P R A C T I C A L C O N S I D E R AT I O N S
W H E N U S I N G X A R E LT O ®
Contents
Patient Types
•Patients With Nonvalvular Atrial Fibrillation . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 2
•Patients With Deep Vein Thrombosis or Pulmonary Embolism .. . . . . . . 4
•Knee or Hip Replacement Surgery Patients.. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 6
Other Considerations With XARELTO®
•Bleeding Risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•Bleed Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Management of Overdose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Increased Risk of Stroke After Discontinuation in Nonvalvular AF .. . .
•Transitioning to and From XARELTO®. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•Important Food Effect Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Dose Adjustments .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•Missed Dose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Administration Options.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Surgery and Other Medical Interventions. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .
•Assessment of Coagulation Status. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
7
8
8
8
9
9
10
10
10
11
11
Additional Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 12
Prescribing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
IMPORTANT SAFETY 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
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
(continued on page 2)
APPROVED FOR MULTIPLE INDICATIONS
Patient Types
IMPORTANT SAFETY INFORMATION (cont’d)
Patients With Nonvalvular Atrial Fibrillation
Indication
XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism
in patients with nonvalvular atrial fibrillation (AF).
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.
Patients Included in Clinical Trial
ROCKET AF was the pivotal phase 3 trial that determined noninferiority of XARELTO® to
dose-adjusted warfarin for reducing the risk of stroke and non–central nervous system
(CNS) systemic embolism in patients with nonvalvular AF. Patients with documented
nonvalvular AF were at a moderate to high risk of stroke.1
In ROCKET AF, XARELTO® was studied in patients with multiple comorbidities reflecting
an elevated risk for stroke. Patients included in the trial had a history of stroke, transient
ischemic attack (TIA), or non–CNS systemic embolism, or ≥2 of the following additional
risk factors1:
Age ≥75 years
Hypertension
Heart failure or left ventricular ejection fraction ≤35%
Diabetes mellitus
The mean CHADS2 score of patients in the trial was 3.5.1
Patient CHADS2 Scores in ROCKET AF 2
44
28.7%
28.7%
5
12.7%
3
2
6
2.0%
13.0%
43.6%
A. PREMATURE DISCONTINUATION OF
XARELTO® INCREASES THE RISK OF
THROMBOTIC EVENTS (cont’d)
pathological bleeding or completion of a
course of therapy, consider coverage with
another anticoagulant.
B. S PINAL/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:
u
se of indwelling epidural catheters
U
C
u
oncomitant use of other drugs that
affect hemostasis, such as non-steroidal
anti-inflammatory drugs (NSAIDs),
platelet inhibitors, other anticoagulants,
see Drug Interactions
u
A
history of traumatic or repeated
epidural or spinal punctures
u
A history of spinal deformity or
spinal surgery
u Optimal timing between the administration
of XARELTO® and neuraxial procedures is
not known
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.
(continued on page 3)
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
2
Patients With Nonvalvular Atrial Fibrillation (cont’d)
IMPORTANT SAFETY INFORMATION (cont’d)
Patients With Renal Impairment
CONTRAINDICATIONS
In the ROCKET AF trial, patients with creatinine clearance (CrCl) >50 mL/min received
XARELTO® 20 mg once daily with the evening meal. Patients with CrCl 30 to 50 mL/min
were administered XARELTO® 15 mg once daily with the evening meal, resulting in serum
concentrations of rivaroxaban and clinical outcomes similar to those in patients with better
renal function administered XARELTO® 20 mg once daily
atients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO®
P
15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar
to those in patients with normal renal function
void use of XARELTO® in nonvalvular AF patients with CrCl <15 mL/min since drug
A
exposure is increased
eriodically assess renal function as clinically indicated (ie, more frequently in situations in
P
which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO®
in patients who develop acute renal failure while on XARELTO®
Additional Important Considerations
remature discontinuation of any oral anticoagulant, including XARELTO®, in the absence
P
of adequate alternative anticoagulation increases the risk of thrombotic events. If
XARELTO® is discontinued for a reason other than pathological bleeding or completion of a
course of therapy, consider coverage with another anticoagulant.
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
u Active pathological bleeding
u
S evere hypersensitivity reaction to XARELTO®
(eg, anaphylactic reactions)
WARNINGS AND PRECAUTIONS
u I ncreased 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.
