ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Xarelto 10 mg film-coated tablets
2.
Each film-coated tablet contains 10 mg rivaroxaban.
Excipients:
Each film-coated tablet contains 27.9 mg lactose monohydrate, see section 4.4.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light red, round tablets marked with the BAYER-cross on one side and "10" and a triangle on the
other side.
4.
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee
replacement surgery.
Posology
The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken
6 to 10 hours after surgery, provided that haemostasis has been established.
The duration of treatment depends on the individual risk of the patient for venous thromboembolism
which is determined by the type of orthopaedic surgery.
For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.
For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended.
If a dose is missed the patient should take Xarelto immediately and then continue the following day
with once daily intake as before.
Xarelto can be taken with or without food.
Renal impairment
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 -
80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) (see section 5.2).
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)
indicate that rivaroxaban plasma concentrations are significantly increased in this patient population,
therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with
creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk (see sections 4.3 and 5.2). Xarelto may be used with caution in cirrhotic patients
2
with moderate hepatic impairment (Child Pugh B) if it is not associated with coagulopathy (see
sections 4.4 and 5.2).
No dose adjustment is necessary in patients with other hepatic diseases.
Elderly population
No dose adjustment.
Body weight
No dose adjustment.
Gender
No dose adjustment.
Paediatric population
The safety and efficacy of Xarelto in children 0 to 18 years have not been established. No data are
available. Therefore, Xarelto is not recommended for use in children below 18 years of
age.
Method of administration
For oral use.
Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 5.2).
Haemorrhagic risk
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are
to be carefully monitored for signs of bleeding complications after initiation of treatment. This may be
done by regular physical examination of the patients, close observation of the surgical wound drainage
and periodic measurements of haemoglobin.
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels
may be significantly increased which may lead to an increased bleeding risk. Use is not recommended
in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with caution in patients with
creatinine clearance 15 - 29 ml/min (see sections 4.2 and 5.2).
Xarelto is to be used with caution in patients with moderate renal impairment (creatinine clearance
30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma
concentrations (see section 4.5).
Hepatic impairment
In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban
plasma levels may be significantly increased which may lead to an increased bleeding risk. Xarelto is
contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant
bleeding risk. Xarelto may be used with caution in cirrhotic patients with moderate hepatic impairment
(Child Pugh B) if it is not associated with coagulopathy (see sections 4.2, 4.3 and 5.2).
3
Interaction with other medicinal products
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). These active substances are strong inhibitors of both CYP3A4 and
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree
which may lead to an increased bleeding risk (see section 4.5).
Fluconazole is expected to have less effect on rivaroxaban exposure and can be co-administered with
caution.
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis
such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, platelet aggregation
inhibitors or other antithrombotic agents. For patients at risk of ulcerative gastrointestinal disease an
appropriate prophylactic treatment may be considered
(see section 4.5).
Other haemorrhagic risk factors
Rivaroxaban, like other antithrombotic agents, is to be used with caution in patients with an increased
bleeding risk such as:
congenital or acquired bleeding disorders
uncontrolled severe arterial hypertension
active ulcerative gastrointestinal disease
recent gastrointestinal ulcerations
vascular retinopathy
recent intracranial or intracerebral haemorrhage
intraspinal or intracerebral vascular abnormalities
recent brain, spinal or ophthalmological surgery.
Hip fracture surgery
Rivaroxaban has not been studied in clinical trials in patients undergoing hip fracture surgery to
evaluate efficacy and safety in these patients. Therefore, rivaroxaban is not recommended in these
patients.
Spinal/epidural anaesthesia or puncture
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed,
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis.
The risk of these events may be increased by the post-operative use of indwelling epidural catheters or
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior
to neuraxial intervention the physician should consider the potential benefit versus the risk in
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
An epidural catheter is not to be removed earlier than 18 hours after the last administration of
rivaroxaban. The next rivaroxaban dose is to be administered not earlier than 6 hours after the removal
of the catheter.
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.
Interaction with CYP3A4 inducers
The concomitant use of rivaroxaban with strong CYP3A4 inducers (e.g. rifampicin, phenytoin,
carbamazepine, phenobarbital or St. John’s Wort) may lead to reduced rivaroxaban plasma
concentrations. Strong CYP3A4 inducers should be co-administered with caution (see section 4.5).
