Rivaxan

Rivaroxaban

Film-coated tablets

2.5 mg tablets: round, biconvex, film-coated, yellow tablets with a pearly luster.
10 mg tablets: round, biconvex, film-coated, brown tablets with a pearly luster.
15 mg tablets: round, biconvex, film-coated, dark orange tablets with a pearly luster.
20 mg tablets: round, biconvex, film-coated, dark red single-scored tablets with a pearly luster. 20 mg tablets can be divided into 2 halves.

Each tablet contains:
Active substance: rivaroxaban 2.5 mg, 10 mg, 15 or 20 mg;
Excipients: microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, sodium lauryl sulfate, sodium stearyl fumarate, and lactose monohydrate;
Shell composition
2.5 mg tablets: hydroxypropyl methylcellulose, macrogol 4000, potassium aluminum silicate (E555), titanium dioxide (E171), iron oxide red (E172).
10 mg, 15 mg, and 20 mg tablets: hydroxypropyl methylcellulose, macrogol 4000, potassium aluminum silicate (E555), iron oxide red (E172).

Antithrombotic agents. Direct factor Xa inhibitors.

B01AF01

Rivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability.
Activation of factor X to form factor Xa (FXa) via intrinsic and extrinsic pathways plays a central role in the blood coagulation cascade. FXa directly converts prothrombin to thrombin via the prothrombinase complex, and ultimately this reaction leads to fibrin clot formation and platelet activation via thrombin. One FXa molecule is capable of producing more than 1000 thrombin molecules due to the amplification nature of the coagulation cascade. In addition, the reaction rate of prothrombinase-related factor FXa is 300,000 times faster than that of free FXa, causing an explosive increase in thrombin formation. Selective FXa inhibitors are able to stop the intense increase in thrombin formation. As a consequence, rivaroxaban interferes with some specific and general coagulation tests. In humans, a dose-dependent inhibition of factor Xa activity was observed.

2.5 mg tablets:

• Rivaroxaban, together with acetylsalicylic acid (ASA) or in combination with ASA and clopidogrel or ticlopidine, is indicated for the prevention of atherothrombosis in adult patients that experienced acute coronary syndrome (ACS) with an increase in cardiac biomarkers;
• Rivaroxaban, together with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic complications in adult patients with coronary heart disease (CHD) or symptomatic peripheral arterial disease (PAD) with a high risk of ischemic events.

10 mg tablets:

• Prevention of venous thromboembolism (VTE) in adult patients undergoing orthopedic surgery on the knee or hip joints.

15 mg and 20 mg tablets:

• Prevention of stroke and systemic embolism in adult patients with atrial fibrillation of non-valvular origin with one or more risk factors, such as congestive heart failure, arterial hypertension, age > 75 years, diabetes mellitus, stroke or transient ischemic attack;
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence of DVT and PE in adults.

Dosing regimen

Acute coronary syndrome
After acute coronary syndrome, the recommended dose is one 2.5 mg tablet of rivaroxaban twice daily. Patients also need to take a daily dose of acetylsalicylic acid 75-100 mg or a daily dose of acetylsalicylic acid 75-100 mg in combination with a daily dose of clopidogrel 75 mg or a standard daily dose of ticlopidine.
The ongoing treatment should be regularly assessed in terms of maintaining a balance between the risk of ischemic events and the risk of bleeding. The duration of treatment is 12 months. Treatment may be extended up to 24 months for selected patients, as there are limited data on treatment for this duration.
Treatment with Rivaxan should begin as soon as possible after the stabilization of the patient during the current ACS (including revascularization procedures). Treatment with the drug should begin at least 24 hours after hospitalization. Rivaxan should be started when parenteral administration of anticoagulants is usually stopped.

CHD / PAD
Patients taking rivaroxaban at a dose of 2.5 mg also need to take acetylsalicylic acid at a daily dose of 75-100 mg.
The duration of treatment should be determined individually for each patient on the basis of regular assessment and taking into account the risk of thrombotic events in comparison with the risk of bleeding.
In patients with an acute thrombotic event or vascular procedure and the need for dual antiplatelet therapy, continued therapy with Rivaxan 2.5 mg twice daily should be evaluated depending on the type of event or procedure and antiplatelet regimen. The safety and efficacy of rivaroxaban 2.5 mg twice daily in combination with ASA plus clopidogrel/ticlopidine has only been studied in patients with recent ACS. Dual antiplatelet therapy has not been studied in combination with rivaroxaban 2.5 mg twice daily in patients with CHD / PAD.
If the next dose is missed, the patient should take the next dose at the scheduled time in accordance with the recommended regimen. Do not double the dose taken to compensate for the missed one.

