Rivaroxaban - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Anticoagulants

Included in the formulation

Xarelto®

pills inwards

Bayer Pharma AG Germany

Xarelto®

pills inwards

Bayer Pharma AG Germany

Xarelto®

pills inwards

Bayer AG Germany

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

B.01.A.F Direct inhibitors of factor Xa

B.01.A.F.01 Rivaroxaban

Pharmacodynamics:

Rivaroxaban is a highly selective direct inhibitor of factor Xa, which has high bioavailability when ingested.

Activation of factor X with the formation of factor Xa through the internal and external ways of coagulation plays a central role in the coagulation cascade. Factor Xa is a component of the emerging prothrombinase complex, the action of which leads to the transformation of prothrombin into thrombin. As a result, these reactions lead to the formation of a fibrin clot and the activation of thrombin by thrombin. One molecule of factor Xa catalyses the formation of more than 1000 molecules of thrombin, which is called the "thrombin explosion". The reaction rate of the factor Xa bound in the prothrombinase increases 300,000 times as compared with that of the free factor Xa, which provides a sharp jump in the level of thrombin. Selective factor Xa inhibitors can stop the "thrombin burst". In this way, rivaroxaban influences the results of some specific or general laboratory studies used to evaluate coagulation systems.In humans, a dose-dependent inhibition of factor Xa activity is observed.

Pharmacokinetics:

After oral administration rivaroxaban absorbed quickly and almost completely. C_max is achieved 2-4 hours after taking the pill. Bioavailability of rivaroxaban when taking 2.5 mg and 10 mg tablets is high (80-100%), regardless of food intake. Eating and eating does not affect AUC and C_max when taking the drug at a dose of 10 mg. Tablets riaroksabana in a dosage of 2.5 mg and 10 mg can be taken with or without food, and on an empty stomach.

The pharmacokinetics of rivaroxaban are characterized by moderate interindividual variability, the coefficient of variability Cv% ranges from 30% to 40%.

Rivaroxaban has a high degree of binding to blood plasma proteins - approximately 92-95%, mainly rivaroxaban binds to serum albumin. The drug has an average Vd of approximately 50 liters.

Rivaroxaban is metabolized by means of CYP3A4 and CYP2J2 isoenzymes, as well as by mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholino group and the hydrolysis of amide bonds.

According to the data received in vitro, rivaroxaban is a substrate for P-gp (P-glycoprotein) and Svrp (breast cancer resistance protein) proteins.

Unchanged rivaroxaban is the only active compound in the blood plasma, the main or active circulating metabolites in plasma are not detected. Rivaroxaban, a systemic clearance of about 10 l / h, can be attributed to drugs with low clearance.

When removing rivaroxaban from plasma, the final half-lifeis from 5 to 9 hours in young patients, and from 11 to 13 hours - in elderly patients.

Pharmacokinetics in special clinical cases

Age. In elderly patients over the age of 65 years, the concentration of rivaroxaban in plasma is higher than in young patients, the mean AUC is approximately 1.5 times higher than the corresponding values in young patients, mainly due to an apparent decrease in total and renal clearance.

Floor. In men and women, clinically significant differences in pharmacokinetics were not detected.

Body mass. Too small or large body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in plasma (the difference is less than 25%).

Childhood. Data on the pharmacokinetics in children are absent.

Interethnic differences. Clinically significant differences in pharmacokinetics and pharmacodynamics in patients of the Caucasian, Negroid, Asian race, and also of Latin American, Japanese or Chinese ethnicity were not observed.

Dysfunction of the liver. The effect of liver failure on the pharmacokinetics of rivaroxaban has been studied in patients distributed according to the Child-Pugh classification (according to standard procedures in clinical trials). Classification Child-Pugh allows you to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled to undergo anticoagulant therapy, a particularly important critical moment of liver dysfunction is a decrease in the synthesis of clotting factors in the liver. As. this indicator corresponds only to one of the five clinical / biochemical criteria that make up the Child-Pugh classification, the risk of bleeding is not clearly correlated with this classification. The treatment of such patients with anticoagulants should be addressed regardless of the Child-Pugh class.

