Approved Drug Label (PDF)
5
Warnings and Precautions
5.4 Use in Patients with Renal Impairment
Additions
underlined
…
![]()
Pediatric Patients
There
are limited clinical data in pediatric patients 1 year or older with moderate
or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the
use of XARELTO in these patients.
There
are no clinical data in pediatric patients younger than 1 year with serum
creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO
in these patients [see Dosage and
Administration (2.2) and Use in Specific Populations (8.6)].
5.5 Use in Patients with Hepatic Impairment
Additions
underlined
![]()
No clinical data
are available for adult patients with severe hepatic impairment.
…
No
clinical data are available in pediatric patients with hepatic impairment.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or
revisions underlined
…
During clinical development for the approved
indications, 34,947 adult patients were exposed to XARELTO.
…
Pediatric Patients
Treatment of
Venous Thromboembolism and Reduction in Risk of Recurrent Venous
Thromboembolism in Pediatric Patients
The safety assessment is based on data from the
EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years
of age. Patients were randomized 2:1 to receive body weight- adjusted doses of
XARELTO or comparator (unfractionated heparin, low molecular weight heparin,
fondaparinux or VKA).
Discontinuation due to bleeding events occurred in
6 (1.8%) patients in the XARELTO group and 3 (1.9%) patients in the comparator
group.
Table 14 shows the number of patients experiencing
bleeding events in the EINSTEIN Junior study. In female patients who had
experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in
23 (27%) female patients in the XARELTO group and 5 (10%) female patients in
the comparator group.
Please refer to
label to view Table 14
Non-bleeding adverse reactions reported in greater
than or equal to 5% of XARELTO-treated patients are shown in Table 15.
Please refer to
label to view Table 15
A clinically relevant adverse reaction in
XARELTO-treated patients was vomiting (10.6% in the XARELTO group vs 8% in the
comparator group).
Thromboprophylaxis
in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan
Procedure
The data below are based on Part B of the UNIVERSE
study which was designed to evaluate the safety and efficacy of XARELTO for
thromboprophylaxis in 98 children with CHD after the Fontan procedure who took
at least one dose of study drug. Patients in Part B were randomized 2:1 to receive
either body weight-adjusted doses
of XARELTO or aspirin (approximately 5 mg/kg).
Discontinuation due to bleeding events occurred in
1 (1.6%) patient in the XARELTO group and no patients in the aspirin group.
Table 16 shows the number of patients experiencing
bleeding events in the UNIVERSE study.
Please refer to
label to view Table 16
Non-bleeding adverse reactions reported in greater
than or equal to 5% of XARELTO-treated patients are shown in Table 17.
Please
refer to label to view Table 17
8
Use in Specific Populations
8.4 Pediatric Use
Subsection
revised; additions underlined
The safety and effectiveness of XARELTO have been
established in pediatric patients from birth to less than 18 years for the
treatment of VTE and the reduction in risk of recurrent VTE. Use of XARELTO is
supported in these age groups by evidence from adequate and well-controlled
studies of XARELTO in adults with additional pharmacokinetic, safety and
efficacy data from a multicenter, prospective, open-label, active-controlled
randomized study in 500 pediatric patients from birth to less than 18 years of
age. XARELTO was not studied and therefore dosing cannot be reliably
determined or recommended in children less
than 6 months who were less than
37 weeks of gestation at birth; had less than 10 days of oral feeding,
or had a body weight of less than 2.6 kg [see
Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology
(12.3) and Clinical Studies (14.8)].
The safety and effectiveness of XARELTO have been
established for use in pediatric patients aged 2 years and older with
congenital heart disease who have undergone the Fontan procedure. Use of
XARELTO is supported in these age groups by evidence from adequate and well-
controlled studies of XARELTO in adults with additional data from a multicenter,
prospective, open-label, active controlled study in 112 pediatric patients to
evaluate the single- and multiple- dose pharmacokinetic properties of XARELTO
and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12
months in children with single ventricle physiology who had the Fontan
procedure [see Dosage and Administration
(2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical
Studies (14.9)].
Clinical studies that evaluated safety, efficacy,
pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15
mg, and 20 mg tablets in pediatric patients. For the XARELTO 2.5 mg tablets,
there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to
support the use in pediatric patients. Therefore, XARELTO 2.5 mg tablets are
not recommended for use in pediatric patients.
Although not all adverse reactions identified in the
adult population have been observed in clinical trials of children and
adolescent patients, the same warnings and precautions for adults should be
considered for children and adolescents.
