Rivarox 20mg 28 tablets

RIVAROX 1. Composition • Active substance: Rivaroxaban 15 mg or 20 mg. Excipients: For a complete list, see section 6.1. 2. Pharmaceutical form Round, biconvex, film-coated tablets, red in color, with an engraving "II" on one side (RIVAROX 15 mg). Round, biconvex, reddish-brown, film-coated tablets (RIVAROX 20 mg). 3. Clinical features 3.1. Therapeutic indications RIVAROX is indicated in adult patients: • For the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation, with one or more risk factors, such as congestive heart failure, arterial hypertension, age > 75 years, diabetes mellitus, history of stroke or transient ischemic attack. • For the treatment of deep vein thrombosis (DVT) and pulmonary artery embolism (PAE) and for the prevention of recurrent DVT and PAE. 3.2. Method of administration and dosage Dosage: For the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation, the recommended dose of RIVAROX is 20 mg (1 tablet) once daily, which is the maximum recommended dose of the drug. Treatment should be continued as long as risk factors for stroke and systemic thromboembolism are present. The duration of treatment depends on the balance between the benefits of treatment and the risk of potential complications. If a dose is missed, the patient should take the missed dose immediately and continue taking the drug the next day according to the recommended regimen. Doubling the dose to compensate for a missed dose is not allowed. Treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT, treatment of pulmonary artery embolism (PAE) and prevention of recurrent PAE The recommended initial dose of RIVAROX is 15 mg twice daily for the first 3 weeks. From the fourth week onwards, for further long-term therapy and prophylaxis, 20 mg once daily is prescribed. The minimum duration of the treatment course (at least 3 months) should be based on an assessment of reversible risk factors (previous surgery, trauma, immobilization). In case of idiopathic DVT and PAE, as well as in patients with a history of recurrent DVT and PAE, the decision to prolong the treatment course should be made on a permanent basis based on the assessment of risk factors. When prolonged treatment is indicated for recurrent DVT and PAE (after completion of 6 months of treatment), the recommended dose is 10 mg once daily. In patients at high risk of developing DVT and PAE (with relevant comorbidities), or in patients who still experience the risk of developing DVT and PAE despite taking the drug at a dose of 10 mg, continuation of treatment at a dose of 20 mg daily should be considered. The duration of treatment and dose selection should be individualized for each patient and based on the assessment of bleeding risk. Duration of treatment Dosage regimen Maximum daily dose Treatment of DVT and prevention of recurrence, treatment of PAE and prevention of recurrence 3 weeks 15 mg twice daily 30 mg From the 4th week 20 mg once daily 20 mg Prevention of recurrent DVT and PAE After at least 6 months of treatment for DVT and PAE 10 mg once daily or 20 mg once daily 10 or 20 mg If a dose is missed during the 3-week treatment period, the patient should take the tablet (15 mg) as soon as they remember to ensure a daily dose of 30 mg. For this purpose, two 15 mg tablets can be taken simultaneously. The recommended regimen should be continued from the next day. If a dose is missed after the 3-week treatment period, when the patient has switched to taking the drug at a dose of 20 mg once daily, the patient should take the tablet (20 mg) as soon as they remember, and the recommended regimen should be continued from the next day. Doubling the dose to compensate for a missed dose is not allowed. Switching from vitamin K antagonists (VKAs) to rivaroxaban For the prevention of stroke and systemic thromboembolism in patients treated with vitamin K antagonists, treatment should be discontinued and treatment with rivaroxaban continued when the International Normalized Ratio (INR) is ≤3. For the treatment of DVT and PAE and prevention of recurrence in patients treated with vitamin K antagonists, treatment should be discontinued and treatment with rivaroxaban continued when the International Normalized Ratio (INR) is ≤2.5. When switching from vitamin K antagonists to rivaroxaban, the INR may be falsely elevated. This value is not used to assess the anticoagulant activity of rivaroxaban and therefore should not be used for this purpose. Switching from rivaroxaban to vitamin K antagonists (VKAs) When switching from rivaroxaban to vitamin K antagonists, insufficient anticoagulant effect is expected. Therefore, continuous adequate anticoagulant effect must be ensured using alternative anticoagulants. It should be noted that rivaroxaban can cause an increase in INR. Patients switching from rivaroxaban to vitamin K antagonists should take vitamin K antagonists until the INR reaches ≥2.0. For the first two days of the transition period, patients should take the standard dose of vitamin K antagonists, followed by dose adjustments based on