Brief Summary of Prescribing Information for XARELTO® (rivaroxaban)
XARELTO® (rivaroxaban) tablets, for oral use
See package insert for full Prescribing Information
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO
INCREASES THE RISK OF THROMBOTIC EVENTS,
(B) SPINAL/EPIDURAL HEMATOMA
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 [see Dosage and Administration (2.2, 2.6) in full Prescribing
Information, Warnings and Precautions, and Clinical Studies (14.1) in full
Prescribing Information].
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 nonsteroidal 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
• optimal timing between the administration of XARELTO and neuraxial
procedures is not known
[see Warnings and Precautions and Adverse Reactions].
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is
necessary [see Warnings and Precautions].
Consider the benefits and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated for thromboprophylaxis [see
Warnings and Precautions].
INDICATIONS AND USAGE
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) in full Prescribing Information].
Treatment of Deep Vein Thrombosis: XARELTO is indicated for the treatment
of deep vein thrombosis (DVT).
Treatment of Pulmonary Embolism: XARELTO is indicated for th e 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.
CONTRAINDICATIONS
XARELTO is contraindicated in patients with:
• active pathological bleeding [see Warnings and Precautions]
• severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions)
[see Adverse Reactions]
WARNINGS AND PRECAUTIONS
Increased Risk of Thrombotic Events after Premature Discontinuation:
Premature discontinuation of any oral anticoagulant, including XARELTO, in
the absence of adequate alternative anticoagulation increases the risk of
thrombotic events. An increased rate of stroke was observed during the
transition from XARELTO to warfarin in clinical trials in atrial fibrillation
patients. If XARELTO is discontinued for a reason other than pathological
bleeding or completion of a course of therapy, consider coverage with
another anticoagulant [see Dosage and Administration (2.2, 2.6) and Clinical
Studies (14.1) in full Prescribing Information].
Risk of Bleeding: XARELTO increases the risk of bleeding and can cause
serious or fatal bleeding. In deciding whether to prescribe XARELTO to
patients at increased risk of bleeding, the risk of thrombotic events should be
weighed against the risk of bleeding.
Promptly evaluate any signs or symptoms of blood loss and consider the
need for blood replacement. Discontinue XARELTO in patients with active
pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5
to 9 hours in healthy subjects aged 20 to 45 years.
Concomitant use of other drugs that impair hemostasis increases the risk of
bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic
agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs)
[see Drug Interactions], selective serotonin reuptake inhibitors, and serotonin
norepinephrine reuptake inhibitors.
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].
Reversal of Anticoagulant Effect: A specific antidote for rivaroxaban is not
available. Because of high plasma protein binding, rivaroxaban is not
expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing
Information]. Protamine sulfate and vitamin K are not expected to affect the
anticoagulant activity of rivaroxaban. Partial reversal of prothrombin time
prolongation has been seen after administration of prothrombin complex
concentrates (PCCs) in healthy volunteers. The use of other procoagulant
reversal agents like activated prothrombin complex concentrate (APCC) or
recombinant factor VIIa (rFVIIa) has not been evaluated.
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 longterm or permanent paralysis [see Boxed Warning].
To reduce the potential risk of bleeding associated with the concurrent use of
rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture,
consider the pharmacokinetic profile of rivaroxaban [see Clinical
Pharmacology (12.3) in full Prescribing Information]. Placement or removal of
an epidural catheter or lumbar puncture is best performed when the
anticoagulant effect of rivaroxaban is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known.
An epidural catheter should not be removed earlier than 18 hours after the
last administration of XARELTO. The next XARELTO dose is not to be
administered earlier than 6 hours after the removal of the catheter. If
traumatic puncture occurs, the administration of XARELTO is to be delayed
for 24 hours.
Should the physician decide to administer anticoagulation in the context of
epidural or spinal anesthesia/analgesia or lumbar puncture, monitor
frequently to detect any signs or symptoms of neurological impairment, such
as midline back pain, sensory and motor deficits (numbness, tingling, or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients
to immediately report if they experience any of the above signs or symptoms.
If signs or symptoms of spinal hematoma are suspected, initiate urgent
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets
diagnosis and treatment including consideration for spinal cord
decompression even though such treatment may not prevent or reverse
neurological sequelae.
Use in Patients with Renal Impairment: Nonvalvular Atrial Fibrillation:
Periodically assess renal function as clinically indicated (i.e., more frequently in
situations in which renal function may decline) and adjust therapy accordingly
[see Dosage and Administration (2.3) in full Prescribing Information]. Consider
dose adjustment or discontinuation of XARELTO in patients who develop acute
renal failure while on XARELTO [see Use in Specific Populations].
