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Prescriber
Guide
20mg
Simply Protecting More Patients
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1
Dear Doctor,
This prescriber guide was produced by Bayer Israel in cooperation with
the Ministry of Health as part of a risk management plan for all new oral
anticoagulants marketed in Israel, in order to provide the most important
information to prescribers and healthcare providers.
The most important safety information for prescribing physicians
At the beginning of this prescriber guide, we would like to draw your attention
to several guidelines for the responsible use of Xarelto, in order to maximize the
efficiency and the safety during Xarelto treatment:
 Dosing should be adjusted according to the patient’s renal function:
Renal function should be evaluated prior to the initiation of Xarelto treatment.
In patients with moderate (creatinine clearance 30 - 49 mL/min) or severe (15 29 mL/min) renal impairment, dose adjustment should be considered according
to the treatment indication, as described in this guide.
The use of Xareltois not recommended in patients with creatinine clearance
lower than 15 mL/min.
 There is no recommendation for dose adjustment according to the patient’s
age or weight.
 Drugs administered concomitantly with Xarelto must be taken into account:
• Xarelto should not be used concomitantly with other anticoagulants (such
as warfarin, dabigatran, apixaban or heparin) except under the circumstances
of switching therapy to or from Xarelto or when heparin is administered at
doses necessary to maintain an open central venous or arterial catheter.
• The use of Xarelto is not recommended in patients receiving concomitant
systemic treatment with azole-antimycotics (such as ketoconazole,
itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g.
ritonavir).
• Patients treated with drugs affecting hemostasis, such as NSAIDs,
acetylsalicylic acid (such as Aspirin) or platelet aggregation inhibitors are at
increased risk for bleeding and should be therefore carefully monitored for
signs and symptoms of bleeding complications.
• For further information regarding Interaction with other drugs, please refer to
sections “Interaction with other drugs” and “Populations Potentially at Higher
Risk of Bleeding”
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 Populations Potentially at Higher Risk of Bleeding:
Like all anticoagulants, Xarelto® may increase the risk of bleeding. Several
sub-groups of patients are at increased risk for bleeding and should be carefully
monitored for signs and symptoms of bleeding complications.
• Patients with renal impairment (as specified above)
• Patients concomitantly receiving other medications (as specified above)
• Patients with other haemorrhagic risk factors, such as:
- Congenital or acquired bleeding disorders
- Uncontrolled severe arterial hypertension
- Gastrointestinal diseases (not including current or recent gastrointestinal
ulceration which is a contra-indication for Xarelto treatment), such as
inflammatory bowel disease, oesophagitis, gastritis and gastro-esophageal
reflux disease.
- Vascular retinopathy
- Bronchiectasis or history of pulmonary bleeding
Treatment decision in these patients should be done after assessment of treatment
benefit against the risk for bleeding.
 Situations, which require treatment discontinuation:
Xarelto administration should be discontinued if severe haemorrhage occurs.
Guidance for bleeding management is provided below in this prescriber guide.
Premature discontinuation of the treatment increases the risk of thrombotic
events.
Premature discontinuation of any anticoagulant, including Xarelto, increases the
risk of thrombotic events. If the treatment with Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy,
consider coverage with another anticoagulant.
Indications:
 Prevention of stroke and systemic embolism in adult patients with non-valvular
atrial fibrillation with one or more risk factors, such as congestive heart failure,
hypertension, age≥75 years, diabetes mellitus, prior stroke or transient ischaemic
attack.
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 Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT and PE in adults.
Xarelto is also available at a dose of 10 mg, which is indicated for the
prevention of venous thromboembolism (VTE) in adult patients undergoing
elective hip or knee replacement surgery. This guide refers to Xarelto 15 mg
and Xarelto 20 mg only. For treatment guidelines for Xarelto 10 mg, please
refer to the full prescribing information.
Contraindications:
1.
2.
3.
4.
5.
6.
Hypersensitivity to any of the drug components.
Active clinically significant bleeding.