8.6 Renal Impairment
Additions
and/or revisions underlined
In
pharmacokinetic studies, compared to healthy adult subjects with normal
creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64%
in adult subjects with renal impairment. Increases in pharmacodynamic
effects were also observed [see Clinical
Pharmacology (12.3)].
…
Pediatric
Use
No
dosage adjustment is required in patients 1 year of age or older with mild
renal impairment (eGFR 50 to less than or equal to 80 mL/min/1.73 m2). There
are limited clinical data in pediatric patients 1 year or older with moderate
or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the
use of XARELTO in these patients.
There
are no clinical data in pediatric patients younger than 1 year with serum
creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO
in these patients [see Dosage and
Administration (2.2)].
8.7 Hepatic Impairment
Additions
and/or revisions underlined
In
a pharmacokinetic study, compared to healthy adult subjects with normal
liver function, AUC increases of 127% were observed in adult subjects with
moderate hepatic impairment (Child- Pugh B).
…
No
clinical data are available in pediatric patients with hepatic impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Extensive additions, please refer to label for complete
information
PATIENT COUNSELING INFORMATION
Additions underlined
For the tablets, advise the patient and/or caregiver
to read the FDA-approved patient labeling (Medication Guide).
For the suspension, advise the patient and/or
caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions
for Use).
Instructions for Patient Use
…
Pediatric Patients
The adult caregiver should
administer the dose. Advise caregivers to use the syringes provided in the
original carton.
Advise the caregiver whether
the dose needs to be taken with food or not [see
Dosage and Administration (2.2)].
Advise the caregiver the
tablet must not be split in an attempt to provide a fraction of a tablet dose [see Dosage and Administration (2.2)].
If a child vomits or spits
up the dose within 30 minutes after receiving the dose, a new dose should be
given. However, if the child vomits more than 30 minutes after the dose is
taken, the dose should not be re-administered and the next dose should be taken
as scheduled. If a child vomits or spits up the dose repeatedly, the caregiver
should contact the child’s doctor right away [see Dosage and Administration (2.2)].
For children who are unable
to swallow whole tablets, XARELTO oral suspension may be used.
If a dose is missed, advise
the patient according to the instructions in the Full Prescribing Information
based on their dosing schedule [see
Dosage and Administration (2.5)].
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
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, 34,947 patients were exposed to XARELTO.
Table
6: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2
Days
Reduction
of Risk of Major Cardiovascular Events in Patients with CAD
In the COMPASS trial overall, the most
frequent adverse reactions associated with permanent drug discontinuation were
bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily vs.
1.2% for placebo on background therapy for all patients with aspirin 100 mg
once daily. The incidences of important bleeding events in the CAD and PAD populations
in COMPASS were similar.
Table
7: Major Bleeding Events in COMPASS - On Treatment Plus 2 days*
* 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 in the safety analysis set in COMPASS patients.
† Treatment schedule: XARELTO 2.5 mg twice
daily or placebo. All patients received background therapy with aspirin
100 mg once daily.
Reduction
of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery
Disease (PAD), Including Patients after Lower Extremity Revascularization due
to Symptomatic PAD
The incidence of premature permanent
discontinuation due to bleeding events for XARELTO
2.5 mg twice daily vs. placebo on
background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6%
and in COMPASS PAD was 2.7% vs. 1.3%, respectively.
Table 8 shows the number of patients
experiencing various types of TIMI (Thrombolysis in Myocardial Infarction)
major bleeding events in the VOYAGER trial. The most common site of bleeding
was gastrointestinal.
Table
8: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 days Newly added table; please refer to label for complete information
* Major bleeding events within each
subcategory were counted once per patient, but patients may have contributed
events to multiple subcategories.
† Treatment schedule: XARELTO 2.5 mg twice
daily or placebo. All patients received background therapy with aspirin 100 mg
once daily.
CABG: Coronary artery bypass graft; CI:
confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial
Infarction Bleeding Criteria
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
Of the total number of adult patients
in clinical trials for the approved indications of XARELTO (N=64,943
patients), 64 percent were 65 years and over, with 27 percent 75
years and over. In clinical trials the efficacy of XARELTO in the
elderly (65 years or older) was similar to that seen in patients younger than
65 years. Both thrombotic and bleeding event rates were higher in these older
patients [see Clinical Pharmacology
(12.3) and Clinical Studies (14)].