Information about excipients
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4
CYP3A4 and P-gp inhibitors
Co-administration of rivaroxaban with ketoconazole (400 mg once a day [od]) or ritonavir (600 mg
twice a day [bid]) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold /
1.6 fold increase in mean rivaroxaban C
max
, with significant increases in pharmacodynamic effects
which may lead to an increased bleeding risk. Therefore, 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. These active substances are
strong inhibitors of both CYP3A4 and P-gp (see section 4.4). Fluconazole is expected to have less
effect on rivaroxaban exposure and can be co-administered with caution.
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg bid), for instance, considered as strong CYP3A4 inhibitor and moderate P-gp
inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in C
max
. This
increase is not considered clinically relevant.
Erythromycin (500 mg three times a day [tid]), which inhibits CYP3A4 and P-gp moderately, led to a
1.3 fold increase in mean rivaroxaban AUC and C
max
. This increase is not considered clinically
relevant.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single
dose) an additive effect on anti-Factor Xa activity was observed without any additional effects on
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any
other anticoagulants (see section 4.4).
NSAIDs/platelet aggregation inhibitors
No clinically relevant prolongation of bleeding time was observed after concomitant administration of
rivaroxaban and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced
pharmacodynamic response.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when
rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a
pharmacokinetic interaction but a relevant increase in bleeding time was observed in a subset of
patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid)
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding
risk (see section 4.4).
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate
50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,
phenobarbital or St. John’s Wort) may also lead to reduced rivaroxaban plasma concentrations. Strong
CYP3A4 inducers should be co-administered with caution.
Other concomitant therapies
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp)
or atorvastatin (substrate of CYP3A4 and P-gp). Rivaroxaban neither inhibits nor induces any major
CYP isoforms like CYP3A4.
No clinically relevant interaction with food was observed (see section 4.2).
5
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of
rivaroxaban (see section 5.1).
4.6 Fertility, pregnancy and breast feeding
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In
a study on male and female fertility in rats no effects were seen (see section 5.3).
Pregnancy
There are no adequate data from the use of rivaroxaban in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic
risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast feeding
No data on the use of rivaroxaban in breast feeding women are available. Data from animals indicate
that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast feeding (see
section 4.3). A decision must be made whether to discontinue breast feeding or to discontinue/abstain
from therapy.
Syncope and dizziness have been reported in the post-operative setting and may affect the ability to
drive and use machines, these adverse reactions have been reported to be uncommon (see section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.
Summary of the safety profile
The safety of rivaroxaban 10 mg has been evaluated in four phase III studies (RECORD 1-4) including
6,097 patients exposed to rivaroxaban undergoing major orthopaedic surgery of the lower limbs (total
hip replacement or total knee replacement) treated for up to 39 days.
In total, about 14 % of the treated patients experienced adverse reactions. Bleedings or anaemia
occurred in approximately 3.3 % and 1 % of patients, respectively. Other common adverse reactions
were nausea, increased GGT and an increase in transaminases. The adverse reactions should be
interpreted within the surgical setting.
Tabulated summary of adverse reactions
The frequencies of adverse reactions reported with Xarelto in the phase III studies in patients
undergoing elective hip or knee replacement surgery are summarized in table 1 below by system organ
class (in MedDRA) and by frequency.
Frequencies are defined as:
Common: ≥ 1/100 to < 1/10
Uncommon: ≥ 1/1,000 to < 1/100
Rare: ≥ 1/10,000 to < 1/1,000
Not known: cannot be estimated from the available data.
6
Table 1:
Treatment-emergent adverse reactions
Common
Uncommon
Rare
Not known
*
Blood and lymphatic system disorders
Anaemia (incl. respective
laboratory parameter),
thrombocythaemia (incl.
platelet count increased)
Immune system disorders
Dermatitis allergic
Hypersensitivity
Nervous system disorders
Dizziness, headache
Syncope (incl. loss of
consciousness)
Cardiac disorders
Tachycardia
Vascular disorders
Post-procedural
haemorrhage (incl.
post-operative
anaemia, and wound
haemorrhage)
Haematoma (incl. rare cases
of muscle haemorrhage),
gastrointestinal tract
haemorrhage (incl. gingival
bleeding, rectal haemorrhage,
haememesis), urogenital tract
haemorrhage, hypotension
(incl. blood pressure
decreased, procedural
hypotension), nose bleed
Bleeding into a
critical organ (e.g.