INR measurements. When rivaroxaban and vitamin K antagonists are taken concurrently, INR should be measured at least 24 hours after taking the previous dose of rivaroxaban, but before taking the next dose. Reliable INR measurement can be obtained 24 hours after discontinuation of rivaroxaban and, consequently, after taking the last dose of the drug. Switching from parenteral anticoagulants to rivaroxaban Patients receiving parenteral anticoagulants should start using rivaroxaban 0-2 hours before the planned parenteral administration of the drug (e.g., low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration of the drug (e.g., intravenous administration of unfractionated heparin). Switching from rivaroxaban to parenteral anticoagulants Rivaroxaban should be discontinued and the first dose of the parenteral anticoagulant should be administered at the time of the next scheduled dose. Additional information for specific patient populations Patients with impaired renal function Limited data in patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate a significant increase in rivaroxaban concentration in plasma. RIVAROX should be used with caution in these patients. The use of the drug is not recommended in patients with creatinine clearance less than 15 ml/min. In patients with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance 15-29 ml/min) renal impairment, the following dosage regimen is recommended: - For the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily. - For the treatment of deep vein thrombosis (DVT), pulmonary artery embolism (PAE) and prevention of recurrent DVT and PAE, 15 mg twice daily is prescribed for 3 weeks. Subsequently, based on the assessment of bleeding risk, treatment may be continued at a lower dose of 15 mg once daily instead of 20 mg daily. If the recommended daily dose is 10 mg, dose adjustment is not required. In patients with mild renal impairment (creatinine clearance 50-80 ml/min), dose adjustment of the drug is not necessary. Patients with impaired liver function RIVAROX is contraindicated in patients with liver diseases associated with coagulopathy and a clinically significant risk of bleeding, as well as in patients with liver cirrhosis and liver failure, according to Child-Pugh classification classes B and C. Elderly patients Dose adjustment is not required. The risk of bleeding increases with age. Sex, body weight Dose adjustment is not required. Children The safety and efficacy of RIVAROX in children and adolescents under 18 years of age have not been established. RIVAROX is not used in children and adolescents under 18 years of age. Cardioversion For the prevention of stroke and systemic thromboembolism, treatment with RIVAROX can be initiated or continued in patients requiring cardioversion. If cardioversion is to be performed (with transesophageal echocardiographic control) in patients who have not previously received anticoagulant therapy, treatment with RIVAROX can be initiated no less than 4 hours before cardioversion to ensure anticoagulant effect. Before cardioversion, confirmation of adherence to RIVAROX prescription is required from each patient. In patients undergoing cardioversion, the decision to initiate and continue treatment with RIVAROX should be made in accordance with established anticoagulant therapy regimens. In patients with non-valvular atrial fibrillation requiring stenting Data on the use of reduced doses of RIVAROX (15 mg once daily, or 10 mg once daily in patients with moderate renal impairment (30-49 ml/min)) in combination with a P2Y12 inhibitor for up to 12 months are insufficient. Method of administration: RIVAROX 15 mg and RIVAROX 20 mg tablets should be taken with food. If the patient cannot swallow the tablet whole, the RIVAROX tablet can be crushed immediately before administration, mixed with water or soft food (e.g., applesauce), and taken orally in this form. After taking the crushed tablets, food should be consumed. In some cases, it may be necessary to administer the crushed RIVAROX tablet via a gastric tube. Before this procedure, it is necessary to ensure that the tube is correctly positioned in the stomach. The crushed tablet should be administered through the tube with a small amount of water, followed by flushing the tube with water. Enteral feeding should be administered after administering the crushed tablets via the tube. 3.3. Contraindications: • Hypersensitivity to any component of the drug. • Active, clinically significant bleeding. • Pathological changes or conditions associated with a risk of massive bleeding, such as: - Recent history of gastrointestinal ulcer or active gastrointestinal ulcer disease, - Malignancy with a high risk of bleeding, - Recent head or spinal cord trauma or injury, - Recent surgery on the head, spinal cord, or eyes, - Recent intracranial hemorrhage, - Established esophageal varices or predisposition to this pathology, - Arteriovenous malformations, - Aneurysms or extensive intraspinal or intracerebral vascular pathologies. • Concomitant treatment with any other anticoagulant, e.g., unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.), except for specific cases of switching to other anticoagulant therapy or administration of unfractionated heparin in doses necessary to maintain the patency of an open central venous or arterial catheter. • Liver diseases associated with coagulopathy and a clinically significant risk of bleeding, including patients with cirrhosis classified as Child-Pugh class B and C. • Pregnancy and lactation. • Age under 18 years (efficacy and safety not established). 