8.6 Renal Impairment
Additions and/or revisions underlined and
bolded:
Reduction of Risk of Major Cardiovascular
Events in Patients with CAD and Reduction of Risk of
Major Thrombotic Vascular Events in Patients with PAD, Including Patients After
Recent Lower Extremity Revascularization due to Symptomatic PAD
Patients
with Chronic Kidney Disease not on Dialysis
Patients with a CrCl <15 mL/min at
screening were excluded from COMPASS and VOYAGER, and limited data are
available for patients with a CrCl of 15 to 30 mL/min …
Patients
with End-Stage Renal Disease on Dialysis
No clinical outcome data is available for the
use of XARELTO with aspirin in patients with ESRD on dialysis since these
patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD …
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Risk of Bleeding
Newly added
information:
Risk of Hemorrhage in Acutely Ill Medical
Patients at High Risk of Bleeding
Acutely ill medical patients with the
following conditions are at increased risk of bleeding with the use of XARELTO
for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation,
or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital
cancer treatment), active gastroduodenal ulcer in the three months prior to
treatment, history of bleeding in the three months prior to treatment, or dual
antiplatelet therapy. XARELTO is not for use for primary VTE prophylaxis in
these hospitalized, acutely ill medical patients at high risk of bleeding.
5.4 Use in
Patients with Renal Impairment
Newly added
information:
Prophylaxis of Venous Thromboembolism in
Acutely Ill Medical Patients at Risk for Thromboembolic Complications
Not at High Risk of Bleeding
Avoid the use of XARELTO in patients with
CrCl less than 30 mL/min due to an expected increase in rivaroxaban exposure
and pharmacodynamic effects in this patient population. Consider
discontinuation of XARELTO in patients who develop acute renal failure while on
XARELTO.
Additions and/or
revisions underlined:
5.10 Increased
Risk of Thrombosis in Patients with Triple Positive Antiphospholipid
Syndrome
Direct-acting oral anticoagulants (DOACs),
including XARELTO, are not recommended for use in patients with triple-positive
antiphospholipid syndrome (APS). For patients with APS (especially those who
are triple positive [positive for lupus anticoagulant, anticardiolipin, and
anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been
associated with increased rates of recurrent thrombotic events compared with
vitamin K antagonist therapy.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or
revisions underlined:
During clinical development for the
approved indications, 31,691 patients were exposed to XARELTO …
4487 patients who received XARELTO 10 mg
orally once daily for prophylaxis of DVT following hip or knee replacement
surgery (RECORD 1-3); 3997 patients who received 10 mg orally once daily for
prophylaxis of VTE and VTE-related death in acutely ill medical patients
(MAGELLAN) and 9134 patients who received XARELTO 2.5 mg orally twice
daily, in combination with aspirin 100 mg once daily, for the reduction in risk
of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).
Newly added
information following Table 5: Bleeding Events in Patients Undergoing Hip or
Knee Replacement Surgeries (RECORD 1-3):
Prophylaxis of
Venous Thromboembolism in Acutely Ill Medical Patients at Risk for
Thromboembolic Complications
Not at High Risk of Bleeding
In the MAGELLAN study, the most frequent
adverse reactions associated with permanent drug discontinuation were bleeding
events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with
bronchiectasis were observed. Patients with bronchiectasis/pulmonary
cavitation, active cancer (i.e., undergoing acute, in-hospital cancer
treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any
bleeding in the previous three months all had an excess of bleeding with
XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN
data presented in Table 6. The incidence of bleeding leading to drug
discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo. Table 6
shows the number of patients experiencing various types of bleeding events in
the MAGELLAN study.
Table 6: Bleeding Events in MAGELLAN*
Study–Safety Analysis Set - On Treatment Plus 2 Days (See label for complete
table information).
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or
revisions underlined:
… In the EINSTEIN DVT, PE and Extension
clinical studies approximately 37% were 65 years and over and about 16% were greater
than 75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and
about 12% were greater than 75 years. In the MAGELLAN study, approximately
67% were 65 years and over and about 37% were greater than 75 years. In the
COMPASS study …
8.6 Renal
Impairment
Prophylaxis of Venous Thromboembolism in
Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at
High Risk of Bleeding
In the MAGELLAN study, patients with a
baseline CrCl less than 30 mL/min were excluded. Avoid use of XARELTO in
patients with CrCl less than 30 mL/min.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or
revisions underlined:
What is the most
important information I should know about XARELTO? XARELTO may cause serious
side effects, including:
Increased risk of
bleeding. XARELTO
can cause bleeding which can be serious and may lead to death. This is because
XARELTO is a blood thinner medicine (anticoagulant) that lowers blood clotting.