brain), adrenal
haemorrhage,
conjunctival
haemorrhage,
haemoptysis,
pseudoaneurysm
formation
following
percutaneous
intervention**
Gastrointestinal disorders
Nausea
Constipation, diarrhoea,
abdominal and gastrointestinal
pain (incl. upper abdominal
pain, stomach discomfort),
dyspepsia (incl. epigastric
discomfort), dry mouth,
vomiting
Hepatobiliary disorders
Hepatic function
abnormal
Jaundice
Skin and subcutaneous tissue disorders
Pruritus (incl. rare cases of
generalised pruritus), rash,
contusion
Urticaria (incl. rare
cases of generalised
urticaria)
Musculoskeletal and connective tissue disorders
Pain in extremity
Compartment
syndrome
secondary to a
bleeding
Renal and urinary disorders
Renal impairment (incl. blood
creatinine increased, blood
urea increased)
Renal
failure/acute renal
failure secondary
to a bleeding
sufficient to cause
hypoperfusion
7
Common
Uncommon
Rare
Not known
*
General disorders and administration site conditions
Fever,
peripheral oedema
Localised oedema, decreased
general strength and energy
(incl. fatigue, asthenia)
Feeling unwell (incl.
malaise)
Investigations
Increased GGT,
increase in
transaminases (incl.
ALT increase, AST
increase)
Increased lipase, increased
amylase, blood bilirubin
increased, increased LDH,
increased alkaline phosphatase
Bilirubin conjugated
increased (with or
without concomitant
increase of ALT)
Injury, poisoning and procedural complications
Wound secretion
*) Adverse events have been reported in other clinical studies than the four phase III studies in patients
undergoing major orthopaedic surgery of the lower limbs or during postmarketing surveillance, for
which a frequency could not be estimated
**) These events ocured in clinical studies in other indications than prevention of VTE in patients
undergoing major orthopaedic surgery
Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased
risk of occult or overt bleeding from any tissue or organ which may result in posthaemorrhagic
anaemia. The signs, symptoms, and severity (including possibly fatal outcome) will vary according to
the location and degree or extent of the bleeding and/or anaemia. The risk of bleedings may be
increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension
and/or on concomitant treatment with other medicinal products affecting haemostasis (see
Haemorrhagic risk in section 4.4).
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained
swelling, dyspnoea, and unexplained shock. In some cases as a consequence of anaemia symptoms of
cardiac ischaemia like chest pain or angina pectoris may occur. Furthermore, known complications
secondary to bleeding, such as compartment syndrome or renal failure might occur. Therefore, the
possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated
patient.
pharmacodynamic properties.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Should bleeding occur, management of the haemorrhage may include the following steps:
delay of next rivaroxaban administration or discontinuation of treatment as appropriate.
Rivaroxaban has mean terminal half-lives between 7 and 11 hours (see section 5.2).
appropriate symptomatic treatment, e.g. mechanical compression, surgical interventions, fluid
replacement and haemodynamic support, blood product or component transfusion should be
considered.
If life-threatening bleeding cannot be controlled by the above measures, administration of recombinant
factor VIIa may be considered. However, there is currently no experience with the use of recombinant
factor VIIa in individuals receiving rivaroxaban. The recommendation is based on limited non-clinical
data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement
of bleeding.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is neither scientific rationale for benefit nor experience with the use of systemic haemostatics
(e.g. desmopressin, aprotinin, tranexamic acid, aminocaproic acid) in individuals receiving
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
8
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX06
Mechanism of Action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of
Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin
(activated Factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of Factor Xa activity was observed in humans. Prothrombin time (PT) is
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR (International Normalized Ratio) is only
calibrated and validated for coumarins and cannot be used for any other anticoagulant. In patients
undergoing major orthopaedic surgery, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet
intake (i.e. at the time of maximum effect) ranged from 13 to 25 s (baseline values before surgery
12 to 15s).
The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently;
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. Anti-
Factor Xa activity is also influenced by rivaroxaban; however, no standard for calibration is available.
There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in
clinical routine.
Clinical efficacy and safety
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the
prevention of VTE, i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism
(PE) in patients undergoing major orthopaedic surgery of the lower limbs. Over 9,500 patients (7,050
in total hip replacement surgery and 2,531 in total knee replacement surgery) were studied in
controlled randomised double-blind phase III clinical studies, the RECORD-programme.