(continued on page 4)
3
Patients With Deep Vein Thrombosis or Pulmonary Embolism
IMPORTANT SAFETY INFORMATION (cont’d)
Indications
WARNINGS AND PRECAUTIONS (cont’d)
XARELTO (rivaroxaban) is indicated for the treatment of deep vein thrombosis (DVT).
u Risk
of Bleeding: XARELTO® increases
the risk of bleeding and can cause serious
or fatal 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.
• A specific antidote for rivaroxaban is not
available. Because of high plasma protein
binding, rivaroxaban is not expected to
be dialyzable.
• Concomitant use of other drugs affecting
hemostasis increases the risk of bleeding.
These include aspirin, P2Y12 platelet
inhibitors, other antithrombotic agents,
fibrinolytic therapy, and NSAIDs.
®
XARELTO® is indicated for the treatment of pulmonary embolism (PE).
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.
Patients Included in Clinical Trials
EINSTEIN DVT and EINSTEIN PE Trials
EINSTEIN DVT and EINSTEIN PE were the multinational, open-label, noninferiority clinical
trials comparing XARELTO® (at an initial dose of 15 mg twice daily with food for the first
3 weeks, followed by XARELTO® 20 mg once daily with food) to enoxaparin (1 mg/kg twice
daily for at least 5 days with warfarin and then continued with warfarin only after the target
international normalized ratio [2.0–3.0] was reached).
Patients were eligible for the EINSTEIN DVT trial if they had acute, symptomatic, objectively
confirmed proximal DVT, without symptomatic pulmonary embolism.3 Patients were eligible
for the EINSTEIN PE trial if they had acute symptomatic PE with objective confirmation, with
or without symptomatic DVT.4
(continued on page 5)
In the EINSTEIN DVT and EINSTEIN PE trials, 49% of patients had an idiopathic DVT/PE at
baseline. Other risk factors are shown below.
Patient Risk Factors in EINSTEIN DVT and EINSTEIN PE Trials
50
40
49%
30
20
19%
10
0
Idiopathic
DVT/PE
Previous
DVT/PE
18%
Recent
Surgery
or Trauma
16%
8%
6%
Immobilization Use of EstrogenKnown
Containing
Thrombophilic
Drug
Conditions
5%
Active
Cancer
More than 8200 patients in both trials were randomized and followed on study treatment for
a mean of 208 days in the XARELTO® group and 204 days in the enoxaparin + warfarin group.
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
4
Patients With Deep Vein Thrombosis or Pulmonary Embolism (cont’d)
IMPORTANT SAFETY INFORMATION (cont’d)
Patients Included in Clinical Trials (cont’d)
WARNINGS AND PRECAUTIONS (cont’d)
EINSTEIN Extension Trial
The EINSTEIN Extension trial was a multinational, double-blind, superiority clinical study
comparing XARELTO® (20 mg once daily with food) with placebo in patients who had
completed 6 to 14 months of treatment for DVT and/or PE following the acute event.
More than 1100 patients were randomized and followed on study treatment for a mean
of 190 days in both the XARELTO® and placebo treatment groups. The mean age was
approximately 58 years. The population was 58% male, 78% Caucasian, 8% Asian, and
2% Black.
In the EINSTEIN Extension trial, approximately 60% of patients had a history of proximal
index DVT without a PE event, and 29% of patients had a PE without a symptomatic
DVT event.
Patients With Renal Impairment
In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded
from the studies
void the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase
A
in rivaroxaban exposure and pharmacodynamic effects in this patient population
u 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 rivaroxaban and epidural or spinal
anesthesia/analgesia or spinal puncture, consider
the pharmacokinetic profile of rivaroxaban.
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), or bowel and/or bladder dysfunction.
Instruct patients to immediately report if they
experience any of the above signs or symptoms.
(continued on page 6)
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
5
Knee or Hip Replacement Surgery Patients
IMPORTANT SAFETY INFORMATION (cont’d)
Indications
WARNINGS AND PRECAUTIONS (cont’d)
XARELTO (rivaroxaban) is indicated for the prophylaxis of DVT, which may lead to PE
in patients undergoing knee replacement surgery.
