Xarelto pills 10 mg 30 pcs
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Active ingredients
Rivaroxaban
Release form
Pills
Composition
Active ingredient: Rivaroxaban (Rivaroxaban) Active ingredient concentration (mg): 10
Pharmacological effect
Mechanism of actionRivaroxaban is a highly selective direct inhibitor of factor Xa, which has high bioavailability when taken orally. Activation of factor X to form factor Xa through the internal and external coagulation pathway plays a central role in the coagulation cascade. Pharmacodynamic effectsDose-dependent inhibition of factor Xa was observed in humans. Rivaroxaban has a dose-dependent effect on prothrombin time and closely correlates with plasma concentrations (r = 0.98) if the Neoplastin kit is used for analysis. When using other reagents, the results will differ. The prothrombin time should be measured in seconds, because the MHO is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants. In patients undergoing large orthopedic operations, 5/95 percentile for prothrombin time (Neoplastin) 2-4 hours after taking the pill (that is, at the maximum effect) varies from 13 to 25 sec. Also rivaroxaban increases the APTT dose-dependently and the result of HepTest; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. It is not necessary to monitor blood clotting parameters during the treatment period with rivaroxaban. However, if there is a clinical rationale for this (for example, in case of overdose of the drug or, if necessary, emergency surgical intervention), rivaroxaban concentration can be measured using a calibrated quantitative anti-factor Xa test (for example, STA-Liquid Anti-Xa, manufacturer Diagnostics , France or similar). In healthy men and women over 50, lengthening of the QT interval was not observed under the influence of rivaroxaban.
Pharmacokinetics
Absorption The absolute bioavailability of rivaroxaban after administration in a dose of 10 mg is high (80-100%). Rivaroxaban is rapidly absorbed; Cmax is achieved in 2-4 hours after taking the pill. When taking rivaroxaban at a dose of 10 mg with food, no changes in AUC and Cmax are noted. Rivaroxaban in a dose of 10 mg can be administered with food or regardless of the meal. The pharmacokinetics of rivaroxaban are characterized by moderate individual variability; individual variability (variation coefficient) ranges from 30% to 40%,except for the day of surgery and the next day, when the variability in the exposure is high (70%). Rivaroxaban absorption depends on the site of release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax, respectively, compared to taking the whole tablet, was observed when rivaroxaban granulate was released in the distal small intestine or ascending colon. The introduction of rivaroxaban in the gastrointestinal tract distal to the stomach should be avoided, since this may entail a decrease in the absorption and, accordingly, the drug exposure. The study evaluated the bioavailability (AUC and Cmax) of 20 mg of rivaroxaban taken orally as a crushed tablet mixed with applesauce or suspended in water , and also entered through a gastric tube with the subsequent reception of liquid food, in comparison with reception of the whole tablet. The results demonstrated a predictable dose-dependent pharmacokinetic profile of rivaroxaban, while the bioavailability at the above indicated corresponded to that when receiving rivaroxaban in lower doses. Distribution Vd is moderate, Vss is approximately 50 liters. Metabolism When ingested, approximately 2/3 of the prescribed dose of rivaroxaban is metabolized and subsequently excreted in equal parts with urine and feces. The remaining 1/3 dose is eliminated by direct renal excretion unchanged, mainly due to active renal secretion. Rivaroxaban is metabolized by isoenzymes CYP3A4, CYP2J2, and also by mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholine group and the hydrolysis of amide bonds. According to data obtained in vitro, rivaroxaban is a substrate for the carrier proteins P-gp (P-glycoprotein) and Vssr (breast cancer resistance protein). The unchanged rivaroxaban is the only active compound in human plasma, no significant or active circulating metabolites are found in plasma. Excretion When removing rivaroxaban from plasma, the final T1 / 2 is 5 to 9 hours in young patients. Rivarox ban,systemic clearance of which is approximately 10 l / h can be attributed to medicinal