Rivaroxaban 10 mg once daily (od) started no sooner than 6 hours post-operatively was compared
with enoxaparin 40 mg once daily started 12 hours pre-operatively.
In all three phase III studies (see table 2), rivaroxaban significantly reduced the rate of total VTE (any
venographically detected or symptomatic DVT, non fatal PE and death) and major VTE (proximal
DVT, non fatal PE and VTE-related death), the pre-specified primary and major secondary efficacy
endpoints. Furthermore, in all three studies the rate of symptomatic VTE (symptomatic DVT, non-
fatal PE, VTE-related death) was lower in rivaroxaban treated patients compared to patients treated
with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treated with
rivaroxaban 10 mg compared to enoxaparin 40 mg.
9
Table 2: Efficacy and safety results from phase III clinical studies
RECORD 1
RECORD 2
RECORD 3
Study
Population
4,541 patients undergoing total hip
replacement surgery
2,509 patients undergoing total hip
replacement surgery
2,531 patients undergoing total knee
replacement surgery
Treatment
dose and
duration
after
surgery
Rivaroxaban
10 mg od
35 ± 4 days
Enoxaparin
40 mg od
35 ± 4 days
p
Rivaroxaban
10 mg od
35 ± 4 days
Enoxaparin
40 mg od
12 ± 2 days
p
Rivaroxaban
10 mg od
12 ± 2 days
Enoxaparin
40 mg od
12 ± 2 days
p
Total VTE 18 (1.1 %) 58 (3.7 %) < 0.001 17 (2.0
%) 81 (9.3 %)
< 0.001
79 (9.6
%) 166 (18.9 %) < 0.001
Major
VTE
4 (0.2 %) 33 (2.0 %) < 0.001
6 (0.6 %) 49 (5.1 %) <
0.001
9 (1.0 %)
24 (2.6 %) 0.01
Sympto-
matic VTE
6 (0.4 %) 11 (0.7 %)
3 (0.4 %) 15 (1.7 %)
8 (1.0 %)
24 (2.7 %)
Major
bleedings
6 (0.3 %)
2 (0.1 %)
1 (0.1 %)
1 (0.1 %)
7 (0.6 %)
6 (0.5 %)
The analysis of the pooled results of the phase III trials corroborated the data obtained in the
individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with
rivaroxaban 10 mg once daily compared to enoxaparin 40 mg once daily.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Xarelto in one or more subsets of the paediatric population in venous thromboembolism. The
European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in
all subsets of the paediatric population in the prevention of venous thromboembolism (in hospitalised
medically ill patients and patients undergoing elective hip and knee replacement surgery) and
thromboembolism (in subjects with non-valvular atrial fibrillation and patients with a recent acute
coronary syndrome). See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
Absorption
The absolute bioavailability of rivaroxaban is high (80 % - 100 %) for the 10 mg dose. Rivaroxaban is
rapidly absorbed with maximum concentrations (C
max
) appearing 2 - 4 hours after tablet intake. Intake
with food does not affect rivaroxaban AUC or C
max
at the 10 mg dose. Rivaroxaban 10 mg dose can be
taken with or without food. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg
once daily. At higher doses rivaroxaban displays dissolution limited absorption with decreased
bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state
than in fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual
variability (CV %) ranging from 30 % to 40 %, apart from the day of surgery and the following day
when variability in exposure is high (70 %).
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being
the main binding component. The volume of distribution is moderate with V
ss
being approximately
50 litres.
Metabolism and Elimination
Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half
then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the
administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly
via active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of
10
biotransformation. Based on
in vitro
investigations rivaroxaban is a substrate of the transporter
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be
classified as a low-clearance drug. After intravenous administration of a 1 mg dose the elimination
half-life is about 4.5 hours. After oral administration of a 10 mg dose the elimination becomes
absorption rate limited with mean terminal half-lives of 7 to 11 hours.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between
male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
Different weight categories
Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma
concentrations (less than 25 %). No dose adjustment is necessary.
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and
pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.
There are no data in patients with severe hepatic impairment.