3.4. Special warnings and precautions: Clinical observation within the framework of established anticoagulant practice is recommended throughout the treatment period. Risk of bleeding As with other anticoagulants, patients taking RIVAROX should be carefully monitored for signs of bleeding. RIVAROX should be used with caution in patients at increased risk of bleeding. In case of severe bleeding, RIVAROX intake should be discontinued. In studies of rivaroxaban, mucosal bleeding (e.g., nasal, gingival, gastrointestinal, and genitourinary bleeding, including pathological vaginal and heavier menstrual bleeding) and anemia were frequently observed during long-term treatment compared to treatment with vitamin K antagonists. Therefore, in addition to standard clinical observation, and if appropriate, laboratory determination of hemoglobin/hematocrit levels may be informative for quantifying occult bleeding and clinically apparent bleeding. In case of unexplained decrease in hemoglobin or arterial blood pressure, it is necessary to identify the site of bleeding and initiate appropriate treatment. Impaired renal function Caution is necessary when prescribing the drug to patients with severe renal impairment (creatinine clearance < 30 ml/min), as there is a significant increase in rivaroxaban concentration in plasma in this category of patients (approximately 1.6-fold), which, in turn, increases the risk of bleeding. The drug should be prescribed with caution to patients with creatinine clearance of 15-29 ml/min. The use of RIVAROX is not recommended in patients with renal failure and creatinine clearance < 15 ml/min. RIVAROX should be prescribed with caution to patients with renal failure receiving other medications that increase rivaroxaban concentration in plasma. Use with other drugs The use of RIVAROX is not recommended in patients receiving systemic azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir). These drugs are potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein, and their use may lead to an increase in plasma rivaroxaban concentration to clinically significant levels (on average 2.6-fold), thereby increasing the risk of bleeding. Caution is necessary when prescribing RIVAROX to patients taking drugs affecting hemostasis (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, other antithrombotic agents, or selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors). In patients at risk of developing gastrointestinal ulcer disease, the need for appropriate prophylactic treatment should be considered. Other risk factors for bleeding RIVAROX, like other antithrombotic drugs, should be used with caution in patients at increased risk of bleeding, e.g., in pathological conditions such as: - Congenital or acquired predisposition to bleeding, - Severe uncontrolled arterial hypertension, - Gastrointestinal diseases without active ulceration that could potentially cause bleeding (e.g., inflammatory bowel disease, esophagitis, gastritis, gastroesophageal reflux, etc.). - Vascular retinopathy, - Bronchiectasis or history of pulmonary hemorrhage, Patients with artificial heart valves The efficacy and safety of rivaroxaban in patients with artificial heart valves have not been studied, therefore, there is no data confirming that the use of rivaroxaban in this category of patients provides adequate anticoagulant effect. The use of rivaroxaban in this category of patients is not recommended. Patients with antiphospholipid syndrome Direct-acting oral anticoagulants, including rivaroxaban, are not recommended for patients with antiphospholipid syndrome who have a history of thrombosis. In these patients, the use of direct-acting oral anticoagulants increases the risk of thrombosis compared to treatment with vitamin K antagonists. In patients with non-valvular atrial fibrillation requiring stenting, primary data on the safety assessment of rivaroxaban in patients with non-valvular atrial fibrillation requiring stenting are available. Efficacy data in this category of patients are limited. Data in patients with a history of stroke or transient ischemic attack are not available. Hemodynamically unstable patients with PAE or patients requiring thrombolysis or pulmonary embolectomy RIVAROX is not recommended as an alternative to unfractionated heparin, as the safety and efficacy of rivaroxaban in this category of patients have not been studied. Neuroaxial (epidural/spinal) anesthesia In patients undergoing neuroaxial (epidural/spinal) anesthesia or spinal puncture, who are receiving