substances with low clearance. Pharmacokinetics in special clinical situations In elderly patients over 65 years of age, plasma rivaroxaban concentration is higher than in younger patients, the average AUC is about 1.5 times exceeds the corresponding values in young patients, mainly due to the apparent decrease in total and renal clearance. When removing rivaroxaban from plasma, the final T1 / 2 in elderly patients ranges from 11 to 13 hours. In men and women, clinically significant differences in pharmacokinetics were not found. Too small or large body weight (less than 50 kg and more than 120 kg) only slightly affects plasma concentration of rivaroxaban (the difference is less than 25%). There are no data on pharmacokinetics in children. Clinically significant differences in pharmacokinetics and pharmacodynamics in patients with Caucasoid, African American, Latin American, Japanese or Chinese ethnicity tion accessories not nablyudalis.Vliyanie hepatic failure was investigated on the pharmacokinetics of rivaroxaban patients distributed into classes according to the Child-Pugh classification (according to standard procedures in clinical studies). Child-Pu's classification allows to evaluate the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled to undergo anticoagulant therapy, a particularly important critical point in the impaired liver function is a decrease in the synthesis of coagulation factors in the liver. Since this indicator corresponds to only one of the five clinical / biochemical criteria that constitute the Child-Pugh classification; the risk of bleeding does not clearly correlate with this classification. Treatment of such patients with anticoagulants should be decided independently of the class according to the Child-Pugh classification. Rivaroxaban is contraindicated in patients with liver diseases with coagulopathy, which cause a clinically significant risk of bleeding. In patients with cirrhosis of the liver with a mild degree of liver failure (class A by Child’s classification). -Pw) rivaroxaban pharmacokinetics was only slightly different (on average, there was an increase in rivaroxaban AUC by a factor of 1.2) from the corresponding indicators in control noy group of healthy subjects.There were no significant differences in pharmacodynamic properties between the groups. In patients with cirrhosis and moderate hepatic insufficiency (Child-Pugh class B), the average AUC of rivaroxaban was significantly increased (2.3 times) compared with healthy volunteers due to significantly reduced clearance of the drug indicating a serious liver disease. The suppression of the activity of factor Xa was more pronounced (by 2.6 times) than in healthy volunteers. The prothrombin time is also 2.1 times higher than in healthy volunteers. Using the measurement of prothrombin time, an external coagulation pathway is estimated, including coagulation factors VII, X, V, II and I, which are synthesized in the liver. Patients with moderate hepatic insufficiency are more susceptible to rivaroxaban, which is a consequence of a closer correlation of pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time. The data from patients with class C child-Pugh classification are not available. an increase in plasma rivaroxaban concentration, inversely proportional to a decrease in renal function, as assessed by QC . In patients with mild renal failure (CK 80-50 ml / min), moderate (CK 50-30 ml / min) or severe (CK 30-15 ml / min), the severity was 1.4-, 1.5- and 1.6-fold. increased concentrations of rivaroxaban in plasma (AUC), respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate and severe renal insufficiency, the overall inhibition of factor Xa activity increased 1.5, 1.9 and 2 times compared with healthy volunteers; The prothrombin time due to the action of factor Xa also increased 1.3, 2.2 and 2.4 times, respectively. Data on the use of rivaroxaban in patients with CK 30–15 ml / min is limited, and therefore care should be taken when using the drug for this category of patients. Data on the use of rivaroxaban in patients with CK less than 15 ml / min are missing, and therefore it is not recommended to use the drug in this category of patients.
Indications
prevention of stroke and systemic thromboembolism in patients with atrial fibrillation of non-valvular origin, treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrence of DVT and pulmonary embolism.