Rivaroxaban is contraindicated in patients with liver diseases that occur with coagulopathy, which causes a clinically significant risk of bleeding.

In patients with cirrhosis of the liver with mild liver failure (class A according to Child-Pugh classification), the pharmacokinetics of rivaroxaban only slightly differed from the corresponding parameters in the control group of healthy volunteers (on average, the rivaroxaban AUC increased 1.2-fold). There were no significant differences in pharmacodynamic properties between the groups.

In patients with cirrhosis of the liver and moderate hepatic insufficiency (class B according to the Child-Pugh classification), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared to healthy volunteers due to a significantly reduced clearance of the drug indicative of a serious liver disease. The inhibition of factor Xa activity was more pronounced (2.6 times) than in healthy volunteers. Prothrombin time was also 2.1 times higher than in healthy volunteers. By measuring the prothrombin time, an external coagulation pathway including clotting factors VII, X, V, II and I, which are synthesized in the liver, is evaluated.Patients with moderate hepatic insufficiency are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

Data on the use of the drug in patients with hepatic insufficiency of Class C according to the Child-Pugh classification are absent. Therefore, in patients with cirrhosis of the liver and a violation of liver function B and C according to the Child-Pugh classification, the use of rivaroxaban is contraindicated.

Impaired renal function. In patients with renal insufficiency, an increase in the exposure of rivaroxaban was observed, inversely proportional to the degree of decrease in renal function, which was assessed by QC.

In patients with renal insufficiency of mild (KK 50-80 ml / min), medium (KK 30-49 ml / min) or severe (Q 15-29 ml / min) severity, 1.4-, 1.5- and 1.6-fold increase was observed concentrations of rivaroxaban in blood plasma (AUC), respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced.

Patients with renal failure are mild,medium and severe, the overall inhibition of factor Xa activity increased 1.5, 1.9 and 2 times compared with healthy volunteers; prothrombin time due to the action of factor Xa also increased in 1.3, 2.2 and 2.4 times, respectively.

Data on the use of rivaroxaban in patients with QC 15-29 ml / min are limited, and therefore care should be taken when using the drug in this category of patients. Data on the use of rivaroxaban in patients with CC <15 ml / min are absent, and therefore it is not recommended to use the drug in this category of patients.

Indications:

Prevention of death due to cardiovascular causes and myocardial infarction in patients after acute coronary syndrome, which occurred with the increase of cardiospecific biomarkers, in combination therapy with acetylsalicylic acid or with acetylsalicylic acid and thienopyridines (clopidogrel or ticlopidine).

ICD-10

IX.I20-I25.I20.0 Unstable angina

IX.I20-I25.I21 Acute myocardial infarction

IX.I26-I28.I26 Pulmonary embolism

IX.I70-I79.I74 Embolism and thrombosis of the arteries

IX.I80-I89.I82 Embolism and thrombosis of other veins

Contraindications:

- hypersensitivity to the components of the drug;

- clinically significant active bleeding (eg, intracranial hemorrhage, gastrointestinal bleeding);

- liver diseases that occur with coagulopathy, which causes a clinically significant risk of bleeding, including liver cirrhosis and violations of class B and C liver function according to the Child-Pugh classification;

- Pregnancy;

- the period of lactation (breastfeeding);

- children and adolescents under 18 years of age (efficacy and safety for patients of this age group not established);

- clinical data on the use of rivaroxaban in patients with severe renal insufficiency (QC <15 ml / min) are absent, therefore the use of rivaroxaban in this category of patients is contraindicated;

- Treatment of ACS with the help of antiaggregants in patients who have suffered a stroke or transient ischemic attack;

- concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (incl. warfarin, apixaban, dabigatran), except for cases of transition from or to rivaroxaban or when unfractionated heparin is used at the doses necessary to ensure the functioning of the central venous or arterial catheter;

- Congenital lactase deficiency, lactose intolerance, malabsorption of glucose-galactose (due to the presence of lactose in the formulation).