Spinal/Epidural Anesthesia or Puncture: (cont’d)
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.
®
Patients Included/Excluded in Clinical Trials
XARELTO® was studied in the RECORD clinical trials with more than 9000 orthopedic
patients undergoing knee or hip replacement surgery.
HIP REPLACEMENT TRIALS
RECORD1 AND RECORD2
KNEE REPLACEMENT TRIAL
RECORD3
Elective total hip/
knee replacement
ean age = 63, with 49% of
M
patients aged ≥65 years
Female = 55%
ean age = 68, with 66%
M
of patients aged ≥65 years
Female = 68%
Patients with these
conditions were
excluded from
the trials
ndergoing staged bilateral
U
total hip replacement
Severe renal impairment
(creatinine clearance [CrCl]
<30 mL/min)
Significant liver disease
(hepatitis or cirrhosis)
S evere renal impairment
(CrCl <30 mL/min)
Significant liver disease
(hepatitis or cirrhosis)
u Use
in Patients With Renal Impairment:
• Nonvalvular Atrial Fibrillation: Avoid the
use of XARELTO® in patients with creatinine
clearance (CrCl) <15 mL/min, since drug
exposure is increased. Discontinue 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 rivaroxaban
exposure and pharmacodynamic effects
in this patient population.
(continued on page 7)
Patients With Renal Impairment
void the use of XARELTO® for the prophylaxis of DVT in patients with severe renal
A
impairment (CrCl <30 mL/min) due to an expected increase in rivaroxaban exposure and
pharmacodynamic effects in this patient population. Use with caution in patients with
moderate impairment (CrCl 30 to 50 mL/min)
ombined analysis of the RECORD1-3 trials did not show an increase in bleeding risk for
C
patients with moderate renal impairment, and reported a possible increase in total venous
thromboembolism in this population. Observe closely and promptly evaluate any signs
or symptoms of blood loss in patients with moderate renal impairment (CrCl 30 to
50 mL/min)
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
6
Other Considerations With XARELTO®
IMPORTANT SAFETY INFORMATION (cont’d)
Bleeding Risk
WARNINGS AND PRECAUTIONS (cont’d)
XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In clinical
trials, the most common adverse reactions with XARELTO® were bleeding complications.
XARELTO® is contraindicated in patients with active pathological 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. Discontinue XARELTO® in patients
with active pathological hemorrhage
Concomitant use of drugs affecting hemostasis increases the risk of bleeding.
These include:
Drugs affecting hemostasis
Aspirin, P2Y12 platelet inhibitors, other antithrombotic agents,
fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs)
Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors increases
rivaroxaban exposure and may increase bleeding risk. These include:
Drugs that are combined P-gp
and CYP3A4 inhibitors
For example, ketoconazole and ritonavir
Bleed Management*
• 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.
u 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.
(continued on page 8)
Promptly evaluate any signs and symptoms of blood loss and consider the need for
blood replacement
Discontinue XARELTO® in patients with active pathological hemorrhage
P
artial reversal of prothrombin time prolongation has been seen after administration
of prothrombin complex concentrates (PCCs) in healthy volunteers
T
he use of other procoagulant reversal agents like activated prothrombin complex
concentrates (APCCs) or recombinant factor VIIa (rFVIIa) has not been evaluated
*This is not intended to replace clinical judgment or determine individual patient care.
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
7
Considerations
IMPORTANT SAFETY INFORMATION (cont’d)
A specific antidote for XARELTO is not available
®
The terminal elimination half-life of XARELTO® is 5 to 9 hours in healthy subjects aged
20 to 45 years and 11 to 13 hours in the elderly
XARELTO® is not expected to be dialyzable due to high plasma protein binding
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
PCCs in healthy volunteers
The use of other procoagulant reversal agents like APCC or recombinant factor VIIa (rFVIIa)
has not been evaluated
Management of Overdose
Overdose of XARELTO® may lead to hemorrhage. A specific antidote for rivaroxaban is
not available (see information above). Discontinue XARELTO® and initiate appropriate
therapy if bleeding complications associated with overdosage occur.
