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
non-steroidal anti-inflammatory drugs (NSAIDs), platelet
inhibitors, other anticoagulants
• a history of traumatic or repeated epidural or spinal punctures
• a history of spinal deformity or spinal surgery
• 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 the
treatment of pulmonary embolism (PE).
Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of
Pulmonary Embolism: XARELTO is indicated for the reduction in the risk
of recurrence of deep vein thrombosis and of pulmonary embolism
following initial 6 months treatment for DVT and/or PE.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
Replacement Surgery: XARELTO is indicated for the prophylaxis of DVT,
which may lead to PE in patients undergoing knee or hip replacement
surgery.
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, and non-steroidal antiinflammatory drugs (NSAIDs) [see Drug Interactions].
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 Informati on]. 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 long-term or permanent paralysis [see Boxed
Warning].
To reduce the potential risk of bleeding associated with the concurrent
use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal
puncture, consider the pharmacokinetic profile of rivaroxaban [see
Clinical Pharmacology (12.3) 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.
XARELTO® (rivaroxaban) tablets
XARELTO® (rivaroxaban) tablets
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.
Use in Patients with Renal Impairment: Nonvalvular Atrial Fibrillation:
Avoid the use of XARELTO in patients with CrCl <15 mL/min since drug
exposure is increased. Periodically assess renal function as clinically
indicated (i.e., more frequently in situations in which renal function may
decline) and adjust therapy accordingly. Discontinue XARELTO in patients
who develop acute renal failure while on XARELTO [see Use in Specific
Populations]
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
wer e 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.
†
Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days
Parameter
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)
Gastrointestinal (GI)¶
221 (2.0)
140 (1.2)
1.61 (1.30, 1.99)
Fatal Bleeding#
27 (0.2)
55 (0.5)
0.50 (0.31, 0.79)
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.
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.
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and
to Reduce the Risk of Recurrence of DVT and of PE: EINSTEIN DVT and
EINSTEIN PE Studies: In the pooled analysis of the EINSTEIN DVT and
EINSTEIN PE clinical studies, the most frequent adverse reactions
leading to permanent drug discontinuation were bleeding events, with
XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of
1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days
for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated
patients.
Table 2 shows the number of patients experiencing major bleeding events
in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and
EINSTEIN PE Studies
Parameter
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)
Non-fatal non-critical organ bleeding§
27 (0.7)
37 (0.9)
Decrease in Hb ≥ 2g/dL
28 (0.7)
42 (1.0)
Transfusion of ≥2 units of whole blood
or packed red blood cells
18 (0.4)
25 (0.6)
357 (8.6)
357 (8.7)
Intra-articular‡
Clinically relevant non-major bleeding
Any bleeding
1169 (28.3)
1153 (28.0)
* Bleeding event occurred after randomization and up to 2 days after the
last dose of study drug. Although a patient may have had 2 or more
events, the patient is counted only once in a category.
† Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies:
XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily;
enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually
titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)]
‡ Treatment-emergent major bleeding events with at least >2 subjects in
any pooled treatment group
§ Major bleeding which is not fatal or in a critical organ, but resulting in
a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood
or packed red blood cells
EINSTEIN Extension Study: In the EINSTEIN Extension clinical study, the
most frequent adverse reactions associated with permanent drug
discontinuation were bleeding events, with incidence rates of 1.8% for
XARELTO vs. 0.2% for placebo treatment groups. The mean duration of
treatment was 190 days for both XARELTO and placebo treatment groups.
Ta ble 3 shows the number of patients experiencing bleeding events in the
EINSTEIN Extension study.