Carefully:

- in the treatment of patients with an increased risk of bleeding (including with a congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, peptic ulcer of the stomach and duodenal ulcer in the acute phase, a recent acute gastric and duodenal ulcer, vascular retinopathy, recently suffered intracranial or intracerebral hemorrhage, with pathology of vessels of the spinal cord or brain, after a recent surgery on the head, spinal cord n and eyes, bronchiectasis or pulmonary hemorrhage in history);

- in the treatment of patients with moderate renal insufficiency (KK 30-49 ml / min), receiving simultaneously drugs that increase the concentration of rivaroxaban in blood plasma;

- Care should be taken when treating patients with severe renal insufficiency (QC 15-29 ml / min), as the concentration of rivaroxaban in blood plasma in such patients can significantly increase (on average 1.6 times) and as a result they have an increased risk of bleeding;

- in patients receiving medications that affect hemostasis (eg, NSAIDs, antiaggregants or other antithrombotic agents);

- rivaroxaban is not recommended for use in patients receiving systemic treatment with antifungal azole agents (eg, ketoconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein. As a consequence, these drugs can increase the concentration of rivaroxaban in plasma to a clinically significant level (an average of 2.6 times), which increases the risk of bleeding. Fluconazole (an antifungal agent of the azole group), a moderate inhibitor of CYP3A4, has a less pronounced effect on the excretion of rivaroxaban and can be used with it simultaneously;

- patients with severe renal insufficiency or an increased risk of bleeding and patients receiving concomitant systemic treatment with antifungal azole agents or HIV protease inhibitors should be closely monitored after the initiation of treatment to detect bleeding complications in a timely manner.

Pregnancy and lactation:

Due to the possible risk of bleeding and the ability to penetrate the placental barrier rivaroxaban contraindicated in pregnancy. Rivaroxaban excreted in breast milk, can be used only after the termination of breastfeeding.

Recommendations FDA category C.

Dosing and Administration:

Take inside 2.5 mg (1 tab.) 2 times / day, regardless of food intake.

Side effects:

From the hemopoietic system and lymphatic system: anemia (including relevant laboratory indicators), thrombocythemia, including increased platelet counts).

From the cardiovascular system: marked decrease in blood pressure, hematoma, tachycardia.

From the side of the organ of vision: hemorrhage in the eye (including hemorrhage in the conjunctiva).

From the digestive system: gingival hemorrhage, gastrointestinal bleeding (including rectal bleeding), abdominal pain, indigestion, nausea, constipation, diarrhea, vomiting, dry mouth.

General disorders: fever, peripheral edema, decrease in overall muscle strength and tone (including weakness and asthenia), worsening of general well-being (including malaise), local edema.

From the liver and bile ducts: abnormal liver function, jaundice.

From the immune system: allergic reaction, allergic dermatitis.

Injuries, poisonings and complications after manipulation: bleeding after medical manipulation (including postoperative anemia and bleeding from a postoperative wound), bruising, secretion of a secret from the wound, vascular pseudoaneurysm.

From the results of laboratory and instrumental research: an increase in the activity of hepatic transaminases, an increase in the concentration of bilirubin, an increase in the activity of the APD, an increase in the activity of LDHA, an increase in lipase A activity, an increase in the activity of amylase A, an increase in the activity of GGT, an increase in the concentration of conjugated bilirubinALT activity or without it).

From the musculoskeletal system, connective tissue and bones: pain in the limbs, hemarthrosis, hemorrhage in the muscle.

From the nervous system: dizziness, headache, intracerebral and intracranial hemorrhages, fainting.

From the urinary and reproductive system: bleeding from the urogenital tract (including hematuria and menorrhagia), kidney damage (including increased blood creatinine, increased urea blood).

C of the respiratory tract: epistaxis, hemoptysis.

From the side of the skin and subcutaneous fat: skin itching (including infrequent cases of generalized itching), rash, ecchymosis, urticaria.