The use of activated charcoal to reduce absorption in case of XARELTO® overdose may
be considered
Due to high plasma protein binding, rivaroxaban is not expected to be dialyzable
Increased Risk of Stroke After Discontinuation in Nonvalvular AF
Discontinuing XARELTO® in the absence of adequate alternative anticoagulation increases
the risk of thrombotic events. An increased rate of stroke was observed during the transition
from XARELTO® to warfarin in clinical trials in atrial fibrillation patients.
WARNINGS AND PRECAUTIONS (cont’d)
u Use
With P-gp and Strong CYP3A4 Inhibitors
or Inducers: Avoid concomitant use of
XARELTO® with combined P-gp and strong
CYP3A4 inhibitors (eg, ketoconazole,
itraconazole, lopinavir/ritonavir, ritonavir,
indinavir/ritonavir, and conivaptan). Avoid
concomitant use of XARELTO® with drugs
that are P-gp and strong CYP3A4 inducers
(eg, carbamazepine, phenytoin, rifampin,
St. John’s wort).
u R
isk 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 and is not readily reversed. Promptly
evaluate any signs or symptoms suggesting
blood loss (eg, a drop in hemoglobin and/or
hematocrit, hypotension, or fetal distress).
(continued on page 9)
If XARELTO® must be discontinued for a reason other than pathological bleeding or
completion of a course of therapy, consider administering another anticoagulant.
The Boxed WARNINGS for XARELTO® are based on the risk associated with permanently
discontinuing XARELTO® therapy without proper transition or management.
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
8
Transitioning to and From XARELTO®
IMPORTANT SAFETY INFORMATION (cont’d)
WARNINGS AND PRECAUTIONS (cont’d)
SWITCHING TO XARELTO®
From warfarin
Stop warfarin and start XARELTO® when INR is <3.0
From unfractionated heparin
Stop the infusion and start XARELTO at the same time
From other anticoagulants
Start XARELTO® 0 to 2 hours prior to the next scheduled evening
administration of the other anticoagulant
®
SWITCHING FROM XARELTO®
To warfarin*
One approach is to stop XARELTO® and start parenteral
anticoagulant and warfarin at time of next scheduled XARELTO® dose
To other anticoagulants†
Stop XARELTO® and start other anticoagulant when the next dose
of XARELTO® would have been given
* 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.
†
Oral or parenteral rapid-onset anticoagulants.
ARELTO® eliminates the need for bridging with a parenteral heparin or
X
low-molecular-weight heparin to oral therapy
Important Food Effect Information
XARELTO® 15-mg and 20-mg tablets should be taken with food, while the 10-mg tablet
can be taken with or without food.
It is recommended that patients with nonvalvular AF take XARELTO® with the evening
meal, as specified in the ROCKET AF trial protocol.
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.
The absolute bioavailability of XARELTO® at a dose of 20 mg in the fasted state
is approximately 66%. Coadministration of XARELTO® with food increases the
bioavailability of the 20-mg dose (mean area under the curve [AUC] and maximum
concentration [Cmax] increasing by 39% and 76%, respectively, with food).
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
u 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.
u Acute
PE in Hemodynamically Unstable
Patients/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.
DRUG INTERACTIONS
u Avoid
concomitant 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.
u X
ARELTO® should not be used in patients
with CrCl 15 to 80 mL/min who are receiving
concomitant combined P-gp and moderate
CYP3A4 inhibitors unless the potential benefit
justifies the potential risk.
(continued on page 10)
9
Dose Adjustments
IMPORTANT SAFETY INFORMATION (cont’d)
No dose adjustments based on age, weight, or gender are required for XARELTO .
®
In clinical studies, elderly subjects exhibited higher rivaroxaban plasma concentrations
than younger subjects with mean AUC values being approximately 50% higher, mainly
due to reduced (apparent) total body and renal clearance. Age-related changes in renal
function may play a role in this age effect
Extremes in body weight (<50 kg or >120 kg) did not influence (less than 25%)
rivaroxaban exposure
Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO®
Missed Dose
If a dose of XARELTO® is not taken at the scheduled time, the dose should be administered
as soon as possible on the same day as follows:
atients receiving 20, 15, or 10 mg once daily should take the missed dose of
P
XARELTO® immediately
atients receiving 15 mg twice daily should take XARELTO® immediately to ensure intake
P
of 30 mg of XARELTO® per day. In this particular instance, two 15-mg tablets may be
taken at once. Patients should continue with the regular 15-mg twice-daily intake as
recommended on the following day
USE IN SPECIFIC POPULATIONS
u P
regnancy Category C: XARELTO® should be
used during pregnancy only if the potential
benefit justifies the potential risk to mother
and fetus. There are no adequate or wellcontrolled 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.
u L abor and Delivery: Safety and effectiveness
of XARELTO® during labor and delivery have
not been studied in clinical trials.
