Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Bayer AG, 51368 Leverkusen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active clinically significant bleeding.
Lesion or condition, if considered to be a significant risk for major bleeding. This 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 varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).
Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA) (see section 4.4).
Concomitant treatment of CAD/PAD with ASA in patients with previous haemorrhagic or lacunar stroke, or any stroke within a month (see section 4.4).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).
Pregnancy and breast-feeding (see section 4.6).
In ACS patients, efficacy and safety of Xarelto 2.5 mg have been investigated in combination with the antiplatelet agents ASA alone or ASA plus clopidogrel/ticlopidine. Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended. In patients at high risk of ischaemic events with CAD/PAD, efficacy and safety of Xarelto 2.5 mg have only been investigated in combination with ASA.
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use of Xarelto in combination with dual antiplatelet therapy in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. In addition these patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2).
In patients with severe renal impairment (creatinine clearance <30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use is not recommended in patients with creatinine clearance <15 ml/min (see sections 4.2 and 5.2).
In patients with moderate renal impairment (creatinine clearance 30-49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be used with caution (see section 4.5).
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 (2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5).
Patients on treatment with Xarelto and ASA or with Xarelto and ASA plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk.
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as:
It should be used with caution in ACS and CAD/PAD patients:
Safety and efficacy of Xarelto have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for these patients.
Xarelto 2.5 mg is contraindicated for the treatment of ACS in patients with a prior stroke or TIA (see section 4.3). Few ACS patients with a prior stroke or TIA have been studied but the limited efficacy data available indicate that these patients do not benefit from treatment.
CAD/PAD patients with previous haemorrhagic or lacunar stroke, or an ischaemic, non-lacunar stroke with in the previous month were not studied (see section 4.3).
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. There is no clinical experience with the use of Xarelto 2.5 mg with ASA alone or with ASA plus clopidogrel or ticlopidine in these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2). However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer’s prescribing information.
If an invasive procedure or surgical intervention is required, Xarelto 2.5 mg should be stopped at least 12 hours before the intervention, if possible and based on the clinical judgement of the physician. If a patient is to undergo elective surgery and anti-platelet effect is not desired, platelet aggregation inhibitors should be discontinued as directed by the manufacturer’s prescribing information. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician (see section 5.2).
Increasing age may increase haemorrhagic risk (see sections 5.1 and 5.2).
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) 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 Cmax, 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).
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 twice a day), for instance, considered as a 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 Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.
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 sections 4.3 and 4.4).
No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) 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 with rivaroxaban (15 mg) 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).
As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
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 (Hypericum perforatum)) may also 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.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.
No clinically relevant interaction with food was observed (see section 4.2).
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see section 5.1).
Safety and efficacy of Xarelto have not been established 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.
Safety and efficacy of Xarelto have not been established in breast-feeding women. 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.
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).
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.
The safety of rivaroxaban has been evaluated in thirteen phase III studies including 53,103 patients exposed to rivaroxaban (see Table 1).
Table 1. Number of patients studied, total daily dose and maximum treatment duration in phase III studies:
| Indication | Number of patients* | Total daily dose | Maximum treatment duration |
|---|---|---|---|
| Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery | 6,097 | 10 mg | 39 days |
| Prevention of VTE in medically ill patients | 3,997 | 10 mg | 39 days |
| Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE) and prevention of recurrence | 6,790 | Day 1-21: 30 mg. Day 22 and onwards: 20 mg. After at least 6 months: 10 mg or 20 mg | 21 months |
| Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation | 7,750 | 20 mg | 41 months |
| Prevention of atherothrombotic events in patients after an ACS | 10,225 | 5 mg or 10 mg respectively, co-administered with either ASA or ASA plus clopidogrel or ticlopidine | 31 months |
| Prevention of atherothrombotic events in patients with CAD/PAD | 18,244 | 5 mg co-administered with ASA or 10 mg alone | 47 months |
* Patients exposed to at least one dose of rivaroxaban.
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly reported bleedings were epistaxis (4.5%) and gastrointestinal tract haemorrhage (3.8%).
Table 2. Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed phase III studies:
| Indication | Any bleeding | Anaemia |
|---|---|---|
| Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery | 6.8% of patients | 5.9% of patients |
| Prevention of venous thromboembolism in medically ill patients | 12.6% of patients | 2.1% of patients |
| Treatment of DVT, PE and prevention of recurrence | 23% of patients | 1.6% of patients |
| Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation | 28 per 100 patient years | 2.5 per 100 patient years |
| Prevention of atherothrombotic events in patients after an ACS | 22 per 100 patient years | 1.4 per 100 patient years |
| Prevention of atherothrombotic events in patients with CAD/PAD | 6.7 per 100 patient years | 0.15 per 100 patient years** |
* For all rivaroxaban studies all bleeding events are collected, reported and adjudicated.
** In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied
The frequencies of adverse reactions reported with Xarelto are summarised in Table 3 below by system organ class (in MedDRA) and by frequency.
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 3. All adverse reactions reported in patients in phase III clinical trials or through post-marketing use*:
Common: Anaemia (incl. respective laboratory parameters)
Uncommon: Thrombocytosis (incl. platelet count increased)A, thrombocytopenia
Uncommon: Allergic reaction, dermatitis allergic, angioedema and allergic oedema
Very rare: Anaphylactic reactions including anaphylactic shock
Common: Dizziness, headache
Uncommon: Cerebral and intracranial haemorrhage, syncope
Common: Eye haemorrhage (incl. conjunctival haemorrhage)
Uncommon: Tachycardia
Common: Hypotension, haematoma
Common: Epistaxis, haemoptysis
Common: Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA
Uncommon: Dry mouth
Common: Increase in transaminases
Uncommon: Hepatic impairment, increased bilirubin, increased blood alkaline phosphataseA, increased GGTA
Rare: Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury)
Common: Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage
Uncommon: Urticaria
Very rare: Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, DRESS syndrome
Common: Pain in extremityA
Uncommon: Haemarthrosis
Rare: Muscle haemorrhage
Not known: Compartment syndrome secondary to a bleeding
Common: Urogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased)A
Not known: Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion
Common: FeverA, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)
Uncommon: Feeling unwell (incl. malaise)
Rare: Localised oedemaA
Uncommon: Increased LDHA, increased lipaseA, increased amylaseA
Common: Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretionA
Rare: Vascular pseudoaneurysmC
A observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery
B observed in treatment of DVT, PE and prevention of recurrence as very common in women <55 years
C observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention)
* A pre-specified selective approach to adverse event collection was applied. As incidence of adverse reactions did not increase and no new adverse reaction was identified, COMPASS study data were not included for frequency calculation in this table.
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 post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 “Management of bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.
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 affecting haemostasis (see section 4.4 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 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 have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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