The inhibition of Factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a
steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk. Xarelto may be used with caution in cirrhotic patients with moderate hepatic
impairment (Child Pugh B) if it is not associated with coagulopathy (see sections 4.3 and 4.4).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min),
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no
data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with
caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
11
Pharmacokinetic/pharmacodynamic relationship
The Pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma
concentration and several PD endpoints (Factor Xa inhibition, PT, aPTT, Heptest) has been evaluated
after administration of a wide range of doses (5 - 30 mg bid). Rivaroxaban 10 mg od results in a steady
state C
max
of about 125 µg/l. The relationship between rivaroxaban concentration and Factor Xa
activity was best described by an E
max
model. For PT, the linear intercept model generally described
the data better. Depending on the different PT reagents used, the slope differed considerably. When
Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 µg/l). The
results of the PK/PD analyses in Phase II were consistent with the data established in healthy subjects.
In patients, baseline Factor Xa and PT were influenced by the surgery resulting in a difference in the
concentration-PT slope between the day post-surgery and steady state.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, phototoxicity and genotoxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant
exposure levels.
In rats, no effects on male and female fertility were seen. Animal studies have shown reproductive
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
6.
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E171)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
12
6.5 Nature and contents of container
PP/Aluminium foil blisters or PVC/PVDC/Aluminium foil blisters in cartons of 5, 10 or 30 tablets or
perforated unit dose blisters in cartons of 10 x 1 or 100 x 1 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/08/472/001-010
9.
30 September 2008
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
13
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Bayer Schering Pharma AG
51368 Leverkusen
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.4 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer Carton
1.
Xarelto 10 mg film-coated tablets
Rivaroxaban
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 10 mg rivaroxaban.
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
5 film-coated tablets
10 film-coated tablets
30 film-coated tablets
10 x 1 film-coated tablets
100 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
18
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Schering Pharma AG,
13342 Berlin,
Germany
EU/1/08/472/001 5 film-coated tablets
(PVC/PVDC/Aluminium foil blisters)
EU/1/08/472/002 10 film-coated tablets
(PVC/PVDC/Aluminium foil blisters)
EU/1/08/472/004 100 x 1 film-coated tablets
(
PVC/PVDC
/Aluminium foil blisters)
EU/1/08/472/005 5 film-coated tablets
(PP/Aluminium foil blisters)
EU/1/08/472/006 10 film-coated tablets
(PP/Aluminium foil blisters)
EU/1/08/472/007 30 film-coated tablets
(PP/Aluminium foil blisters)
EU/1/08/472/008 100 x 1 film-coated tablets
(PP/Aluminium foil blisters)
EU/1/08/472/009 10 x 1 film-coated tablets
(PVC/PVDC/Aluminium foil blisters)
EU/1/08/472/010 10 x 1 film-coated tablets
(PP/Aluminium foil blisters)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Xarelto 10 mg
19
EU/1/08/472/003 30 film-coated tablets
(PVC/PVDC/Aluminium foil blisters)
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister
1.
Xarelto 10 mg tablets
Rivaroxaban
2.
Bayer (logo)
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
Xarelto 10 mg film-coated tablets
Rivaroxaban
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Xarelto is and what it is used for
3.
How to take Xarelto
4.
Possible side effects
5.
How to store Xarelto
6.
Further information
1.
WHAT XARELTO IS AND WHAT IT IS USED FOR
Xarelto is used to prevent blood clots in your veins after a hip or knee replacement operation. Your
doctor has prescribed this medicine for you because after an operation you are at an increased risk of
getting blood clots.
Xarelto belongs to a group of medicines called
antithrombotic agents
. It works by blocking a blood
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.
2.
BEFORE YOU TAKE XARELTO
Do not take Xarelto
-
if you are allergic
(hypersensitive) to rivaroxaban or any of the other ingredients of Xarelto.
The ingredients are listed at the end of this leaflet
-
if you are bleeding excessively
-
if you have a liver disease
which leads to an increased risk of bleeding
-
if you are pregnant or breast feeding
Do not take Xarelto
and tell your doctor
if any of these apply to you.
Take special care with Xarelto
- if you have
moderate or severe kidney disease
- if you have
moderate liver disease
- if you have
an increased risk of bleeding
such as:
▪
bleeding disorders
▪
very high blood pressure,
not controlled by medical treatment
▪
active ulcer or a recent ulcer
of your stomach or bowel
▪
a problem with the blood vessels in the back of your eyes
(retinopathy)
▪
recent bleeding in your brain
(intracranial or intracerebral bleeding)
▪
problems with the blood vessels in your brain or spinal column
▪
a recent operation on your brain, spinal column or eye
Tell your doctor
before you take Xarelto, if any of these apply to you. Your doctor will decide, if you
should be treated with Xarelto and if you should be kept under closer observation.