During treatment with XARELTO you are likely to bruise more easily, and it may
take longer for bleeding to stop. You may have a higher risk of bleeding if
you take XARELTO and have certain other medical problems.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Risk of Bleeding
(addition underlined)
…
Concomitant use of other drugs that impair hemostasis
increases the risk of bleeding. These include aspirin, P2Y12
platelet inhibitors, dual antiplatelet therapy, other antithrombotic
agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs,
selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake
inhibitors.
…
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions
underlined)
…
During clinical development for the approved indications,
27,694 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); 6962 patients who received XARELTO 15 mg orally twice daily
for three weeks followed by 20 mg orally once daily to treat DVT or PE
(EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN
Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE;
4487 patients who received XARELTO 10 mg orally once daily for prophylaxis
of DVT following hip or knee replacement surgery (RECORD 1-3); and 9134
patients who received XARELTO 2.5 mg orally twice daily, in combination
with aspirin 100 mg once daily, for the reduction in risk of major
cardiovascular events in patients with chronic CAD or PAD (COMPASS).
…
Reduction
of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD
In the COMPASS trial, the most frequent
adverse reactions associated with permanent drug discontinuation were bleeding
events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in
combination with aspirin 100 mg once daily vs. 1.2% for aspirin
100 mg once daily.
Table 6 shows the number of patients
experiencing various types of major bleeding events in the COMPASS trial.
(please
refer to label to view Table 6)
8
Use in Specific Populations
8.5 Geriatric Use
(additions underlined)
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 EINSTEIN CHOICE, approximately 39% were 65
years and over and about 12% were >75 years. In the COMPASS study,
approximately 76% were 65 years and over and about 17% were >75 years. In
clinical trials the efficacy of XARELTO in the elderly (65 years or older)
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 Renal Impairment
(additions underlined)
…
Nonvalvular Atrial Fibrillation
Patients
with Chronic Kidney Disease not on Dialysis
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 rivaroxaban and clinical outcomes similar to those in
patients with better renal function administered XARELTO 20 mg once daily.
Patients with CrCl less than or equal to 30 mL/min were not
studied, but administration of XARELTO 15 mg once daily is expected to
result in serum concentrations of rivaroxaban similar to those in patients with moderate
renal impairment.
…
Reduction of Risk of Major Cardiovascular
Events in Patients with Chronic CAD or PAD
Patients
with Chronic Kidney Disease not on Dialysis
Patients with a CrCl <15 mL/min at
screening were excluded from COMPASS, and limited data are available for
patients with a CrCl of 15-30 mL/min. In patients with CrCl less than or
equal to 30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an
exposure similar to that in patients with moderate renal impairment, whose
efficacy and safety outcomes were similar to those with preserved renal
function.
Patients
with End-Stage Renal Disease on Dialysis
No clinical outcome data is available for the
use of XARELTO with aspirin in patients with ESRD on dialysis since these patients
were not enrolled in COMPASS. In patients with ESRD maintained on intermittent
hemodialysis, administration of XARELTO 2.5 mg twice daily will result in
concentrations of rivaroxaban and pharmacodynamic activity similar to those
observed in moderate renal impaired patients in the COMPASS study. It is not
known whether these concentrations will lead to similar CV risk reduction and
bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions,
please refer to label)
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions
and/or revisions underlined:
During clinical development for the
approved indications, 18560 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); 6962 patients who received XARELTO 15 mg orally twice daily
for three weeks followed by 20 mg orally once daily to treat DVT or PE
(EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN
Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or
PE …
Treatment
of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)
EINSTEIN DVT and EINSTEIN PE Studies
In the pooled analysis of the EINSTEIN DVT
and EINSTEIN PE clinical studies …
Reduction
in the Risk of Recurrence of DVT and/or PE
EINSTEIN CHOICE Study
In the EINSTEIN CHOICE clinical
study, the most frequent adverse reactions associated with permanent drug
discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10
mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100
mg. The mean duration of treatment was 293 days for XARELTO 10
mg-treated patients and 286 days for aspirin 100 mg-treated patients.
Table 3 shows the number of patients
experiencing bleeding events in the EINSTEIN CHOICE study.
Table 3: Bleeding Events* in EINSTEIN CHOICE There have been changes in the
symbols (in table) and definitions following the table, please refer to label
for complete information.
In the EINSTEIN CHOICE study, there was an
increased incidence of bleeding, including major and CRNM bleeding in the XARELTO
20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.
