Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
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. 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.

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 (see section 4.9).

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).

Renal impairment
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).

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 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 sections 4.5 and 5.1).
Patients on treatment with Xarelto and ASA or with Xarelto and ASA plus clopidogrel should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk.

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
•      other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)
•      vascular retinopathy
•      bronchiectasis or history of pulmonary bleeding 
It should be used with caution in ACS and CAD/PAD patients:
• ≥ 75 years of age if co-administered with ASA alone or with ASA plus clopidogrel. The benefit- risk of the treatment should be individually assessed on a regular basis.
• with lower body weight (< 60 kg) if co-administered with ASA alone or with ASA plus clopidogrel.

•   CAD patients with severe symptomatic heart failure. Study data indicate that such patients may benefit less from treatment with rivaroxaban (see section 5.1).

Patients with cancer
Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban therapy.
In patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated (see section 4.3).

Patients with prosthetic valves
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). 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.

Patients with antiphospholipid syndrome
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.


Patients with prior stroke and/or TIA
Patients with ACS
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.

Patients with CAD/PAD
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).

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 [See boxed warning].
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 in these situations. Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer’s prescribing information.

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.
Dosing recommendations before and after invasive procedures and surgical intervention 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).

Elderly population
Increasing age may increase haemorrhagic risk (see sections 5.1 and 5.2).

Dermatological reactions
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.

Information about excipients
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially “sodium-free”.


Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including Xarelto, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Xarelto to warfarin in clinical trials in atrial fibrillation patients. If Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [for conversion instructions see Dosage and Administration (4.2)]

Effects on Driving

4.7   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 section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.