Prevention of venous thromboembolism (VTE)
The duration of therapy depends on the type of major orthopedic surgery.
In order to prevent VTE during major orthopedic surgery, rivaroxaban is recommended to prescribe one 10 mg tablet once daily.
Treatment duration:

• 5 weeks after major hip surgery;
• 2 weeks after major knee surgery.

The first dose should be taken 6-10 hours after surgery, provided that hemostasis is achieved.
If a dose is missed, the patient should take Rivaxan immediately and continue treatment on the next day, one tablet daily, as before the missed dose.

Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation
The recommended dose is 20 mg (one tablet) once daily. For patients with moderate renal insufficiency (CC < 50-30 ml/min) the recommended dose of Rivaxan is 15 mg once daily.
Treatment should be continued as long as risk factors for stroke and systemic thromboembolism persist.
If the next dose is missed, the patient should immediately take Rivaxan and on the next day continue to take Rivaxan regularly in accordance with the recommended regimen. Do not double the dose taken to compensate for the missed one.
The recommended maximum daily dose of Rivaxan is 20 mg per day.

Treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT, treatment of pulmonary embolism (PE) and prevention of recurrent PE
The recommended initial dose of Rivaxan is 15 mg twice daily for the first 3 weeks (days 1-21) followed by Rivaxan 20 mg once daily (from Day 22 onwards) for long-term therapy and prevention of recurrent DVT or pulmonary embolism (PE).
Treatment should be continued as long as risk factors for venous thromboembolism persist.
If the next dose is missed while taking a dose of 15 mg twice daily, the patient should immediately take Rivaxan in order to ensure that the daily dose of 30 mg is received. To achieve this, the patient can simultaneously take two tablets of Rivaxan at a dose of 15 mg each. On the next day the patient should continue taking Rivaxan regularly at a dose of 15 mg twice daily in accordance with the recommended regimen.
If the next dose is missed while taking a dose of 20 mg, the patient should immediately take Rivaxan in order to ensure that the daily dose of 20 mg is received. On the next day the patient should continue taking Rivaxan regularly at a dose of 20 mg once a day in accordance with the recommended regimen.

Switching from vitamin K antagonists (VKA) to Rivaxan
2.5 mg tablets:
When switching patients from VKA to Rivaxan, after taking Rivaxan, the INR values ​​will be erroneously high. INR is not suitable for determining the anticoagulant activity of Rivaxan, and therefore should not be used for this purpose (see Section Interaction with other medicines).

10 mg tablets:
For curing patients with deep vein thrombosis (DVT) and preventing recurrent DVT and pulmonary embolism (PE) with INR <2.5, treatment with VKA should be discontinued and treatment with Rivaxan should be started.
When patients switch from VKA to Rivaxan, after taking Rivaxan, the INR values ​​will be erroneously high. INR is not suitable for determining the anticoagulant activity of Rivaxan, and therefore should not be used for this purpose (see Section Interaction with other medicines).

15 mg and 20 mg tablets:
In order to prevent stroke and systemic thromboembolism in patients with INR ≤ 3.0, VKA treatment should be stopped and treatment with Rivaxan should be started.
In patients with the aim of treating deep vein thrombosis (DVT) and preventing recurrent DVT and pulmonary embolism (PE) with INR <2.5, VKA treatment should be discontinued and treatment with Rivaxan should be started.
When patients switch from VKA to Rivaxan, after taking Rivaxan, the INR values ​​will be erroneously high. INR is not suitable for determining the anticoagulant activity of Rivaxan, and therefore should not be used for this purpose (see Section Interaction with other medicines).

Switching from Rivaxan to vitamin K antagonists (VKA)
There is a possibility of an insufficient anticoagulant effect when switching from Rivaxan to VKA. In this regard, it is necessary to ensure a continuous sufficient anticoagulant effect during such a transition using alternative anticoagulants. It should be noted that rivaroxaban may increase INR.
When switching from Rivaxan to VKA, VKA should be taken simultaneously until the INR reaches >2.0. During the first two days of the transition period, a standard dose of VKA should be used, followed by a dose of VKA depending on the INR measurement value. While taking Rivaxan and VKA, the INR should be measured no earlier than 24 hours after taking the previous dose, but before starting the next dose of Rivaxan.
After discontinuation of Rivaxan, a reliable measurement of INR can be carried out 24 hours after taking the last dose of Rivaxan (see Section Interaction with other medicines).