Contraindications
hypersensitivity to rivaroxaban or any of the excipients contained in the tablet; clinically significant active bleeding (for example, intracranial hemorrhage, gastrointestinal bleeding); damage or condition associated with an increased risk of major bleeding, for example, an existing or recently transferred gastrointestinal ulcer , the presence of malignant tumors with a high risk of bleeding, recent injuries of the brain or spinal cord, surgery on the brain, spinal cord or eyes, inside Cranial hemorrhage, diagnosed or suspected esophageal varicose veins, arteriovenous malformations, vascular aneurysms, or vascular pathology of the brain or spinal cord, and concomitant therapy with any other anticoagulants, such as unfractionated heparin, low heparin (Enoxaparin, dalteparin, enoxaparin, dalteparin, heparin, low-heparin (enoxaparin, dalteparin, enaroxamine) fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.), except when switching from or to rivaroxaban (see section "Dosage and administration") or when using unfractionated heparin in doses necessary to ensure the functioning of the central venous or arterial catheter; liver diseases occurring with coagulopathy, which causes a clinically significant risk of bleeding; pregnancy and breastfeeding period; children and adolescents under 18 years old (efficacy and safety in patients of this age group have not been established), renal failure (creatinine clearance less than 15 ml / min) (clinical There are no data on the use of rivaroxaban in this category of patients), congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose in the composition).
Precautionary measures
Do not exceed recommended doses.
Use during pregnancy and lactation
The efficacy and safety of Xarelto in pregnant women have not been established. The data obtained in experimental animal studies,showed a pronounced toxicity of rivaroxaban for the maternal organism, associated with the pharmacological action of the drug (for example, complications in the form of hemorrhages) and leading to reproductive toxicity. Primary teratogenic potential was not detected. Due to the possible risk of bleeding and the ability to penetrate the placental barrier rivaroxaban is contraindicated in pregnancy. Women with reproductive ability should use effective methods of contraception during treatment with rivaroxaban. The data obtained in experimental animal studies show that rivaroxaban is excreted in breast milk. Rivaroxaban can be used only after the abolition of breastfeeding. Studies have shown that rivaroxaban does not affect male and female fertility in rats. Research on the effect of rivaroxaban on human fertility has not been conducted.
Dosage and administration
If the patient is not able to swallow the tablet whole, Xarelto may be crushed and mixed with water or liquid food, such as applesauce, just before taking it. After taking the crushed pills Xarelto 15 mg or 10 mg, you should immediately take a meal. The crushed Xarelto tablet can be administered via a gastric tube. The position of the probe in the gastrointestinal tract must be further coordinated with the doctor before taking Xarelto. The crushed tablet should be administered through a stomach tube in a small amount of water, after which a small amount of water must be introduced in order to wash off the remnants of the preparation from the probe walls. After taking the crushed Xarelto tablet 15 mg or 10 mg, it is necessary to immediately take enteral nutrition.
Side effects
On the part of the circulatory and lymphatic systems: often - anemia (including appropriate laboratory parameters); rarely - thrombocythemia (including elevated platelet count) 1. From the side of the heart: rarely - tachycardia. On the part of the organ of vision: often - bleeding in the eye (including bleeding in the conjunctiva). From the digestive system: often - bleeding gums, gastrointestinal bleeding (including rectal bleeding)pain in the gastrointestinal tract, dyspepsia, nausea, constipation1, diarrhea, vomiting1; infrequently - dry mouth. Systemic disturbances and reactions at the injection site: often - fever1, peripheral edema, deterioration of general well-being (including weakness, asthenia); infrequently - indisposition (including anxiety); rarely, local edema1. From the side of the liver: infrequently, impaired liver function; rarely - jaundice. From the immune system: rarely - allergic reactions, allergic dermatitis. Injuries, poisoning and procedural complications: often - hemorrhages after the procedures (including postoperative anemia and bleeding from the wound), excessive hematoma with bruising of the musculoskeletal system and connective tissue: often - pain in the limbs1; infrequently - hemarthrosis; rarely - a hemorrhage in the muscles. From the nervous system: often - dizziness, headache; infrequently - intracerebral and intracranial hemorrhage, short-term syncope. From the kidneys and urinary tract: often - bleeding from the urogenital tract (including hematuria and menorrhagia 2), renal failure (including increased creatinine, urea levels) From the respiratory tract: often - nose bleeding, hemoptysis. On the side of the skin and subcutaneous tissues: often - itching (including infrequent cases of generalized itching), rash, ecchymosis, skin and subcutaneous hemorrhages; infrequently - urticaria. From the side of blood vessels: often - hypotension, hematoma.