Prophylaxis
of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
Other Adverse Reactions
Non-hemorrhagic adverse reactions reported
in greater than or equal to 1% of XARELTO-treated patients in the EINSTEIN DVT
and EINSTEIN PE studies are shown in Table 5.
Table 5: Other Adverse Reactions* Reported
by greater than or equal to 1% of XARELTO-Treated Patients in EINSTEIN DVT
and EINSTEIN PE Studies
8
Use in Specific Populations
8.1 Pregnancy
PLLR
conversion; additions underlined:
Risk
Summary
The limited available data on XARELTO in
pregnant women are insufficient to inform a drug- associated risk of adverse
developmental outcomes. 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. Consider
the benefits and risks of XARELTO for the mother and possible risks to the
fetus when prescribing XARELTO to a pregnant woman.
Adverse outcomes in pregnancy occur
regardless of the health of the mother or the use of medications. The estimated
background risk of major birth defects and miscarriage for the indicated
populations is unknown. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Disease-Associated
Maternal and/or Embryo/Fetal Risk
Pregnancy is a risk factor for venous
thromboembolism and that risk is increased in women with inherited or acquired
thrombophilias. Pregnant women with thromboembolic disease have an increased
risk of maternal complications including pre-eclampsia. Maternal thromboembolic
disease increases the risk for intrauterine growth restriction, placental
abruption and early and late pregnancy loss.
Fetal/Neonatal
Adverse Reactions
Based on the pharmacologic activity of
Factor Xa inhibitors and the potential to cross the placenta, bleeding may
occur at any site in the fetus and/or neonate.
Labor or Delivery
All patients receiving anticoagulants,
including pregnant women, are at risk for bleeding and this risk may be
increased during labor or delivery. The risk of bleeding should be balanced
with the risk of thrombotic events when considering the use of XARELTO in this
setting.
Data
Human Data
There are no adequate or well-controlled
studies of XARELTO in pregnant women, and dosing for pregnant women has not
been established. Post-marketing experience is currently insufficient to
determine a rivaroxaban-associated risk for major birth defects or miscarriage.
In an in vitro placenta perfusion model,
unbound rivaroxaban was rapidly transferred across the human placenta.
Animal
Data
Rivaroxaban crosses the placenta in
animals … Fetal body weights decreased when pregnant rats were given oral doses
of 120 mg/kg during the period of organogenesis. This dose corresponds
to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding
…
8.2 Lactation
PLLR
conversion; additions underlined:
Risk Summary
Rivaroxaban has been detected in human milk. There
are insufficient data to determine the effects of rivaroxaban on the breastfed
child or on milk production. Rivaroxaban and/or its metabolites were present
in the milk of rats. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for
XARELTO and any potential adverse effects on the breastfed infant from
XARELTO or from the underlying maternal condition.
Data
Animal data
Following a single oral administration of
3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between
Day 8 to 10 postpartum, the concentration of total radioactivity was determined
in milk samples collected up to 32 hours post-dose. The estimated amount of
radioactivity excreted with milk within 32 hours after administration was 2.1%
of the maternal dose.
8.3 Females and Males of Reproductive Potential
PLLR
conversion; additions underlined:
Females of reproductive potential requiring anticoagulation …
8.5 Geriatric Use
Additions
and/or revisions underlined:
… In the EINSTEIN DVT, PE and Extension
clinical studies approximately 37% were 65 years and over and about 16% were
greater than 75 years. In EINSTEIN CHOICE, approximately 39% were 65 years
and over and about 12% were greater than 75 years. In clinical trials the
efficacy of XARELTO in the elderly …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Advise
patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or
20 mg tablets with food at approximately the same time every day.
Advise patients who are at a continued risk of recurrent
DVT and/or PE after at least 6 months of initial treatment, to take XARELTO 10
mg once daily with or without food.
Lactation
Advise patients to discuss with their
physician the benefits and risks of XARELTO for the mother and for the child
if they are nursing or intend to nurse during anticoagulant treatment.
Females
and Males of Reproductive Potential
Advise patients who can become pregnant …
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.2
Risk of Bleeding
… Concomitant use
of drugs that
are known combined
P-gp and strong CYP3A4
inhibitors increases rivaroxaban exposure and may increase bleeding risk.
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.
7
Drug Interactions
Additions
and/or revisions underlined:
7.1 General Inhibition and Induction
Properties
Rivaroxaban 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 rivaroxaban and may
increase the risk of bleeding. Combined P-gp and strong CYP3A4 inducers
decrease exposure to rivaroxaban 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 (e.g., ketoconazole and ritonavir).
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.
7.4 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 …
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