Xarelto 15 mg film-coated tablets

Each film-coated tablet contains 15 mg rivaroxaban.

Excipient with known effect:

Each film-coated tablet contains 24.13 mg lactose (as monohydrate), see section 4.4.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the BAYER-cross on one side and “15” and a triangle on the other side.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients).

Posology

Prevention of stroke and systemic embolism

The recommended dose is 20 mg once daily, which is also the recommended maximum dose.

Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding (see section 4.4).

If a dose is missed the patient should take Xarelto immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE

The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE, as indicated in the table below.

The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.

If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

If a dose is missed during the once daily treatment phase (day 22 and onwards), the patient should take Xarelto immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

Converting from Vitamin K Antagonists (VKA) to Xarelto

For patients treated for prevention of stroke and systemic embolism, VKA treatment should be stopped and Xarelto therapy should be initiated when the International Normalized Ratio (INR) is ≤ 3.0.

For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 2.5.

When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should not be used (see section 4.5).

Converting from Xarelto to Vitamin K antagonists (VKA)

There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.

In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).

Converting from parenteral anticoagulants to Xarelto

For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).

Converting from Xarelto to parenteral anticoagulants

Give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.

Special populations

Renal impairment

Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. 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).

In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15 - 29 ml/min) renal impairment the following dosage recommendations apply:

- For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2).

- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients should be treated with 15 mg twice daily for the first 3 weeks.

Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) (see section 5.2).

Hepatic impairment

Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).

Elderly population

No dose adjustment (see section 5.2).

Body weight

No dose adjustment (see section 5.2).

Gender

No dose adjustment (see section 5.2).

Paediatric population

The safety and efficacy of Xarelto in children aged 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.

Patients undergoing cardioversion

Xarelto can be initiated or continued in patients who may require cardioversion.

For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

Method of administration

For oral use.

The tablets are to be taken with food (see section 5.2).

For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.

The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).

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).

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).

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, genito urinary) 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 below, 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 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).

Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (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 and platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5).

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.

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.

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.

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.

There is no clinical experience with the use of 15 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.

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 section 5.2). 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.

Dosing recommendations before and after invasive procedures and surgical intervention

If an invasive procedure or surgical intervention is required, Xarelto 15 mg 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 section 5.2).

Elderly population

Increasing age may increase haemorrhagic risk (see section 5.2).

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.

CYP3A4 and P-gp inhibitors

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 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).

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 C_max. This increase is not considered clinically relevant. (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 C_max. This increase is not considered clinically relevant.

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 C_max. This increase is not considered clinically relevant. (For patients with renal impairment: see section 4.4).

Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.

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 sections 4.3 and 4.4).

NSAIDs/platelet aggregation inhibitors

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).

Warfarin

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 C_trough 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.

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 (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.

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), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.

Laboratory parameters

Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see section 5.1).

Pregnancy

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.

Breast feeding

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.

Fertility

No specific studies with rivaroxaban in humans have been conducted to eva luate 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.