Overdose
Rare cases of overdose have been reported with rivaroxaban up to 600 mg without bleeding or other adverse reactions. Due to limited absorption, a saturation effect is expected without further increasing the average plasma rivaroxaban at hypertherapeutic doses (50 mg or higher). Treatment The rivaroxaban specific antidote is unknown. In case of overdose, activated carbon can be used to reduce the absorption of rivaroxaban. Given the intense binding to plasma proteins, it is expected that rivaroxaban will not be eliminated during dialysis. If a complication of bleeding occurs, the following procedure should be postponed or treatment should be canceled, depending on the situation. T1 / 2 rivaroxaban leaves approximately 5-13 hours.Treatment should be selected individually, in accordance with the severity and localization of the bleeding. If necessary, appropriate symptomatic treatment can be applied, such as mechanical compression (for example, in severe nosebleeds), surgical hemostasis with assessment of its effectiveness (control of bleeding), replenishment of fluid volume and hemodynamic support, the use of blood products (erythrocyte mass or fresh frozen plasma, depending on concomitant anemia or coagulopathy) or platelet If the measures listed above do not lead to the elimination of bleeding, a specific procoagulant may be prescribed, for example, a concentrate of the prothrombin complex, a concentrate of activated prothrombin complex or a recombinant factor VIIa (rf VIIa). However, at present, the experience of using these drugs in patients receiving Xarelto is very limited. It is expected that Protamine Sulfate and Vitamin K will not affect rivaroxaban's anticoagulant activity. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients. receiving xarelto. The scientific rationale for the feasibility or experience of using the systemic hemostatic drug desmopressin in patients receiving Xarelto is absent.
Interaction with other drugs
Pharmacokinetic interaction Rivaroxaban is eliminated mainly through metabolism in the liver mediated by the cytochrome P450 system (CYP3A4, CYP2J2) and also by renal excretion of unchanged drug substance using P-gp / Bcrp vector systems (P-glycoprotein / breast cancer resistance protein) .Rivaroxaban does not inhibit and does not induce CYP3A4 isoenzyme and other important cytochrome isoforms. Simultaneous use of rivaroxaban and strong inhibitors of CYP3A4 isoenzyme and P-glycoprotein ozhet lead to lower renal and hepatic clearance and thereby significantly increase the system vozdeystvie.Sovmestnoe application rivaroxaban and antifungal azoles from the group consisting of ketoconazole (400 mg 1 time / day), which is a potent inhibitor of CYP3A4 and P-glycoproteinled to an increase in the equilibrium AUC of rivaroxaban by a factor of 2.6 and an increase in the mean Cmax of rivaroxaban by a factor of 1.7, which was accompanied by a significant increase in the pharmacodynamic effect of the drug. -glycoprotein, led to an increase in the average equilibrium AUC of rivaroxaban by 2.5 times and an increase in the average Cmax of rivaroxaban by 1.6 times, which was accompanied by a significant increase in the pharmacodynamic effect of pr Paraty. In this regard, rivaroxaban is not recommended for use in patients receiving systemic treatment with antifungal drugs of the azoles group or HIV protease inhibitors. It is expected that other drugs strongly suppressing only one of the ways of rivaroxaban removal - with the participation of CYP3A4 CYP3A4 or P-glycoprotein to increase the concentration of rivaroxaban in plasma to less significant values. Clarithromycin (500 mg 2 times / day), a strong inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-glycoprotein, caused an increase in AUC 1.5 times and Cmax rivaroxaban 1.4 times. This increase has the order of the normal variability of AUC and Cmax and is considered clinically insignificant. Erythromycin (500 mg 3 times / day), a moderate inhibitor of the CYP3A4 isoenzyme and P-glycoprotein, caused an increase in the AUC and Cmax values of rivaroxaban 1.3 times. This increase has the order of the normal variability of AUC and Cmax and is considered clinically insignificant. In patients with renal insufficiency (CK ≤ 80-50 ml / min), erythromycin (500 mg 3 times / day) caused an increase in the AUC values of rivaroxaban 1.8 times and Cmax 1.6. times compared with