Switching from parenteral anticoagulants to Rivaxan
For patients receiving parenteral anticoagulants, the use of Rivaxan should begin 0-2 hours before the next scheduled parenteral administration of the medicine (e.g. low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration of the medicine (e.g. intravenous administration of unfractionated heparin).

Switching from Rivaxan to parenteral anticoagulants
Rivaxan should be canceled and the first dose of parenteral anticoagulant should be administered at the time when the next dose of Rivaxan has been scheduled.

Special patient groups

Patients with impaired renal function
Limited clinical data obtained in patients with severe renal impairment (CC 15-29 ml/min) indicate that the plasma concentration of rivaroxaban in this patient population is significantly increased. Therefore, rivaroxaban should be used with caution in these patients. The use of Rivaxan is not recommended in patients with CC < 15 ml/min (see Section Warnings and precautions).
Dose adjustment is not required if tablets of 2.5 mg or 10 mg are used in patients with impaired renal function of mild (CC 50-80 ml/min) or moderate (CC 30-49 ml/min) severity.
In patients with impaired renal function of moderate severity (CC 30-49 ml/min) or severe (CC 15-29 ml/min), the following dosing regimen is recommended:

• The recommended dose for prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation is 15 mg once daily.
• For the treatment of DVT and PE, and for prevention of recurrent DVT and PE, patients should take 15 mg tablets twice daily for the first 3 weeks. Thereafter, the recommended dose is 20 mg once daily. Consider reducing the daily dose of rivaroxaban from 20 mg to 15 mg if the patient’s estimated risk of bleeding outweighs the risk of recurrent DVT and PE. The 15 mg dose recommendation is based on pharmacokinetic modeling and has not been studied in this clinical setting.
  Dose adjustment is not required in patients with mild renal impairment (CC 50-80 ml/min).

Patients with impaired liver function
Rivaroxaban is contraindicated in patients with hepatic diseases that occur with coagulopathy leading to a clinically significant risk of bleeding, including patients with cirrhosis of the liver (Child-Pugh classes B and C) (see Section Contraindications).

Elderly patients
Dose adjustment depending on age is not required (see Section Warnings and precautions).

Body weight
Dose adjustment depending on body weight is not required (see Section Warnings and precautions).

Sex
Sex-related dose adjustment is not required.

Children and adolescents
The safety and efficacy of rivaroxaban in children and adolescents under 18 years old have not been established. The use of rivaroxaban is not recommended in children under 18 years old.

Cardioversion
Treatment with rivaroxaban can be initiated or continued in patients who may require cardioversion. In the case of cardioversion accompanied by transesophageal echocardiography (TEE) for patients who have not previously received anticoagulant therapy, rivaroxaban treatment should be started at least 4 hours before cardioversion to ensure proper anticoagulant effect. Prior to initiating cardioversion it should be confirmed that each patient has taken Rivaxan as prescribed. The decision to initiate and continue treatment should be made taking into consideration the approved protocols for anticoagulant treatment in patients undergoing cardioversion.

Administration
Oral formulation
2.5 mg and 10 mg tablets can be taken with or without food.
15 mg and 20 mg tablets should be taken with meals.
For patients who cannot swallow whole tablets, a Rivaxan tablet can be crushed and mixed with water or light food (e.g. apple sauce) immediately before administration.
A crushed tablet of Rivaxan can be administered through a gastric tube. Before taking Rivaxan, the placement of the probe in the stomach should be confirmed. The crushed tablet should be administered with a small amount of water through a gastric tube. After that it must be rinsed with water.

Security profile summary
The safety of rivaroxaban was evaluated in thirteen phase III studies involving 53,103 patients treated with rivaroxaban. The most commonly reported adverse reactions in patients receiving rivaroxaban were bleeding (see Section Warnings and precautions and Description of individual adverse reactions). The most commonly reported bleeding events (>4%) were nosebleed (4.5%) and gastrointestinal bleeding (3.8%).

List of adverse reactions
Adverse reactions are presented by classes of organ systems and frequency of occurrence: very common (≥ 1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); not known (it is impossible to determine the frequency using the available data).