Overdose:

Rare cases of overdose with rivaroxaban up to 600 mg without the development of bleeding or other undesirable reactions have been reported. Due to limited absorption, formation of a concentration plateau is expected without further increase in the average concentration of rivaroxaban in plasma when administered at excessive doses of 50 mg or higher.

Treatment: the specific antivote of rivaroxaban is unknown.In the case of an overdose of rivaroxaban to reduce the absorption of rivaroxaban, Activated carbon. Due to the significant binding of rivaroxaban to plasma proteins, it is expected that rivaroxaban will not be excreted by hemodialysis.

If complications occur in the form of bleeding, the next dose of the drug should be postponed or even canceled with the drug. Half-liferivaroxaban leaves approximately 5-13 hours. Treatment should be selected individually, depending on the severity and localization of bleeding.

If necessary, appropriate symptomatic treatment, such as mechanical compression (for example, with severe nasal bleeding), surgical haemostasis with an assessment of its effectiveness (bleeding control), infusion therapy and hemodynamic support, the use of blood products (erythrocyte mass or fresh frozen plasma, depending on from whether anemia or coagulopathy occurred) or platelets.

If the measures listed above do not lead to the elimination of bleeding, it is possible to use specific procoagulant drugs of the reverse action,such as a prothrombin complex concentrate, an activated prothrombin complex concentrate, or a recombinant factor VIIa. However, at present experience in the use of these drugs in patients receiving rivaroxaban, is very limited.

It is assumed that Protamine sulfate and vitamin K will not affect the anticoagulant activity of rivaroxaban.

Experience in the use of antifibrinolytic drugs (tranexamic acid, aminocaproic acid) in patients receiving rivaroxaban, absent. Scientific justification of the expediency or experience of using systemic haemostatic drugs desmopressin and aprotinin in patients receiving rivaroxaban, absent.

Interaction:

Simultaneous use of the drug rivaroxaban and azole antifungal drug ketoconazole (400 mg 1 time / day), a powerful inhibitor of CYP3A4 and P-glycoprotein, resulted in an increase in the average equilibrium AUC of rivaroxaban by 2.6 times and an increase in the mean C_max rivaroxaban 1.7 times, which was accompanied by a significant increase in the pharmacodynamic effects of rivaroxaban.

Simultaneous use of rivaroxaban with an HIV protease inhibitor ritonavir (600 mg 2 times / day), which is a strong inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the mean equilibrium AUC of rivaroxaban by a factor of 2.5 and an increase in the mean Cmax of rivaroxaban by 1.6 times, which was accompanied by a significant increase in the pharmacodynamic effects of the drug.

Therefore, the drug rivaroxaban It is not recommended to use in patients receiving Systemic treatment with antifungal azole agents or HIV protease inhibitors.

Other active substances that inhibit at least one of the ways of eliminating rivaroxaban, mediated by either CYP3A4 or P-gp, are probably less likely to increase rivaroxaban concentrations in the blood plasma.

Clarithromycin (500 mg 2 times / day), a potent inhibitor of the isoenzyme CYP3A4 and a moderate inhibitor of the P-glycoprotein, caused an increase in AUC values by 1.5 times and Cmax of rivaroxaban by 1.4 times. This increase is of the order of normal variability of AUC and Cmax and is considered clinically insignificant.

Erythromycin (500 mg 3 times / day), a moderate inhibitor of the isoenzyme CYP3A4 and P-glycoprotein, caused an increase in the values of AUC and Cmax of rivaroxaban by 1.3 times.This increase is of the order of normal variability of AUC and Cmax and is considered clinically insignificant.

Fluconazole (400 mg 1 time / day), a moderate inhibitor of the isoenzyme CYP3A4, caused an increase in the mean AUC of rivaroxaban by 1.4 times and an increase in the mean Cmax by 1.3. This increase is of the order of normal variability of AUC and Cmax and is considered clinically insignificant.