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].
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].
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].
Use with P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant
use of XARELTO with combined P-gp and strong CYP3A4 inhibitors
(e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and
conivaptan) [see Drug Interactions].
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].
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).
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.
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.
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]
• Bleeding risk [see Warnings and Precautions]
• Spinal/epidural hematoma [see Boxed Warning and Warnings and
Precautions]
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].
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.
Figure 1 shows the risk of major bleeding events across major subgroups.
Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days
Parameter
Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in
ROCKET AF – On Treatment Plus 2 Days
Note: The figure above presents effects in various subgroups all of which are
baseline characteristics and all of which were pre-specified (diabetic status
was not pre-specified in the subgroup, but was a criterion for the CHADS2
score). The 95% confidence limits that are shown do not take into account
how many comparisons were made, nor do they reflect the effect of a
particular factor after adjustment for all other factors. Apparent homogeneity
or heterogeneity among groups should not be over-interpreted.
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to
Reduce the Risk of Recurrence of DVT and of PE: EINSTEIN DVT and
EINSTEIN PE Studies: In the pooled analysis of the EINSTEIN DVT and
EINSTEIN PE clinical studies, the most frequent adverse reactions leading to
permanent drug discontinuation were bleeding events, with XARELTO vs.
enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%,
respectively. The mean duration of treatment was 208 days for XARELTOtreated 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
Major bleeding event
XARELTO†
N = 4130
n (%)
40 (1.0)
Enoxaparin/
VKA†
N = 4116
n (%)
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)
0
4 (<0.1)
Intra-articular‡
Non-fatal non-critical organ bleeding§
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-m ajor bleeding
Any bleeding
357 (8.6)
357 (8.7)
1169 (28.3)
1153 (28.0)
* Bleeding event occurred after randomization and up to 2 days after the last
dose of study drug. Although a patient may have had 2 or more events, the
patient is counted only once in a category.
† Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO
15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/
VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to
achieve a target INR of 2.5 (range: 2.0-3.0)]
‡ Treatment-emergent major bleeding events with at least >2 subjects in any
pooled treatment group
§ Major bleeding which is not fatal or in a critical organ, but resulting in a
decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or
packed red blood cells
XARELTO
N = 7111
n (%/year)
Warfarin
N = 7125
n (%/year)
395 (3.6)
386 (3.5)
XARELTO vs.
Warfarin
HR
(95% CI)
1.04 (0.90, 1.20)
55 (0.5)
84 (0.7)
0.67 (0.47, 0.93)
Hemorrhagic Stroke§
36 (0.3)
58 (0.5)
0.63 (0.42, 0.96)
Other ICH
19 (0.2)
26 (0.2)
0.74 (0.41, 1.34)
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.
Gastrointestinal (GI)¶
221 (2.0)
140 (1.2)
1.61 (1.30, 1.99)
Table 3: Bleeding Events* in EINSTEIN Extension Study
Fatal Bleeding#
27 (0.2)
55 (0.5)
0.50 (0.31, 0.79)
24 (0.2)
42 (0.4)
0.58 (0.35, 0.96)
Major Bleeding†
Intracranial
Hemorrhage (ICH)‡
ICH
Non-intracranial
3 (0.0)
13 (0.1)
0.23 (0.07, 0.82)
Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically
Relevant Non-Major.
* Major bleeding events within each subcategory were counted once per
patient, but patients may have contributed events to multiple
subcategories. These events occurred during treatment or within 2 days of
stopping treatment.
† Defined as clinically overt bleeding associated with a decrease in
hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or
whole blood, bleeding at a critical site, or with a fatal outcome.
‡ Intracranial bleeding events included intraparenchymal, intraventricular,
subdural, subarachnoid and/or epidural hematoma.
§ Hemorrhagic stroke in this table specifically refers to non-traumatic
intraparenchymal and/or intraventricular hematoma in patients on
treatment plus 2 days.
¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal
bleeding.
# Fatal bleeding is adjudicated death with the primary cause of death from
bleeding.
Parameter
Major bleeding event‡
XARELTO†
20 mg
N = 598
n (%)
Placebo†
N = 590
n (%)
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
32 (5.4)
7 (1.2)
104 (17.4)
63 (10.7)
Clinically relevant non-major bleeding
Any bleeding
* 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.