Lesion or condition, if considered to be a significant risk for major bleeding. This
®
Xarelto
Prescriber
Guide
may
include
current
or recent gastrointestinal ulceration, presence of malignant
neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain,
spinal or ophthalmic surgery, recent intracranial haemorrhage, known or
suspected
oesophageal
Patient Alert
Cardvarices, arteriovenous malformations, vascular
aneurysms
or card
intraspinal
intracerebral
vascular
A patient alert
must beorprovided
to each
patient abnormalities.
who is prescribed Xarelto®
Concomitant
treatment
with anyofother
anticoagulant
(such
as warfarin,
15 or 20 mg, and
the implications
anticoagulant
treatment
should
be
dabigatran,
apixaban
or heparin)
except under
circumstances
of switching
explained. Specifi
cally, the
need for compliance
andthe
signs
of bleeding and
therapy
or medical
from rivaroxaban
or when
heparin iswith
given
doses necessary to
when to to
seek
attention should
be discussed
theat
patient.
maintain an open central venous or arterial catheter.
The patient alert card will inform physicians and dentists about the patient‘s
Hepatic
disease associated with increased risk for bleeding including cirrhotic
anticoagulation treatment and will contain emergency contact information.
patients
with Child Pugh B and C.
The patient should be instructed to carry the patient alert card at all times and
Pregnancy
and breast feeding.
present it to every health care provider.
Drug
information:
Dosing
Recommendations
Dosing
Recommendations
Dosing
in patients with atrial fibrillation
The recommended
dose for
prevention
of stroke
and systemic embolism in
Dosing
recommendations
in patients
with
atrial fibrillation
with non-valvular
fibrillation
is 20 mg
daily. embolism in adult
Thepatients
recommended
dose for atrial
prevention
of stroke
andonce
systemic
patients with non-valvular atrial fibrillation is 20 mg once daily.
DOSING SCHEME
CONTINUOUS TREATMENT
Xarelto® 20 mg
once daily*
TAKE WITH FOOD
* In patients with moderate or severe
renal impairment the recommended dose is 15 mg once daily.
*In patients with moderate or severe renal impairment the recommended dose is 15 mg once daily.
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Patients with renal impairment:
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe
Patients with renal impairment
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe
(15 - 29 ml/min) renal impairment the recommended dose is 15 mg once daily.
Xarelto use is not recommended in patients with creatinine clearance lower than 15
mL/min.
Duration of therapy
Xarelto® should be administered continuously and for long-term, provided that the
benefit of stroke prevention therapy outweighs the potential risk of bleeding.
Missed dose
If a dose is missed the patient should take Xarelto® immediately and continue on
the following day with the once daily intake as recommended. The dose should not
be doubled within the same day to make up for a missed dose**.
** These instructions refer to atrial fibrillation patients. Instructions for a missed dose concerning
the indication of deep vein thrombosis (DVT) and pulmonary embolism
treatmentGuide
as well as the
®
Xarelto(PE)
Prescriber
prevention of DVT and PE recurrence are listed below in this guide.
Dosing recommendations for the treatment of deep vein thrombosis (DVT) and
Dosing in the treatment of deep vein thrombosis (DVT) and prevention of
pulmonary
embolism (PE), and prevention of recurrent DVT and PE
recurrent DVT and pulmonary embolism (PE)
Patients are initially treated with 15 mg twice daily for the first three weeks. This
The
recommended dose is 15 mg twice daily for the first three weeks. Afterwards
initial treatment is followed by 20 mg once daily for continued treatment period.
the recommended dose is 20 mg once daily for the continued treatment period.
DOSING SCHEME
INITIAL TREATMENT
Xarelto® 15 mg
twice daily
FIRST 3 WEEKS
CONTINUOUS TREATMENT
Xarelto® 20 mg
once daily*
BEYOND 3 WEEKS
TAKE WITH FOOD
* Please see below for recommendations
for dose
adjustment
in patients
with impaired
function
*In patients with moderate
or severe
renal impairment
the recommended
dose is 15 mgrenal
once daily.
Patients with renal
Patients
renal impairment:
impairment:
In patients
with
moderate(creatinine
(creatinine clearance
clearance 30
Patients
with
moderate
30--49
49ml/min)
ml/min)ororsevere
severe (15 - 29
(15 - 29 ml/min)
renal impairment
should
be 15
treated
with 15
mgfor
twice
ml/min)
renal impairment
shouldpatients
be treated
with
mg twice
daily
the first 3
daily forThereafter,
the first 3 weeks.
Thereafter,
recommended
15 mg
daily.
weeks.
a reduction
of thethe
dose
from 20 mgdose
onceis daily
toonce
15 mg
once
Use isshould
not recommended
in patients
with creatinine
clearance
15 ml/min.
daily
be considered
if the patient’s
assessed
risk for<bleeding
outweighs the
Duration of therapy:
The duration of therapy should be individualised after assessment of the treatment
benefit against the risk for bleeding.