antithrombotic drugs to prevent thromboembolic complications, there is a risk of developing epidural or spinal hematomas, which can lead to prolonged paralysis. The risk of developing these events is further increased with the use of continuous epidural catheters or concomitant drugs affecting hemostasis. Trauma sustained during epidural puncture, spinal puncture, or multiple punctures may also contribute to increased risk. Patients should be regularly monitored for symptoms of neurological impairment (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). In case of neurological impairment, urgent diagnosis and treatment are necessary. In patients receiving or planning to receive anticoagulants for the prevention of thrombosis before neuroaxial anesthesia, the physician should assess the risk-benefit ratio, although there is no clinical experience with the use of rivaroxaban 15 mg and 20 mg in such situations. To reduce the potential risk of bleeding associated with neuroaxial (epidural/spinal) anesthesia or spinal puncture during the use of rivaroxaban, the pharmacokinetic profile of rivaroxaban should be considered. Insertion/removal of an epidural catheter or lumbar puncture should preferably be performed when the antithrombotic effect of rivaroxaban is considered low. At the same time, the exact time required to achieve a sufficiently low level of anticoagulant effect for each patient is unknown. For removal of an epidural catheter, at least 18 hours (in young patients) and 26 hours (in elderly patients) must have passed since the last dose of the drug. Rivaroxaban should be administered no earlier than 6 hours after removal of the catheter. In case of traumatic puncture, the administration of rivaroxaban should be postponed for 24 hours. Dosage recommendations before and after surgery In case of invasive procedures or surgery, the administration of RIVAROX 15 mg or 20 mg should be discontinued at least 24 hours before the procedure, based on the physician's clinical judgment. If the procedure cannot be postponed, the necessity of urgent intervention should be assessed against the increased risk of bleeding. After completion of the invasive procedure or surgery, if clinical parameters and hemostasis are within normal limits, RIVAROX intake should be resumed as soon as possible. Elderly patients The risk of bleeding increases with age. Dermatological reactions Severe skin reactions, including Stevens-Johnson syndrome / toxic epidermal necrolysis, have been reported during rivaroxaban studies. Patients at high risk of developing these reactions, at the initial stage of therapy: Reactions mostly occur in the first weeks of treatment. Treatment with rivaroxaban should be discontinued immediately upon the appearance of severe skin rash (e.g., widespread, pronounced and/or blistering rash), or in case of any other hypersensitivity reactions with mucosal lesions. Important information about some excipients: RIVAROX contains lactose. It is not recommended for patients with congenital lactase deficiency, lactose intolerance, or glucose-galactose malabsorption. 3.5. Interactions with other medicinal products and other types of interactions: CYP3A4 isoenzyme and P-glycoprotein inhibitors The use of RIVAROX with strong inhibitors of CYP3A4 isoenzyme and P-glycoprotein may lead to a decrease in renal and hepatic clearance and, consequently, significantly enhance the systemic effect of the drug. Concomitant use of RIVAROX and the azole antifungal drug ketoconazole (400 mg once daily), a strong inhibitor of CYP3A4 isoenzyme and P-glycoprotein, leads to a 2.6-fold increase in rivaroxaban AUC and a 1.7-fold increase in Cmax, with a significant concomitant enhancement of the drug's pharmacodynamic effects. Concomitant administration of RIVAROX and the HIV protease inhibitor ritonavir (600 mg twice daily), a strong inhibitor of CYP3A4 isoenzyme and P-glycoprotein, leads to a 2.5-fold increase in rivaroxaban AUC and a 1.6-fold increase in Cmax, with a significant concomitant enhancement of the drug's pharmacodynamic effects. The use of RIVAROX is not recommended in patients receiving systemic treatment with azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors. Clarithromycin (500 mg twice daily), a strong inhibitor of CYP3A4 isoenzyme and a moderate inhibitor of P-glycoprotein, leads to a 1.5-fold increase in rivaroxaban AUC and a 1.4-fold increase in Cmax. Erythromycin (500 mg three times daily), a moderate inhibitor of CYP3A4 isoenzyme and P-glycoprotein, leads to a 1.3-fold increase in rivaroxaban AUC and Cmax. This increase in AUC and Cmax is within the normal range and is considered clinically insignificant. In patients with mild renal impairment, erythromycin (500 mg three times daily) leads to an 1.8-fold increase in rivaroxaban AUC and a 1.6-fold increase in Cmax compared to patients with normal renal function without concomitant medications. In patients with moderate renal impairment, erythromycin leads to a 2.0-fold increase in rivaroxaban AUC and a 1.6-fold increase in Cmax compared to subjects with normal