(continued on page 11)
Administration Options
F or patients who are unable to swallow whole tablets, XARELTO® 10-mg, 15-mg, or 20-mg
tablets may be crushed and mixed with applesauce prior to use and administered orally
fter the administration of a crushed XARELTO® 15-mg or 20-mg tablet, the dose should be
A
immediately followed by food
Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric
placement of the tube, XARELTO® 10-mg, 15-mg, or 20-mg tablets may be crushed and
suspended in 50 mL of water, and administered via an NG tube or gastric feeding tube.
Since rivaroxaban 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
rushed XARELTO® 10-mg, 15-mg, or 20-mg tablets are stable in water and in applesauce for up
C
to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban
from a water suspension of a crushed XARELTO® tablet to PVC or silicone NG tubing
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
10
Surgery and Other Medical 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
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. If oral medication cannot be taken after
surgical intervention, consider administering a parenteral anticoagulant
Assessment of Coagulation Status
No routine monitoring of INR or other coagulation parameters is required for patients
taking XARELTO®3-5
•INR should not be used to monitor XARELTO®, as INR is only calibrated and validated
for vitamin K antagonists (eg, warfarin)
•Dose-dependent inhibition of Factor Xa activity was observed in humans and the
Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT),
and HepTest® are prolonged dose-dependently
•Anti-Factor Xa activity is also influenced by rivaroxaban
IMPORTANT SAFETY INFORMATION (cont’d)
USE IN SPECIFIC POPULATIONS (con’t)
u N
ursing Mothers: It is not known if
rivaroxaban is excreted in human milk.
u Pediatric
Use: Safety and effectiveness in
pediatric patients have not been established.
u Females
of Reproductive Potential: Females
of reproductive potential requiring
anticoagulation should discuss pregnancy
planning with their physician.
OVERDOSAGE
u D
iscontinue XARELTO® and initiate appropriate
therapy if bleeding complications associated
with overdosage occur. A specific antidote
for rivaroxaban is not available. The use of
activated charcoal to reduce absorption in
case of XARELTO® overdose may be considered.
Due to the high plasma protein binding,
rivaroxaban is not expected to be dialyzable.
(continued on page 12)
Neoplastin® and HepTest® are trademarks of their respective owners.
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
11
IMPORTANT SAFETY INFORMATION (cont’d)
ADVERSE REACTIONS IN CLINICAL STUDIES
Visit www.XareltoHCP.com for detailed information about XARELTO
and resources to address access and affordability questions.
u The
most common adverse reactions with
XARELTO® were bleeding complications.
If you have questions about XARELTO®, call Janssen Medical Information
at 1-800-JANSSEN (1-800-526-7736), Monday - Friday, 9:00 am - 8:00 pm ET,
Saturday - Sunday, 9:00 am - 5:00 pm ET.
Please see accompanying full Prescribing Information,
including Boxed WARNINGS.
®
011416-140307
Additional Resources
Direct patients and their caregivers to www.XareltoCarePath.com for
additional information, including educational videos, tools, and access to
the XARELTO® CarePath™ Support Program.
A comprehensive support program to help
patients start and stay on therapy
Help patients start on therapy
by making treatment
accessible and affordable
to eligible patients
Help keep patients informed
about their disease and the
importance of staying on treatment
to help support their success
Help patients stay on therapy
through useful tools
and reminders
Please see Important Safety Information throughout and accompanying
full Prescribing Information, including Boxed WARNINGS.
12
References
1. P
atel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus
warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.
2. Data on file. Janssen Pharmaceuticals, Inc.
3. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
4. EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med.
2012;366(14):1287-1297.
5. Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct
Factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203-216.
XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany.
© Janssen Pharmaceuticals, Inc. 2015 March 2015 015447-150128
Janssen Pharmaceuticals, Inc.