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risk for recurrent DVT and PE.
The use of Xarelto® is not recommended in patients with creatinine clearance < 15
ml/min.
Duration of therapy
The duration of therapy should be individualized after assessment of the treatment
benefit against the risk for bleeding.
Missed dose
• Twice daily treatment period (15 mg b.i.d. for the first three weeks): If a dose
is missed, the patient should take Xarelto® immediately to ensure intake of 30
mg Xarelto® per day. Continue with the regular 15 mg twice daily intake on the
following day.
• Once daily treatment period (beyond three weeks): If a dose is missed, the
patient should take Xarelto® immediately and continue on the following day
with the once daily intake as recommended. The dose should not be doubled
within the same day to make up for a missed dose.
Premature discontinuation of the treatment increases the risk of thrombotic
events
Premature discontinuation of any anticoagulant, including Xarelto, increases the
risk of thrombotic events. If the treatment with Xarelto is discontinued for a reason
other than pathological bleeding or completion of a course of therapy, consider
coverage with another anticoagulant.
Intake with food
Xarelto® 15 mg and 20 mg must be taken with food. The intake of these doses with
food at the same time supports the required absorption of the drug, thus ensuring
high oral bioavailability.
* Note: Xarelto® is also available at a 10 mg dose for the prevention of venous thromboembolism (VTE)
in adult patients undergoing elective hip or knee replacement surgery. This dose can be taken with
or without food.
Instructions prior to surgery or invasive treatment
If an invasive procedure or surgical intervention is required, Xarelto® 15/20 mg
should be discontinued, if possible, at least 24 hours before the intervention
and based on the clinical judgment of the physician. If the procedure cannot be
delayed, the increased risk of bleeding should be assessed against the urgency of
the intervention.
Xarelto® should be restarted after the invasive procedure or surgical intervention as
6
Xarelto® Prescriber Guide
soon as possible provided the clinical situation allows and adequate hemostasis has
been
Oralestablished.
Intake
Xarelto® 15 mg and 20 mg must be taken with food. The intake of these doses
In
patients
procedures
with
a low absorption
risk of bleeding
with
food atundergoing
the same time
support the
required
of the(e.g.
drug,dental
thus
Interventions
ororal
cataract
surgery)Note:
interruption
treatment
may
ensuring a high
bioavailability.
Xarelto®of
is Xarelto
also available
at a 10
mg not
dosebe
required.
Avoid performing
elective procedures
at peak
rivaroxaban
activity (i.e.
for the prevention
of venous thromboembolism
(VTE)
in adult
patients undergoing
within
hours
afterreplacement
tablet intake).
elective4hip
or knee
surgery. This dose can be taken without food.
Neuraxial
anesthesiaManagement
(Spinal/epidural) or spinal puncture - When neuraxial
Perioperative
anaesthesia
or spinal
puncture
is employed,
If an invasive (spinal/epidural)
procedure or surgical
intervention
is required,
Xarelto®patients
should betreated with
anticoagulant
increased
riskintervention,
of developing
an epidural
or spinal
stopped at leastare
24 at
hours
before the
if possible
and based
on thehaematoma.
Please
to theoffull
detailed
guidance
this topic.
clinical refer
judgement
theprescribing
physician. Ifinformation
the procedurefor
cannot
be delayed
the on
increased
risk of bleeding should be assessed against the urgency of the intervention.
Converting from Vitamin K Antagonists (VKA) to Xarelto
®
Xarelto
should
be restarted
after the invasive
procedure
or surgical
intervention
For
patients
treated
for prevention
of stroke
and systemic
embolism,
treatment
as
soon
as
possible
provided
the
clinical
situation
allows
and
adequate
with VKA should be stopped and Xarelto® therapy should be initiated when the INR
has been established.
ishaemostasis
3.0 or lower.
Converting from VKA to Xarelto®
For patients treated for DVT, PE and prevention of recurrent DVT and PE,
For patients treated for prevention of stroke and systemic embolism,
treatment with VKA should be stopped and Xarelto®
therapy should be initiated
treatment with VKA should be stopped and Xarelto® therapy should be initiated
when the INR is 2.5 or lower.
when the INR is
3.0.
For measurement
patients treatedisfor
DVT
and prevention
of recurrent
DVT and PE,
INR
not
appropriate
to measure
the anticoagulant
activity of
®
treatmentand
withtherefore
VKA should
be stopped
therapy
should
be initiated
Xarelto®,
should
not be and
usedXarelto
for this
purpose.