renal function without concomitant medications. Fluconazole (400 mg once daily), a moderate inhibitor of CYP3A4 isoenzyme, leads to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax, which is within the normal range of AUC and Cmax variation and is considered clinically insignificant. Due to the lack of clinical data, concomitant use of rivaroxaban and dronedarone is not recommended. Anticoagulants Following the co-administration of enoxaparin (single dose 40 mg) and rivaroxaban (single dose 10 mg), an additive effect on anti-factor Xa was observed, without additional effects on blood coagulation tests (prothrombin time, aPTT). Enoxaparin does not alter the pharmacokinetics of rivaroxaban. Due to the increased risk of bleeding, patients should be cautious when using rivaroxaban with other anticoagulants. NSAIDs/antiplatelet agents Following the co-administration of rivaroxaban (15 mg dose) and naproxen (500 mg dose), no clinically significant prolongation of bleeding time was observed. However, in individual subjects, the pharmacodynamic effect may be more pronounced. No clinically significant pharmacokinetic or pharmacodynamic interactions are observed with the co-administration of rivaroxaban and aspirin (500 mg dose). No pharmacokinetic interaction is observed between rivaroxaban (15 mg dose) and clopidogrel (loading dose 300 mg, followed by maintenance doses of 75 mg), but at the same time, concomitant use of these drugs prolongs bleeding time, which does not correlate with the degree of platelet aggregation and P-selectin content or GPIIb/IIIa receptor. Caution should be exercised when co-administering non-steroidal anti-inflammatory drugs (including acetylsalicylic acid) and platelet aggregation inhibitors, as these drugs generally increase the risk of bleeding. Selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors The risk of bleeding increases with concomitant use of rivaroxaban with selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors. Warfarin Switching patients from vitamin K antagonist warfarin (INR 2.0-3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin increases the prothrombin time/INR (Neoplastin) ratio to a greater extent than expected from simple summation of effects (individual INR values may reach 12), while the effect on aPTT, factor Xa inhibition, and endogenous thrombin potential is additive. If it is necessary to study the pharmacodynamic effects of rivaroxaban during the transition period, anti-Xa, Pict, and HepTest activity measurements can be used as necessary tests that are not affected by warfarin. From the 4th day after discontinuation of warfarin, all test results (including prothrombin time, aPTT, factor Xa activity inhibition, etc.) reflect only the effect of rivaroxaban. If it is necessary to study the pharmacodynamic effects of warfarin during the transition period, INR can be used as a necessary test with minimal influence from rivaroxaban, according to rivaroxaban trough levels (24 hours after the last dose of rivaroxaban). No pharmacokinetic interaction between warfarin and rivaroxaban is observed. CYP3A4 isoenzyme and P-glycoprotein inducers Concomitant administration of rivaroxaban and rifampicin (a strong inducer of CYP3A4 isoenzyme and P-glycoprotein) leads to a decrease in rivaroxaban AUC by approximately 50% and a reduction in its pharmacodynamic effects. Concomitant administration of rivaroxaban with other strong inducers of CYP3A4 isoenzyme (e.g., phenytoin, carbamazepine, phenobarbital, and St. John's wort) may also lead to a decrease in plasma rivaroxaban concentration. Concomitant use of rivaroxaban with strong inducers of CYP3A4 isoenzyme requires special caution. Other concomitant therapy Clinically significant pharmacokinetic or pharmacodynamic interactions are not observed with the concomitant use of rivaroxaban with midazolam (CYP3A4 substrate), digoxin (P-gp substrate), atorvastatin (CYP3A4 and P-gp substrate), or omeprazole (proton pump inhibitor). Effect on laboratory parameters Given the mechanism of action of rivaroxaban, the effect on blood coagulation parameters (prothrombin time, aPTT, HepTest) is as expected. 3.6. Fertility, pregnancy and lactation Pregnancy The safety and efficacy of the drug during pregnancy have not been established. Women of childbearing potential should use effective methods of contraception during treatment with RIVAROX. RIVAROX is not used during pregnancy. Lactation The safety and efficacy of the drug during lactation have not been established. A decision should be made to discontinue breastfeeding or to discontinue/refrain from treatment. RIVAROX is not used during breastfeeding. Fertility No data on the effect of rivaroxaban on human fertility are available. 3.7. Ability to drive and operate machinery Data on dizziness (frequent side effect) or syncope (infrequent side effect) during the use of rivaroxaban are available, which may affect the ability to drive or operate machinery. Patients experiencing such reactions should refrain from driving or operating machinery. 