22
-
Keep this leaflet. You may need to read it again.
2.
Before you take Xarelto
-
in children and adolescents,
Xarelto is
not recommended for people under 18 years of age.
There is not enough information on its use in children and adolescents.
-
if your operation involves a catheter or injection into your spinal column
(e.g. for epidural
or spinal anaesthesia or pain reduction):
▪
it is very important to take Xarelto before and after the injection or removal of the
catheter exactly at the times you have been told by your doctor
▪
tell your doctor immediately if you get numbness or weakness of your legs or problems
with your bowel or bladder after the end of anaesthesia, because urgent care is necessary.
Taking other medicines
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
-
If you are taking:
▪ some
medicines for fungal infections
(e.g. ketoconazole, itraconazole, voriconazole,
posaconazole, fluconazole), unless they are only applied to the skin
▪ some
anti-viral medicines for HIV / AIDS
(e.g. ritonavir)
▪ other medicines to
reduce blood clotting
(e.g. enoxaparin or clopidogrel)
▪
anti-inflammatory and pain relieving medicines
(e.g. naproxen or acetylsalicylic acid)
Tell your doctor
before taking Xarelto, because its effect may be increased. Your doctor will
decide, if you should be treated with Xarelto and if you should be kept under closer observation.
If your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he
may also use a preventative ulcer treatment.
-
If you are taking:
▪ some
medicines for treatment of epilepsy
(phenytoin, carbamazepine, phenobarbital)
,
▪
St Johns Wort,
a herbal product used for depression,
▪
rifampicin,
an antibiotic.
Tell your doctor
before taking Xarelto, because its effect may be reduced. Your doctor will
decide, if you should be treated with Xarelto and if you should be kept under closer observation.
Taking Xarelto with food and drink
Xarelto can be taken with or without food.
Pregnancy and breast feeding
If you are pregnant or breast feeding
do not take Xarelto. If there is a chance that you could become
pregnant, use a reliable contraceptive while you are taking Xarelto. If you become pregnant while you
are taking Xarelto, immediately tell your doctor, who will decide how you should be treated.
Driving and using machines
Xarelto may cause side effects such as dizziness or fainting. You should not drive or use machines if
you are affected by these symptoms. For Xarelto, these side effects are uncommon (see section 4
“Possible side effects”).
Important information about some of the ingredients of Xarelto
Xarelto contains lactose.
If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking Xarelto.
3.
HOW TO TAKE XARELTO
Always take Xarelto exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
How much to take
The usual dose is one tablet (10 mg) once a day
.
23
-
Xarelto is
not recommended after an operation of a hip fracture.
Swallow the tablet preferably with water.
Xarelto can be taken with or without food.
When to take Xarelto
Take the first tablet 6 - 10 hours after your operation.
Then take a tablet every day until your doctor tells you to stop.
Try to take the tablet at the same time every day to help you to remember it.
If you have had a major hip operation
you will usually take the tablets for 5 weeks.
If you have had a major knee operation
you will usually take the tablets for 2 weeks.
If you take more Xarelto than you should
Contact your doctor immediately
if you have taken too many Xarelto tablets. Taking too much
Xarelto increases the risk of bleeding.
If you forget to take Xarelto
If you have missed a dose, take it as soon as you remember. Take the next tablet on the following day
and then carry on taking a tablet once a day as normal.
Do not take a double dose to make up for a forgotten tablet.
If you stop taking Xarelto
Don’t stop taking Xarelto without talking to your doctor first, because Xarelto prevents the
development of a serious condition.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Xarelto can cause side effects, although not everybody gets them.
Like other similar medicines (antithrombotic agents), Xarelto may cause bleedings which may
potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure
(shock). In some cases these bleedings may not be obvious.
Tell your doctor
, if you experience any of the following side effects:
- long or excessive bleeding
- exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling,
breathlessness, chest pain or angina pectoris.
Your doctor may decide to keep you under closer observation or change how you should be treated.
The frequency of possible side effects listed below is defined using the following convention:
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
not known (frequency cannot be estimated from the available data).