patients with normal renal function who did not receive concomitant therapy. In patients with renal insufficiency (CK 50–30 ml / min), erythromycin caused an increase in AUC of rivaroxaban by a factor of 2.0 and Cmax by a factor of 1.6 compared with patients with normal renal function who did not receive concomitant therapy. Fluconazole (400 mg 1 time / day ), a moderate inhibitor of the isoenzyme CYP3A4, caused an increase in the average AUC of rivaroxaban 1.4 times and an increase in the average Cmax 1.3 times. This increase has the order of the normal variability of AUC and Cmax and is considered clinically insignificant. Simultaneous use of rivaroxaban with dronedarone should be avoided due to limited clinical data on combined use. Combined use of rivaroxaban and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, led to a decrease in mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects.The combined use of rivaroxaban with other strong inducers of CYP3A4 (for example, phenytoin, carbamazepine, phenobarbital, or Hypericum perforatum) can also lead to a decrease in plasma concentrations of rivaroxaban. A decrease in plasma concentrations of rivaroxaban was considered clinically insignificant. Pharmacodynamic interaction After co-administration of enoxaparin sodium (single dose 40 mg) and rivaroxaban (single dose 10 mg), a cumulative effect was observed on anti-factor Xa activity, not accompanied by additional cumulative effects on clotting blood (prothrombin time, APTT). Enoxaparin did not alter the pharmacokinetics of rivaroxaban. After co-administration of rivaroxaban in a dose of 15 mg and naproxen in a dose of 500 mg, no clinically significant prolongation of bleeding time was observed. However, in individuals, a more pronounced pharmacodynamic response is possible. There is no pharmacokinetic interaction between rivaroxaban at a dose of 15 mg and clopidogrel (a loading dose of 300 mg followed by a maintenance dose of 75 mg), but in some patients a significant increase in bleeding time was found, not correlated with the degree of platelet aggregation and the content of P-selectin or GPIIb / IIIa receptor. Transfer of patients from warfarin (MHO from 2 to 3) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (MHO from 2 to 3) with was accompanied by a more than additive increase in prothrombin time / INR (Neoplastin) (in some cases up to 12), whereas the effects of changes in the APTT, inhibition of factor Xa activity and the endogenous potential of thrombin (EPT) were additive. To evaluate the pharmacodynamic effects of Xarelto during the transition period, analysis of anti-Xa factor, PiCT and HepTest, if warfarin did not affect the indicators determined in their course. Starting from the 4th day after the cancellation of warfarin, all analyzes (including PV, APTT, suppression of factor Xa activity and EPT (endogenous thrombin potential)) exclusively reflected the effect of Xarelto. To evaluate the pharmacodynamic effects of warfarin during the transition period, you can use the indicator MHO, measured at the time of reaching Cmax rivaroxaban (24 hours after receiving a dose of rivaroxaban), because at this point in time the effect of rivaroxaban on the results of analyzes is minimal. The pharmacokinetic interaction between warfarin and rivaroxaban was not found. Drug interaction of Xarelto with AVK phenindione was not studied.As far as possible, it is recommended to avoid transferring patients from Xarelto therapy to AVK therapy with phenyndione and vice versa. There is limited experience transferring patients from AVK therapy with acenocoumarol to Xarelto. , daily monitoring of the pharmacodynamic effects of drugs (MHO, prothrombin time) should be carried out immediately before taking the next dose of the drug sarelto. If it becomes necessary to transfer a patient from AVK therapy with phenindione or acenocoumarol to therapy with Xarelto, then special care should be taken, control of the pharmacodynamic effects of the drugs is not required. Concurrent use with other drugs substrate CYP3A4), digoxin (substrate P-glycoprotein) or atorvastatin (substrate CYP3A4 and P-glycopte rotein). Clinically significant interaction with food was not observed. Incompatibility Unknown. Effect on laboratory parameters. Effect on blood clotting indicators (EF, APTT, HepTest) are as expected with regard to the mechanism of action of Xarelto.