Blood and lymphatic system disorders
Common: anemia (including relevant laboratory parameters);
Uncommon: thrombocythemia (including an increase in the number of platelets)^A, thrombocytopenia.

Immune system disorders
Uncommon: an allergic reaction, allergic dermatitis, angioedema and allergic edema;
Very rare: anaphylactic reactions, including anaphylactic shock.

Nervous system disorders
Common: dizziness, headache;
Uncommon: intracerebral and intracranial hemorrhage, fainting.

Eye disorders
Common: hemorrhage in the eye (including conjunctival hemorrhage).
Cardiac disorders
Uncommon: tachycardia.

Vascular disorders
Common: hypotension, and hematoma.

Respiratory, thoracic and mediastinal disorders
Common: nosebleed, blood spitting.

Gastrointestinal disorders
Common: bleeding gums, gastrointestinal bleeding (including rectal bleeding), pain in the gastrointestinal tract and in the abdomen, dyspepsia, nausea, constipation^A, diarrhea, vomiting^A;
Uncommon: dry mouth.

Hepatobiliary disorders
Common: increased activity of hepatic transaminases;
Uncommon: a violation of liver function, an increase in the concentration of bilirubin, an increase in the activity of alkaline phosphatase^A, an increase in the activity of GGT^A;
Rare: jaundice, increased concentration of conjugated bilirubin (with or without a corresponding increase in ALT activity), cholestasis, hepatitis (including damage to hepatocytes).

Skin and subcutaneous tissue disorders
Common: skin itch (including infrequent cases of pruritus generalisatus), rash, ecchymosis, skin and subcutaneous hemorrhages;
Uncommon: urticaria;
Very rare: Stevens-Johnson syndrome / toxic epidermal necrolysis, DRESS syndrome.

Musculoskeletal and connective tissue disorders
Common: pain in the extremities^A;
Uncommon: hemarthrosis;
Rare: hemorrhage in the muscle;
Not known: compartment syndrome with bleeding.

Renal and urinary disorders
Common: bleeding from the urogenital tract (including hematuria and menorrhagia^B), kidney damage (including increased blood creatinine, increased blood urea)^A;
Not known: renal failure / acute renal failure secondary to bleeding, sufficient to cause hypoperfusion.

General disorders and administration site conditions
Common: fever^A, peripheral edema, decreased overall muscle strength and tone (including weakness and asthenia);
Uncommon: deterioration in general well-being (including malaise);
Rare: localized edema^A.

Laboratory tests and instrumental studies interaction
Uncommon: an increase in LDH^A activity, an increase in lipase^A activity, an increase in amylase^A activity.

Injury, poisoning and procedural complications
Common: bleeding after medical procedures (including postoperative anemia and an issue of blood from a wound), bruise, secretion from the wound^A;
Rare: vascular pseudoaneurysm^C.

A Observed in the prevention of venous thromboembolism (VTE) in adult patients who underwent elective hip or knee replacement;
B Observed in treatment of DVT, PE, and relapse prevention as very common in women < 55 years;
C Observed infrequently in the prevention of atherothrombotic episodes in patients after ACS (after percutaneous coronary angioplasty).

Description of individual adverse reactions
Due to the pharmacological mechanism of rivaroxaban, its use may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which can lead to post-hemorrhagic anemia. Signs, symptoms, and severity (including death) will vary depending on the location and grade or extent of bleeding and/or anemia (see Section Management of bleeding). In clinical studies, mucosal bleeding (i.e. nosebleed, gum bleeding, gastrointestinal bleeding, urinary tract bleeding) and anemia were observed more frequently with long-term rivaroxaban therapy compared with vitamin K antagonist therapy. Thus, in addition to appropriate clinical supervision, laboratory studies of hemoglobin/hematocrit are considered appropriate. The risk of bleeding may increase in certain groups of patients. For example, in patients with uncontrolled severe hypertension and/or concomitant medication that affects hemostasis (see Hemorrhagic risk in the Section Warnings and precautions). An increase and/or extension of menstrual bleeding duration are possible. Hemorrhagic complications may be associated with weakness, pallor, dizziness, headache, or unexplained edema, dyspnea, and unexplained shock. In some cases, as a consequence of anemia, symptoms of cardiac ischemia, such as chest pain or angor pectoris have been observed.

Known complications of severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported with rivaroxaban. Accordingly, the possibility of bleeding should be considered when evaluating any patient using anticoagulants.