Common side effects
- bleeding following your operation
- feeling sick, fever, swelling in your limbs
- blood tests may show an increase in some liver enzymes
Uncommon side effects
- bleeding in your stomach or bowel, urogenital bleeding, nose bleed
- bleeding into tissue or a cavity of your body (haematoma, bruising)
- oozing of blood or fluid from surgical wound
- raised heartbeat
- low blood pressure
- decreased general strength and energy (weakness, tiredness), headache, dizziness
24
- reduction in red blood cells which can make your skin pale and cause weakness or breathlessness
- stomach ache, indigestion, constipation, diarrhoea, being sick
- dry mouth
- localised swelling
- pain in your limbs
- rash, itchy skin
- impaired function of your kidneys
- blood tests may show an increase in bilirubin, some pancreatic enzymes or in the number of platelets
Rare side effects
- impaired function of your liver
- allergic skin reactions, hives
- fainting, feeling unwell
Side effects where frequency is not known
- bleeding into a critical organ (e.g. your brain)
- adrenal bleeding
- bleeding from the whites of your eyes
- collection of blood (haematoma) following complication in a cardiac procedure where a catheter is
inserted to treat narrowed coronary arteries (pseudoaneurysm)
- coughing up blood
- increased pressure within muscles of your legs or arms after a bleeding, which leads to pain,
swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding)
- kidney failure after a severe bleeding
- yellowing of the skin and eye (jaundice)
- hypersensitivity
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
5.
HOW TO STORE XARELTO
Keep out of the reach and sight of children.
Do not use Xarelto after the expiry date which is stated on the carton and on each blister after EXP.
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Xarelto contains
-
The active substance is rivaroxaban. Each tablet contains 10 mg of rivaroxaban.
-
The other ingredients are:
Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate,
hypromellose, sodium laurilsulfate, magnesium stearate.
Film coat: macrogol 3350, hypromellose, titanium dioxide (E171), iron oxide red (E172).
25
What Xarelto looks like and contents of the pack
The film-coated tablets are light red, round and marked with the BAYER-cross on one side and "10"
and a triangle on the other side. They come in blisters in cartons of 5, 10 or 30 tablets or unit dose
blisters in cartons of 10 x 1 or 100 x 1 tablets.
Not all pack-sizes may be marketed.
Marketing Authorisation Holder
Bayer Schering Pharma AG
13342 Berlin
Germany
Manufacturer
Bayer Schering Pharma AG
51368 Leverkusen
Germany
26
For more information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België / Belgique / Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Luxembourg / Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
България
Байер България ЕООД
Тел: +359-(0)2-81 401 01
Magyarország
Bayer Hungária KFT
Tel: +36-1-487 4100
Česká republika
Bayer s.r.o.
Tel: +420-266 101 111
Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05
Danmark
Bayer A/S
Tlf: +45-45 235 000
Nederland
Bayer B.V., Bayer Schering Pharma
Tel: +31–(0)297-28 06 66
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Norge
Bayer AS
Tlf: +47-24 11 18 00
Eesti
Bayer OÜ
Tel: +372-655 85 65
Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 460
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30-210-618 75 00
Polska
Bayer Sp. z o.o.
Tel: +48-22-572 35 00
España
Bayer Hispania S.L.
Tel: +34-93-495 65 00
Portugal
Bayer Portugal S.A
Tel: +351-21-416 42 00
France
Bayer Santé
Tél: +33-(0)3-28 16 34 00
România
SC Bayer SRL
Tel: +40-(0)21-528 59 00
Ireland
Bayer Limited
Tel: +353-(0)1-2999 313
Slovenija
Bayer d. o. o.
Tel: +386-(0)1-58 14 400
Ísland
Icepharma hf.
Sími: +354-540 80 00
Slovenská republika
Bayer, spol. s r.o.
Tel: +421-(0)2-59 21 31 11
Italia
Bayer S.p.A.
Tel: +39-02-3978 1
Suomi/Finland
Bayer Oy, Bayer Schering Pharma
Puh/Tel: +358-(0)20-78521
Κύπρος
NOVAGEM Limited
Τηλ: +357-22-747 747
Sverige
Bayer AB
Tel: +46-(0)8-580 223 00
Latvija
SIA Bayer
Tel: +371-67 84 55 63
United Kingdom
Bayer plc
Tel: +44-(0)1635-563000
Lietuva
UAB Bayer
Tel: +370-5-233 68 68
This leaflet was last approved in
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
27
Source: European Medicines Agency
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