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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 (2.6-fold on average) which may lead to an increased bleeding risk (see Interactions).
Care should be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see Interactions).
Xarelto 10 mg: The Azole anti-mycotic fluconazole, a moderate CYP3A4 inhibitor, has however, less effect on rivaroxaban exposure and can be co-administered (see Interactions).
Any unexplained fall in hemoglobin or blood pressure should lead to a search for a bleeding site.
Dosing recommendations before and after invasive procedures and surgical intervention: If an invasive procedure or surgical intervention is required, Xarelto should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement 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 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 Pharmacology: Pharmacokinetics under Actions).
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.
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see Pharmacology: Pharmacokinetics under Actions). Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered.
If traumatic puncture occurs, the administration of rivaroxaban is to be delayed for 24 hours.
Xarelto 15 and 20 mg: There is no clinical experience with the use of 15 mg and 20 mg rivaroxaban 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. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
Other haemorrhagic risk factors: As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as congenital or acquired bleeding disorders, uncontrolled severe arterial hypertension, vascular retinopathy, and bronchiectasis or history of pulmonary bleeding.
Xarelto 10 mg: Active ulcerative gastrointestinal disease, recent gastrointestinal ulcerations and intracranial or intracerebral hemorrhage, intraspinal or intracerebral vascular abnormalities, recent brain, spinal or ophthalmological surgery.
Xarelto 15 and 20 mg: Other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease).
Xarelto 15 and 20 mg: Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.
Haemorrhagic risk: 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, genitourinary) 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, as judged to be appropriate.
Several sub-groups of patients, as detailed as follows, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see Adverse Reactions).
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 Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Patients with prosthetic valves: Safety and efficacy of Xarelto have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto 20 mg (15 mg in patients with moderate or severe renal impairment) provides adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for these patients.
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement: Clinical data are available from an interventional study with the primary objective to assess safety in patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions). No data are available for such patients with a history of stroke/TIA.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Xarelto have not been established in these clinical situations.
Dermatological reactions: Serious skin reactions, including Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see Adverse Reactions). 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.
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.
Effects on ability to drive and use machines: 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 Adverse Reactions). Patients experiencing these adverse reactions should not drive or use machines.
Renal Impairment: Xarelto 10 mg: Xarelto is to be used with caution in patients with moderate renal impairment (CrCl <50-30 mL/min) receiving co-medications leading to increased rivaroxaban plasma concentrations (see Interactions).
In patients with severe renal impairment (CrCl <30 mL/min), rivaroxaban plasma levels may be significantly elevated (1.6-fold on average) which may lead to an increased bleeding risk. Due to the underlying disease these patients are at an increased risk of both bleeding and thrombosis.
Due to limited clinical data Xarelto should be used with caution in patients with CrCl <30-15 mL/min (see Pharmacology: Pharmacokinetics under Actions)
No clinical data are available for patients with severe renal impairment (CrCl <15 mL/min). Therefore, use of Xarelto is not recommended in these patients. (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration.)
Patients with severe renal impairment or increased bleeding risk and patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors are to be carefully monitored for signs of bleeding complications after initiation of treatment (see Interaction).
This may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of hemoglobin.
Xarelto 15 and 20 mg: 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 Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see Interactions).
Use in the Elderly: Increasing age may increase haemorrhagic risk (see Pharmacology: Pharmacokinetics under Actions).