Immediately consult your healthcare provider if you experience any adverse reactions. This recommendation applies to any possible adverse reactions, including those not listed in this leaflet. By reporting adverse reactions you help to collect more information about the safety of Rivaxan.

• Hypersensitivity to rivaroxaban or excipients of Rivaxan;
• Active clinically significant bleeding;
• Pathological change or condition associated with an increased risk of massive bleeding. These may include existing or recent gastrointestinal ulcers, malignancies with a high risk of bleeding, recent trauma to the brain or spinal cord, surgery to the brain, spinal cord, or eyes, intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or vessel pathology in the brain or spinal cord;
• Concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.), except in cases of switching from or to rivaroxaban (see Section Dosage and administration) or when using unfractionated heparin in doses necessary to ensure the functioning of a central venous or arterial catheter;
• Liver diseases accompanied by coagulopathy, which causes a clinically relevant risk of bleeding;
• Pregnancy and breast-feeding.

When taking a larger dose than prescribed by a healthcare provider, immediately seek medical advice for timely medical assistance!
Rare cases of overdose have been reported with rivaroxaban up to 600 mg without bleeding or other adverse reactions. Due to limited absorption, the development of a low-level plateau in the concentration of Rivaxan is expected without a further increase in its average concentration in the blood plasma when exceeding therapeutic doses equal to 50 mg and above.
The specific antidote for rivaroxaban is unknown. In case of overdose, activated charcoal can be used to reduce the absorption of rivaroxaban.

Management of bleeding
If a bleeding complication occurs in a patient receiving rivaroxaban, the next dose of Rivaxan should be postponed. When necessary, treatment with Rivaxan should be discontinued. The excretion half-life of rivaroxaban is approximately 5-13 hours. Treatment should be individualized depending on the severity and location of bleeding. If necessary, appropriate symptomatic treatment can be used, such as mechanical compression (e.g. for severe nosebleeds), surgical hemostasis with evaluation of its effectiveness, fluid therapy and hemodynamic support, use of blood products (packed red blood cells or fresh frozen plasma, depending on whether anemia or coagulopathy appears), or platelets.

If the above measures do not eliminate bleeding, specific reversible procoagulant agents can be prescribed; such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (r-FVIIa). However, current experience with these medicinal products in patients receiving rivaroxaban is very limited.

Consideration should be given to re-administration of recombinant factor VIIa and adjusting its dose depending on the effectiveness of the bleeding treatment. In the event of massive bleeding, consultation with a coagulation expert should be considered.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients receiving rivaroxaban. There is no evidence to support the necessity and no experience in using the systemic haemostatic agent desmopressin in patients receiving rivaroxaban. Given the high plasma protein binding, rivaroxaban is not expected to be removed by dialysis.

CYP3A4 and P-glycoprotein inhibitors
Co-administration of rivaroxaban with ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily) resulted in a 2.6/2.5-fold increase in average steady-state AUC, and a 1.7/1.6-fold increase in average C_max rivaroxaban. There was a significant increase in pharmacodynamic effects, which might lead to an increased risk of bleeding. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole antifungals such as ketoconazole, itraconazole, voriconazole, and posaconazole, or HIV protease inhibitors. These medicines are both potent inhibitors of CYP3A4 and P-glycoprotein (P-gp) (see Section Warnings and precautions).
Active agents that inhibit only one of the rivaroxaban elimination routes, mediated by either CYP3A4 or P-gp, are likely to increase plasma concentration of rivaroxaban to a lesser extent. For example, clarithromycin (500 mg twice daily) is considered a potent inhibitor of CYP3A4 and a moderate inhibitor of P-gp. Its administration resulted in a 1.5-fold increase in average rivaroxaban AUC and a 1.4-fold increase in its C_max. This increase was considered clinically insignificant. (For patients with impaired renal function see Section Warnings and precautions).

Erythromycin (500 mg three times a day) moderately inhibits CYP3A4 and P-gp. Its administration resulted in a 1.8-fold increase in the average AUC and C_max of rivaroxaban. This increase was considered clinically insignificant.

When patients with mild renal impairment took erythromycin (500 mg three times a day), a 1.8-fold increase in the average AUC and a 1.6-fold increase in C_max of rivaroxaban was reported, compared to patients with normal renal function. In patients with moderate renal impairment while taking erythromycin, a 2-fold increase in the average AUC of rivaroxaban and a 1.6-fold increase in C_max of rivaroxaban were observed, compared to patients without impaired renal function. The effect of erythromycin is additive to impaired renal function (see Section Warnings and precautions).