special instructions
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with antifungal drugs of the azoles group (for example, ketoconazole) or HIV protease inhibitors (for example, ritonavir). These drugs are strong inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the concentration of rivaroxaban in the blood plasma to clinically significant values (2.6 times on average), which can lead to an increased risk of bleeding. However, the antifungal drug of the azoles group fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on rivaroxaban exposure and can be used simultaneously. Xarelto should be used with caution in patients with moderate renal impairment (CC 49-30 ml / min) receiving concomitant medications which may lead to increased plasma rivaroxaban concentrations.In patients with renal insufficiency with QA less than 30 ml / min, the concentration of rivaroxaban in plasma may be significantly increased (1.6 times on average), which may lead to an increased risk of bleeding. Therefore, due to the presence of this underlying disease, these patients have an increased risk of developing both bleeding and thrombosis. Due to the limited amount of clinical data, the drug Xarelto should be used with caution in patients with CC 29-15 ml / min. Clinical data on the use of rivaroxaban in patients with severe renal impairment (CC less than 15 ml / min) are not available. Therefore, the use of Xarelto is not recommended in these patients. Patients with severe renal dysfunction or increased risk of bleeding, as well as patients receiving concomitant systemic treatment with antifungal drugs of the azoles group or HIV protease inhibitors, need to be monitored for signs of bleeding start of treatment. The use of Xarelto during surgery for a fracture of the proximal femur has not been studied in the interval tional clinical studies. There are limited clinical data obtained in observational studies in patients undergoing surgical interventions for fractures of the lower extremities, including at fracture of the proximal femur. Xarelto, like other antithrombotic agents, should be used with caution in patients with an increased risk of bleeding, including: - patients with congenital or acquired bleeding tendency; - patients with uncontrolled severe arterial hypertension ; - patients with gastric ulcer and duodenal ulcer in the acute phase; - patients who have recently had gastric ulcer and duodenal ulcer; - patients with vascular retinopathy; ENTOV recently underwent intracranial or intracerebral hemorrhage; -patsientov with pathology of the brain or spinal cord vessels; -patsientov recently undergone surgery on the brain, spinal cord or eyes; -patsientov with bronchiectasis or pulmonary hemorrhage caution in anamneze.Sleduet,if a patient simultaneously receives medications that affect hemostasis, such as NSAIDs, platelet aggregation inhibitors or other antithrombotic drugs. Patients at risk for developing gastric ulcer and duodenal ulcer may be given appropriate preventive treatment. If there is an inexplicable decrease in hemoglobin or AD, you should look for a source of bleeding Against the background of treatment with rivaroxaban, prolongation of the QT interval was not observed. When performing epidural / spinal anesthesia or spinal cords th 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 with the use of a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis. Traumatic epidural or spinal puncture or repeated puncture may also increase the risk. Patients should be supervised to identify signs and symptoms of neurological disorders (such as numbness or weakness of the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary. The physician must compare the potential benefits and risks before conducting spinal interventions to patients receiving anticoagulants or who are scheduled to receive anticoagulants for the prevention of thrombosis. In order to reduce the potential risk of bleeding associated with the simultaneous use of rivaroxaban and epidural / spinal anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. The installation or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is assessed as weak. The epidural catheter is removed no earlier than 18 hours after the last dose of rivaroxaban is prescribed. Xarelto should not be administered earlier than 6 hours after removing the epidural catheter.In the case of a traumatic puncture, the administration of Xarelto should be postponed for 24 hours. If an invasive procedure or surgery is necessary, Xarelto should be stopped for at least 24 hours before the intervention, if possible, and on the basis of a doctor's opinion. If the procedure cannot be postponed, the increased risk of bleeding should be evaluated in comparison with the need for urgent intervention. Taking Xarelto should be resumed after an invasive procedure or surgery, provided that there are appropriate clinical parameters and adequate hemostasis. Safety data obtained from preclinical studies With the exception of the effects associated with increased pharmacological action (bleeding), the analysis of preclinical data obtained in studies on pharmacological safety, specific