Simultaneous application rivaroxaban and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a decrease in the mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects. Simultaneous use of the drug rivaroxaban with other strong inductors CYP3A4 (for example, phenytoin, carbamazepine, phenobarbital or preparations of St. John's wort perfumed) can also lead to a decrease in the concentration of rivaroxaban in plasma.

Powerful inducers of CYP3A4 should be used with caution in patients after ACS receiving the drug rivaroxaban on 2.5 mg 2 times / day.

Pharmacodynamic interaction

After simultaneous application sodium enoxaparin (40 mg once) and the drug rivaroxaban (10 mg once), the summation effect of inhibition of Xa anti-factor activity was observed without any additional influence on the coagulation factors (prothrombin time, APTT). Enoxaparin does not affect the pharmacokinetics of rivaroxaban.

No pharmacokinetic interaction was observed clopidogrel (a saturating dose of 300 mg followed by a maintenance dose of 75 mg) with rivaroxaban (15 mg dose), but there was a significant increase in bleeding time in the subgroup of patients that did not correlate with the degree of platelet aggregation, the number of P-selectin or GPIIb receptors / IIIa.

After simultaneous application of the drug rivaroxaban (15 mg) and naproxen (500 mg) there was no clinically significant prolongation of bleeding time. Nevertheless, in some patients a more pronounced pharmacodynamic response is possible.

Caution should be exercised when rivaroxaban is used together with dronedarone Due to limited clinical data on joint use.

In view of the increased risk of bleeding, caution should be exercised when combined with any other anticoagulants.

Use with caution rivaroxaban jointly with NSAIDs (including acetylsalicylic acid) and antiplatelet agents, since the use of these drugs usually increases the risk of bleeding.

Transfer of patients with warfarin (MHO from 2 to 3) at rivaroxaban (20 mg) or from the preparation rivaroxaban (20 mg) per warfarin (MHO from 2 to 3) increased prothrombin time / INR more than with simple summation of effects (individual INR values can reach 12), whereas the effects of APTT change, inhibition of factor Xa activity and endogenous thrombin potential (EPT) were additive.

If necessary, study the pharmacodynamic effects of the drug rivaroxaban during the transition period as necessary tests, which are not affected warfarin, anti-factor Xa activity, prothrombinase-induced coagulation time and Hep Test® can be used. Starting from the 4th day after warfarin cancellation, all analyzes (including prothrombin time, APTT, inhibition of factor Xa activity and on EPT (endogenous thrombin potential)) reflect only the effect of the drug.

To assess the pharmacodynamic effects of warfarin during the transition period, the MHO measured at the time of achievement of C_max rivaroxaban (24 hours after taking the dose of rivaroxaban), because at this point in time rivaroxaban practically has no effect on this indicator.

Special instructions:

The use of rivaroxaban is not recommended in patients receiving concomitant Systemic treatment with azole antifungal agents (eg, ketoconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are potent inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the concentration of rivaroxaban in blood plasma to clinically significant values (an average of 2.6 times), which can lead to an increased risk of bleeding.

However, the azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used with it simultaneously.

Effects of the drug rivaroxaban the duration of the QTc interval was not revealed.

Renal insufficiency

Caution should be applied rivaroxaban in patients with moderate renal dysfunction (CK 30-49 ml / min) receiving concomitant drugs that can lead to an increase in rivaroxaban concentration in plasma.

In patients with severe renal dysfunction (CK <30 ml / min), the concentration of rivaroxaban in plasma can be significantly increased (1.6 times on average), which can lead to an increased risk of bleeding. Therefore, due to the presence of this underlying disease, such patients have an increased risk of developing both bleeding and thrombosis. Due to the limited amount of clinical data, the drug should be used with caution in patients with QC 15-29 ml / min.

Clinical data for patients with severe renal impairment (QC <15 mL / min) are not available. Therefore, in this category of patients the use of rivaroxaban is contraindicated.

Patients with severe renal dysfunction or an increased risk of bleeding, as well as patients receiving concomitant systemic treatment with azole antifungal drugs or HIV protease inhibitors, need careful monitoring to detect signs of bleeding after initiation of treatment.Observation can be carried out by conducting regular physical examination of patients, careful monitoring of the state of drainage of the postoperative wound, and also by periodic determination of hemoglobin.