Treatment
with
when theonly
INRdoes
is 2.5.
Xarelto®
not require routine coagulation monitoring.
CONVERTING FROM VKA TO XARELTO®
Stop VKA
Xarelto®*
VKA
PREVENTION OF STROKE AND SYSTEMIC EMBOLISM:
Initiate Xarelto® once INR ≤ 3.0
INR testing
(duration according to
individual decrease of
VKA plasma levels)
DVT AND PREVENTION OF RECURRENT DVT AND PE:
Initiate Xarelto® once INR ≤ 2.5
DAYS
* Please see dosing recommendations for required daily dose
*See dosing recommendations for required daily dose
INR measurement is not appropriate to measure the anticoagulant activity
of Xarelto®, and therefore should not be used for this purpose. Treatment with
Xarelto® only does not require routine coagulation monitoring.
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Converting from Xarelto® to VKA
It is important to ensure adequate anticoagulation while minimizing the risk of
bleeding during conversion of therapy.
Xarelto® Prescriber Guide
When converting to VKA, Xarelto® and VKA should be given overlapping until the
INR is 2.0. For the first two days of the conversion period, standard initial dosing of
VKA should be used followed by VKA dosing
guided by INR testing.
®
Converting from Xarelto to VKA
It is important to ensure adequate anticoagulation while minimizing the risk of
INR measurement
is not
appropriate
to measure the anticoagulant activity of
bleeding during
conversion
of therapy.
Xarelto®. While patients are on both Xarelto® and VKA the INR should not be tested
converting
to VKA,
Xarelto® and
VKA
be the
given
overlapping
until the
earlierWhen
than 24
hours after
the previous
dose
butshould
prior to
next
dose of Xarelto®.
INR
is
2.0.
For
the
fi
rst
two
days
of
the
conversion
period,
standard
initial
Once Xarelto® is discontinued, INR values can be reliably obtained at least 24dosing
hours
of VKA
should
used followed by VKA dosing guided by INR testing.
after the
last dose
ofbe
Xarelto.
CONVERTING FROM XARELTO® TO VKA
Standard VKA dose
INR adapted VKA dose
Xarelto® can be stopped
once INR ≥ 2.0
Xarelto®*
INR testing
before Xarelto® administration
DAYS
* Please see dosing recommendations for required daily dose
*See dosing recommendations for required daily dose
INR measurement is not appropriate to measure the anticoagulant activity
Converting
from Parenteral Anticoagulants to Xarelto®
of Xarelto®. While patients are on both Xarelto® and VKA the INR should not
 Patients with continuously administered intravenous heprin- Xarelto® should be
be tested earlier than 24 hours after the previous dose but prior to the
started at the time of discontinuation.
next dose of Xarelto®. Once Xarelto® is discontinued INR testing may be done
 Patients treated with Low Molecular Weight Heparin – Xarelto should be started
reliably at least 24 hours after the last dose.
0 to 2 hours before the time of the next scheduled administration of the
parenteral
drug. from Parenteral Anticoagulants to Xarelto®
Converting
Patients
continuously
administered
parenteral drug such as
Converting
fromwith
Xarelto®
to Parenteral
Anticoagulants
®
intravenous
unfractionated
heparin: Xarelto
should
be started
atof
thethe next
The first dose
of the parenteral
anticoagulant
should
be given
instead
time at
of the
discontinuation.
Xarelto® dose
same time.
8
Patients with parenteral drug on a fixed dosing scheme such as LMWH:
Xarelto® should be started 0 to 2 hours before the time of the next scheduled
administration of the parenteral drug.
Converting from Xarelto® to Parenteral Anticoagulants
Interaction with other drugs
 The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g.
phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to
reduced rivaroxaban plasma concentrations. Therefore, concomitant
administration of strong CYP3A4 inducers should be avoided unless the patient
is closely observed for signs and symptoms of thrombosis.
For additional interactions please see information below in the section “Populations
Potentially at Higher Risk of Bleeding”
Populations Potentially at Higher Risk of Bleeding
Like all anticoagulants, Xarelto® may increase the risk of bleeding; therefore
a bleeding source should be searched in any case of unexplained decrease in
hemoglobin levels or blood pressure.
Careful attention should be given to the contraindications listed above.
Several sub-groups of patients are at increased risk for bleeding and should be
carefully monitored for signs and symptoms of bleeding complications.
Treatment decision in these patients should be taken after assessment of treatment
benefit against the risk for bleeding.