3.8. Possible side effects Due to the mechanism of pharmacological action of RIVAROX, its use may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may lead to post-hemorrhagic anemia. The risk of bleeding increases in patients with uncontrolled arterial hypertension and/or concomitant use of RIVAROX with drugs affecting hemostasis. The signs, symptoms, and severity of bleeding (including fatal outcomes) depend on the location, intensity, and duration of bleeding. Menstrual bleeding may also be increased or prolonged during treatment with rivaroxaban. Hemorrhagic complications may manifest as weakness, pallor, dizziness, or unexplained swelling, shock, dyspnea. In some cases, as a result of anemia, symptoms of cardiac ischemia may develop (chest pain, angina attack). In addition, severe complications such as compartment syndrome and renal failure due to hypoperfusion may occur during the use of the drug. When assessing the condition of any patient receiving anticoagulants, the probability of bleeding must be taken into account. Data on the frequency of side effects are categorized as follows: very common (≥1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100); rare (≥ 1/10,000, <1/1000); very rare (<1/10,000); unknown (frequency cannot be determined from available data). Hematopoietic system: Common – anemia (including relevant laboratory parameters); Uncommon – thrombocythemia (including increased platelet count)*. Unknown – thrombocytopenia. Cardiovascular system: Common – hypotension, hematoma; Uncommon – tachycardia. Organ of vision: Common – eye hemorrhage (including conjunctival bleeding). Digestive system: Common – gingival bleeding, gastrointestinal bleeding (including rectal bleeding), gastrointestinal pain, abdominal pain, dyspepsia, nausea, constipation*, vomiting; Uncommon – dry mouth. Liver and biliary tract: Uncommon – impaired liver function; Rare – jaundice. Unknown – cholestasis, hepatitis (including hepatocellular disorder). Nervous system: Common – dizziness, headache; Uncommon – brain hemorrhage and intracranial hemorrhage, syncope. Urinary system: Common – genitourinary bleeding (including hematuria and menorrhagia**), renal failure (with increased creatinine and urea concentration in blood)*. Unknown – renal failure/acute renal failure as a consequence of hypoperfusion due to bleeding. Respiratory system: Common – epistaxis, bloody cough. Skin and subcutaneous tissue: Common – pruritus (including infrequent cases of generalized pruritus), rash, ecchymosis, skin and subcutaneous hematomas; Uncommon – urticaria. Immune system: Uncommon – allergic reaction, allergic dermatitis. Unknown – angioneurotic edema and allergic edema. Musculoskeletal system: Common – limb pain*; Uncommon – hemarthrosis; Rare – muscle hemorrhage; Unknown – compartment syndrome as a complication of bleeding. General disorders and administration site reactions: Common – fever*, peripheral edema, general weakness and lack of energy (including fatigue and asthenia); Uncommon – malaise; Rare – localized edema*. Traumatisms, complications of procedures: Common – bleeding after procedures (including postoperative anemia and wound bleeding), contusion, wound discharge*; Rare – vascular pseudoaneurysm***. Laboratory and instrumental data: Common – increased liver transaminase activity; Uncommon – increased bilirubin, increased alkaline phosphatase in blood*, lactate dehydrogenase*, lipase*, amylase*, gamma-glutamyl transpeptidase*; Rare – increased conjugated bilirubin (with or without concomitant increase in alanine transaminase). *: Observed after major orthopedic surgery; **: Observed as very common during treatment and prevention of recurrence of DVT, PAE in women under 55 years of age. ***: Observed as uncommon in the prevention of atherothrombotic events in patients after acute myocardial infarction (after coronary angioplasty). 3.9. Overdose Symptoms: There are reports of rare cases of overdose (up to 600 mg of rivaroxaban) without the development of bleeding or other adverse reactions. When using doses higher than the therapeutic dose, equal to 50 mg or more, a low plateau of rivaroxaban concentration is expected to develop without further increase, which is related to limited absorption of rivaroxaban. Treatment: A specific antidote for rivaroxaban is unknown. In case of overdose, activated charcoal may be used to reduce the absorption of rivaroxaban. Given the high binding to plasma proteins, rivaroxaban is not expected to be removed by dialysis. Treatment in case of bleeding: If bleeding occurs during treatment with RIVAROX, the drug intake should be postponed or, if necessary, discontinued. Treatment should be individualized according to the location and severity of bleeding. If necessary, appropriate symptomatic therapy may be used, such as mechanical compression (e.g., in case of severe epistaxis), surgical hemostasis with assessment of its effectiveness, infusion therapy and hemodynamic support, administration of blood (erythrocyte mass or fresh frozen plasma depending on whether anemia or coagulopathy has developed) or platelet preparations. If these measures do not stop the bleeding, specific reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa (r-FVIIa) may be administered. Currently, experience with the use of these drugs in patients treated with rivaroxaban is limited. Protamine sulfate and vitamin K are unlikely to affect the anticoagulant activity of rivaroxaban. Experience with the use of tranexamic acid in patients receiving rivaroxaban is limited, and there is no experience with the use of aminocaproic acid and atipamezole. There is no scientific evidence for the use or appropriateness of concomitant use of the systemic hemostatic agent desmopressin with rivaroxaban. 