Patients with a history of stroke or transient ischemic attack (TIA)

Taking rivaroxaban 2.5 mg twice daily is contraindicated in patients with ACS who have a stroke or TIA in the anamnesis. A study of only a few patients with ACS with a history of stroke or TIA was conducted, so the data on the effectiveness of the drug in such patients is extremely limited.

Risk of bleeding

Rivaroxaban, like other antithrombotic agents, should be used with caution in diseases and conditions associated with an increased risk of bleeding, such as:

- Congenital or acquired coagulation disorders;

uncontrolled severe arterial hypertension;

- active gastrointestinal pathology with ulceration;

- recently transferred acute gastric ulcer;

- Vascular retinopathy;

- recent intracranial or intracerebral haemorrhage;

intraspinal or intracerebral vascular anomalies;

- A recent surgery on the brain, spinal cord or ophthalmic operation;

- bronchiectasis or an episode of pulmonary hemorrhage in an anamnesis.

Care must be taken if the patient is simultaneously receives drugs affecting hemostasis, such as NSAIDs, platelet aggregation inhibitors or other antithrombotic drugs.

Patients after ACS receiving rivaroxaban in combination with acetylsalicylic acid or rivaroxaban in combination with acetylsalicylic acid and clopidogrel / ticlopidine, as long concurrent treatment NSAIDs can receive only if the positive effects of treatment available to justify the risk of bleeding.

Patients with a risk of ulcerative lesions of the gastrointestinal tract appropriate preventive treatment can be used.

For any unexplained decrease in hemoglobin or blood pressure, a source of bleeding should be established.

The efficacy and safety of rivaroxaban have been studied in combination with antiplatelet agents with acetylsalicylic acid and clopidogrel / ticlopidine.The use of combination therapy with other antiplatelet agents (e.g., prasugrel or ticagrelor) has not been studied for this reason, it is not recommended for use.

Spinal anesthesia

When the epidural / spinal anesthesia or spinal puncture in patients receiving platelet aggregation inhibitors in the prevention of thromboembolic complications, the risk of developing an epidural or spinal hematoma, which can result in permanent paralysis.

The risk of these events is further increased by the use of a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis. Traumatic performance of an epidural or spinal puncture or repeated puncture can also increase the risk. Patients should be monitored for signs or symptoms of neurological disorders (such as numbness or weakness of the legs, bowel dysfunction or bladder). If neurological disorders are detected, urgent diagnosis and treatment is necessary.The physician should compare the potential benefit and the relative risk before performing spinal surgery to patients receiving anticoagulants, or who are scheduled to administer anticoagulants for the prevention of thrombosis. The epidural catheter is removed no earlier than 18 hours after the administration of the last dose of rivaroxaban. Rivaroxaban should be prescribed no earlier than 6 hours after the extraction of the epidural catheter. In the case of a traumatic puncture, the appointment of rivaroxaban should be postponed for 24 hours.

Surgical operations and interventions

If an invasive procedure or surgical intervention is necessary, rivaroxaban 2.5 mg should be discontinued at least 24 hours before the intervention, if possible, and on the basis of a clinical evaluation by the physician.

If a patient who undergoes a routine surgery does not need an antiaggregant effect, the use of platelet aggregation inhibitors should be discontinued, as indicated in the instructions for use of the drug provided by the manufacturer.

If the procedure can not be postponed, a comparative assessment of the increased risk of bleeding should be made and the need for urgent intervention to be resolved.

The administration of rivaroxaban should be resumed after an invasive procedure or surgical intervention as soon as possible, provided that the clinical indices permit and adequate hemostasis is achieved.

Against the background of taking the drug, there was the appearance of fainting and dizziness, which may influence the ability to drive vehicles or other mechanisms. Patients who develop such undesirable reactions should not drive vehicles or other mechanisms.

Instructions

Rivaroxaban (Rivaroxaban)