 Patients with renal impairment - please see above recommendations for dose
adjustments for patients with moderate (creatinine clearance 30 - 49 mL/min) or
severe (15 - 29 mL/min) renal impairment.
The use of Xarelto® is not recommended in patients with creatinine clearance
lower than 15 mL/min.
 Patients concomitantly receiving other drugs
• Systemic azole-antimycotics (such as ketoconazole, itraconazole, voriconazole
and posaconazole) or HIV protease inhibitors (e.g. ritonavir): use of Xarelto® is
not recommended.
• Drugs affecting hemostasis such as NSAIDs, acetylsalicylic acid (such as
Aspirin), or platelet aggregation inhibitors
• Dronedarone - given the limited clinical data available with dronedarone, co administration with rivaroxaban should be avoided.
9
 Patients with other haemorrhagic risk factors
• Congenital or acquired bleeding disorders
• Uncontrolled severe arterial hypertension
• Gastrointestinal disease (not including current or recent gastrointestinal
ulceration which is a contra-indication for Xarelto treatment) such as
inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal
reflux disease.
• Vascular retinopathy
• Bronchiectasis or history of pulmonary bleeding
Overdose
Due to limited absorption, a ceiling effect with no further increase in average
plasma exposure is expected at supratherapeutic doses of 50 mg Xarelto® and
above. The use of activated charcoal to reduce absorption in case of overdose may
be considered.
Should a bleeding complication arise in a patient receiving Xarelto®
The next Xarelto® administration should be delayed or treatment should be
discontinued as appropriate.
Individualized bleeding management may include:
 Symptomatic treatment, such as mechanical compression, surgical intervention,
fluid replacement
 Hemodynamic support - blood product or blood component transfusion
 For life-threatening bleeding that cannot be controlled with the above
measures, administration of a specific procoagulant agent should be considered,
such as prothrombin complex concentrate (PCC), activated prothrombin
complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However,
there is currently very limited clinical experience with the use of these products
in individuals receiving Xarelto®
Due to the high plasma protein binding Xarelto® is not expected to be dialyzable.
Coagulation Testing
Xarelto® does not require routine coagulation monitoring. However, measuring
Xarelto® levels may be useful in exceptional situations where knowledge of Xarelto®
exposure may help to take clinical decisions, e.g., overdose and emergency surgery.
Anti-FXa assays with Xarelto®-(rivaroxaban) specific calibrators to measure
rivaroxaban levels are now commercially available.
10
If clinically indicated, hemostatic status can also be assessed by PT
using Neoplastin as described in the full prescribing information.
The following coagulation tests might be increased:
Prothrombin time (PT), activated partial thromboplastin time (aPTT) and calculated
PT international normalized ratio (INR).
Since the INR was developed to assess the effects of VKAs on the PT, it is therefore
not appropriate to use the INR to measure activity of Xarelto®. Dosing or treatment
decisions should not be based on results of INR except when converting from
Xarelto® to VKA as described above.
Patient Safety Information Card
Please provide a Patient card to each patient who is prescribed with Xarelto® 15 or
20 mg. Explain to the patient the implications of anticoagulant treatment, including
the need for compliance. Please also explain the signs of bleeding and when to
seek medical attention.
The patient card will inform physicians and dentists about the patient‘s
anticoagulation treatment and will contain emergency contact information. The
patient should be instructed to carry the patient card at all times and present it to
every health care provider, who is treating him/her.
Additional information
This prescriber guide is aimed to provide the most important information to the
prescribing physician and to healthcare providers. For additional information,
please refer to the full prescribing information.
For additional information please contact Bayer Israel:
36 Hacharash St., Hod Hasharon, IL-4527702
Telephone number: 09-7626700
Fax number: 09-7626730
Reporting adverse events
Adverse events can be reported to the Ministry of Health using the online form
for adverse event reporting which can be found on the Ministry of Health website:
www.health.gov.il
or by using the following link:
https://forms.gov.il/globaldata/getsequence/getsequence.
[email protected]
Adverse events can be also reported to the Bayer Israel, according to following
contact details: Email: [email protected], Fax: 09-7626741
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15
20mg
Simply Protecting More Patients
15mg
Simply Protecting More Patients
09-7626730 :‫ פקס‬,09-7626700 :‫ טלפון‬,4527702 ,‫השרון‬-‫ הוד‬,36 ‫ החרש‬:‫באייר ישראל בע”מ‬