4. Pharmacological properties 4.1. Pharmacodynamics Pharmacological group: Antithrombotic agent, direct inhibitor of factor Xa. Pharmacological action: Pharmacodynamics: Mechanism of action Rivaroxaban is a highly selective direct inhibitor of blood coagulation factor Xa, which has high bioavailability after oral administration. Activation of blood factor X, accompanied by the formation of factor Xa through extrinsic and intrinsic pathways of blood coagulation, plays a crucial role in the process of blood coagulation. Blood factor Xa is a component of the prothrombinase complex, which directly converts prothrombin to thrombin, ultimately leading to the formation of a fibrin clot and platelet activation. One molecule of factor Xa catalyzes 1000 molecules of thrombin (the so-called "thrombin burst"). Furthermore, the reaction rate of factor Xa bound to prothrombinase increases 300,000-fold compared to the reaction rate of free factor Xa, which leads to a jump in thrombus levels. Rivaroxaban, a selective inhibitor of factor Xa, leads to the cessation of such thrombin formation and, consequently, affects the laboratory results of general and specific blood coagulation tests. Pharmacodynamic effects Inhibition of factor Xa activity is dose-dependent. During analysis, using the Neoplastin kit, rivaroxaban has a dose-dependent effect on prothrombin time, which, in turn, is closely correlated with plasma rivaroxaban concentration (correlation coefficient is 0.98), while results differ when using other reagents. Prothrombin time should be measured in seconds, as the International Normalized Ratio (INR) is calibrated and validated only for coumarins and cannot be used for other anticoagulants. Rivaroxaban dose-dependently increases activated partial thromboplastin time (aPTT) and HepTest results, however, the use of these parameters is not recommended for assessing the pharmacodynamic effects of rivaroxaban. Monitoring of blood coagulation parameters is not necessary during treatment with the drug, but if clinical justification is required, rivaroxaban concentration can be measured using a calibrated quantitative test for anti-Xa factor. 4.2. Pharmacokinetics Absorption and bioavailability After oral administration, rivaroxaban is rapidly absorbed. Maximum plasma concentration (Cmax) is reached within 2-4 hours. Bioavailability is almost complete (80-100%) when taking 2.5 mg or 10 mg of the drug and is independent of whether the drug is taken with or without food. Food intake also does not affect the area under the curve "concentration-time" (AUC) or Cmax values, therefore, 2.5 mg or 10 mg rivaroxaban tablets can be taken with or without food. Rivaroxaban pharmacokinetics are characterized by moderate individual variability (coefficient of variation is 30-40%). Rivaroxaban absorption depends on the part of the digestive tract where it is released. There are reports of a 29% and 56% reduction in rivaroxaban AUC and Cmax when release occurs in the distal small intestine or ascending colon. For better absorption and high bioavailability, it is preferable for rivaroxaban to be released in the stomach. Distribution In the human body, a large portion of rivaroxaban (92-95%) is bound to plasma proteins. The main binding component is serum albumin. Vss (steady-state volume of distribution) is moderate and is approximately 50 L. Metabolism and excretion After oral administration, approximately 2/3 of the administered dose is metabolized and excreted in equal amounts in urine and feces. The remaining one-third of the dose is excreted unchanged by direct renal excretion, mainly through active renal secretion. Rivaroxaban is metabolized by cytochrome P450 system isoenzymes CYP3A4, CYP2J2, and also by mechanisms independent of this system. The main sites of biotransformation are the morpholine group, which undergoes oxidation, and the amide groups, which are hydrolyzed. Based on in vitro study data, rivaroxaban is a substrate for P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein) transporters. The most active compound in blood plasma is unchanged rivaroxaban. High concentrations of major metabolites or active circulating metabolites are not detected in blood plasma. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low-clearance drug. The terminal elimination half-life (t1/2) of rivaroxaban from plasma is 5-9 hours in young patients and 11-13 hours in elderly patients. Pharmacological characteristics in special populations Sex/elderly patients No clinically significant pharmacokinetic differences are observed between men and women. In elderly patients, rivaroxaban concentration in plasma is higher than in young patients. Also, the mean AUC value is approximately 1.5 times higher than in young patients, mainly due to reduced total and renal clearance. Dose adjustment is not required. Body weight Very low or high body weight (less than 50 kg and more than 120 kg) has only a minor effect on plasma rivaroxaban concentration (difference is less than 25%). Dose adjustment is not required. Ethnic differences No clinically significant pharmacokinetic or pharmacodynamic differences are observed in patients of different ethnic backgrounds. Liver failure The effect of liver failure on rivaroxaban pharmacokinetics has been studied in patients classified by Child-Pugh classification. This classification is used to assess the prognosis of chronic liver disease, primarily liver cirrhosis. During anticoagulant therapy, a significantly adverse consequence of impaired liver function is reduced synthesis of coagulation factors. Since this indicator corresponds to only one of the five clinical-biochemical criteria of the Child-Pugh classification, the risk of bleeding in patients does not correlate sufficiently clearly with this classification. The decision to prescribe anticoagulant treatment in these patients should be made independently of the Child-Pugh classification. Rivaroxaban is contraindicated in patients with liver diseases associated with coagulopathy and a clinically significant risk of bleeding. According to conducted studies, in patients with mild liver cirrhosis (Child-Pugh class A), rivaroxaban pharmacokinetics differ only slightly from those of healthy individuals (on average, a 1.2-fold increase in rivaroxaban AUC is observed). Also, no significant difference in pharmacodynamic characteristics is observed between patients and healthy individuals. In patients with liver cirrhosis and moderate liver failure (Child-Pugh class B), compared to healthy volunteers, due to a significant decrease in drug clearance, indicating severe liver disease, rivaroxaban AUC increases significantly (2.3-fold). Inhibition of factor Xa activity is more pronounced in patients with liver disease (2.6-fold) than in healthy individuals. Prothrombin time also exceeds the data of healthy volunteers by 2.1 times. Patients with moderate liver failure are more sensitive to rivaroxaban, which is manifested by a closer pharmacokinetic and pharmacodynamic relationship between plasma rivaroxaban concentration and prothrombin time. The drug is contraindicated in patients with liver diseases associated with coagulopathy and a clinically significant risk of bleeding, as well as in patients with liver cirrhosis and liver failure, according to Child-Pugh classification classes B and C. Renal impairment In patients with renal impairment, an increase in rivaroxaban exposure in plasma is observed, which is inversely proportional to renal function determined by creatinine clearance. In patients with mild (creatinine clearance 50-80 ml/min), moderate (30-49 ml/min), and severe (15-29 ml/min) renal impairment, rivaroxaban AUC increased by 1.4, 1.5, and 1.6 times, respectively. The corresponding increase in pharmacodynamic effects is more pronounced. In patients with mild, moderate, and severe renal impairment, the overall inhibition of blood factor Xa activity increases by 1.5, 1.9, and 2 times compared to healthy volunteers. Prothrombin time also increases by 1.3, 2.2, and 2.4 times. Data on the use of the drug in patients with creatinine clearance < 15 ml/min are not available, therefore, the use of the drug in this category of patients is not recommended. Special caution is required when prescribing the drug to patients with creatinine clearance of 15-29 ml/min. In patients with severe renal impairment, the risk of bleeding and thrombosis is high. Children and adolescents The safety and efficacy of the drug in children and adolescents under 18 years of age have not been established. 5. Pharmaceutical characteristics 5.1. Excipients Tablet core: Lactose monohydrate, sodium lauryl sulfate, hypromellose, croscarmellose sodium, microcrystalline cellulose, magnesium stearate. Tablet coating: Red film coating powder – macrogol 3350, hypromellose, iron oxide red (E172), titanium dioxide (E171) (RIVAROX 15 mg); macrogol 3350, hypromellose, iron oxide red (E172) (RIVAROX 20 mg). 5.2. Incompatibility Not known 5.3. Shelf life 2 years. Use within the expiry date: Do not use RIVAROX after the expiry date indicated on the packaging. Do not use RIVAROX if you notice that the drug or its packaging is damaged. 5.4. Storage conditions The drug does not require special storage conditions. Keep out of reach of children! 5.5. Packaging Each box contains 28 (15 mg) and 28 (20 mg) film-coated tablets. 5.6. Dispensing category: Pharmaceutical product group II, dispensed by prescription N3. See also: Xarelto 20mg 28 tablets