357 (8.6)
1169 (28.3)
357 (8.7)
1153 (28.0)
* Bleeding event occurred after randomization and up to 2 days after the
last dose of study drug. Although a patient may have had 2 or more
events, the patient is counted only once in a category.
† Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies:
XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily;
enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually
titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)]
‡ Treatment-emergent major bleeding events with at least >2 subjects in
any pooled treatment group
§ Major bleeding which is not fatal or in a critical organ, but resulting in
a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood
or packed red blood cells
EINSTEIN Extension Study: In the EINSTEIN Extension clinical study, the
most frequent adverse reactions associated with permanent drug
discontinuation were bleeding events, with incidence rates of 1.8% for
XARELTO vs. 0.2% for placebo treatment groups. The mean duration of
treatment was 190 days for both XARELTO and placebo treatment groups.
Table 3 shows the number of patients experiencing bleeding events in
the EINSTEIN Extension study.
Table 3: Bleeding Events* in EINSTEIN Extension Study
Parameter
Major bleeding event‡
Decrease in Hb ≥2 g/dL
Transfusion of ≥2 units of whole blood or
packed red blood cells
Gastrointestinal
Menorrhagia
Clinically relevant non-major bleeding
Any bleeding
XARELTO†
20 mg
N = 598
n (%)
4 (0.7)
4 (0.7)
2 (0.3)
Placebo†
3 (0.5)
1 (0.2)
32 (5.4)
104 (17.4)
0
0
7 (1.2)
63 (10.7)
N = 590
n (%)
0
0
0
* Bleeding event occurred after the first dose and up to 2 days after the
last dose of study drug. Although a patient may have had 2 or more
events, the patient is counted only once in a category.
† Treatment schedule: XARELTO 20 mg once daily; matched placebo
once daily
‡ There were no fatal or critical organ bleeding events.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
Surgery: In the RECORD clinical trials, the overall incidence rate of
adverse reactions leading to permanent treatment discontinuation was
3.7% with XARELTO.