Fluconazole (400 mg once daily) is considered a moderate inhibitor of CYP3A4. Its administration resulted in a 1.4-fold increase in the average AUC of rivaroxaban and a 1.3-fold increase in the average C_max. This increase was considered clinically insignificant. (For patients with impaired renal function: see Section Warnings and precautions).
Taking into consideration the limited clinical data available on dronedarone, its co-administration with rivaroxaban should be avoided.

Anticoagulants
After simultaneous use of enoxaparin (40 mg once) with rivaroxaban (10 mg once), an additive effect on anti-factor Xa activity was observed. It was not complemented with additional effects on blood coagulation tests (prothrombin time (PT), aPTT). Enoxaparin had no effect on the pharmacokinetics of rivaroxaban.
Taking into consideration the increased risk of bleeding, caution should be exercised in patients who are simultaneously receiving other anticoagulants (see Sections Contraindications and Warnings and precautions).

Non-steroidal anti-inflammatory drugs (NSAIDs) / platelet aggregation inhibitors
After simultaneous administration of rivaroxaban (15 mg) and naproxen (500 mg), no clinically significant increase in bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in individuals.
No clinically significant pharmacokinetic and pharmacodynamic interactions were identified when rivaroxaban and acetylsalicylic acid (500 mg) were co-administered.
Clopidogrel (loading dose of 300 mg followed by maintenance doses of 75 mg) showed no pharmacokinetic interaction with rivaroxaban (15 mg), but a relevant increase in bleeding time was found in a subgroup of patients, which did not correlate with platelet aggregation and the content of P-selectin or GPIIb/IIIa- receptor.
Caution must be exercised in patients who simultaneously take NSAIDs (including acetylsalicylic acid) and inhibitors of platelet aggregation, since these medicines usually increase the risk of bleeding (see Section Warnings and precautions).

Selective serotonin reuptake inhibitors (SSRIs) / selective serotonin and norepinephrine reuptake inhibitors (SNRIs)
As with other anticoagulants, there may be a possibility that patients are at increased risk of bleeding when Rivaxan is used concomitantly with SSRIs or SNRIs, due to effects on platelets. With simultaneous administration of rivaroxaban during the clinical program, a higher incidence of major or minor clinically significant bleeding was observed in all treatment groups.

Warfarin
When transferring patients from warfarin (INR from 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR from 2.0 to 3.0), PT/INR (Neoplastin) increased more than with a simple summation of effects. Individual INR values ​​can reach 12, while the effect on aPTT, suppression of factor Xa activity and effect on endogenous thrombin potential (ETP) was additive.

If it is necessary to study the pharmacodynamic effects of rivaroxaban during the transition period, experts can use anti-factor Xa activity, prothrombinase-induced clotting time, and the HepTest as necessary tests that are not affected by warfarin. Starting from the 4^th day after discontinuation of warfarin, all laboratory parameters (including PT, aPTT, inhibition of factor Xa activity and EPT) reflect only the effect of rivaroxaban.

If it is necessary to investigate the pharmacodynamic effects of warfarin during the transition period, the INR value at C_trough of rivaroxaban (24 hours after the previous dose of rivaroxaban) can be used, since rivaroxaban has minimal effect on this indicator at that period.
No pharmacokinetic interactions have been reported between warfarin and rivaroxaban.

CYP3A4 inductors
The use of rivaroxaban in conjunction with the potent CYP3A4 inducer rifampicin resulted in an approximately 50% reduction in the average AUC of rivaroxaban while reducing its pharmacodynamic effects. Co-administration of rivaroxaban with other potent CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital, or common or St. John’s wort (Hypericum perforatum)) may also result in decreased plasma levels of rivaroxaban. Therefore, concomitant administration of rivaroxaban with strong CYP3A4 inducers should be avoided unless the patient is closely monitored for signs and symptoms of thrombosis.

Other types of concomitant therapy
Co-administration of rivaroxaban with midazolam (CYP3A4 substrate), digoxin (a P-gp substrate), atorvastatin (CYP3A4 and P-gp substrate), or omeprazole (proton pump inhibitor) did not result in clinically significant pharmacokinetic or pharmacodynamic interactions. Rivaroxaban does not inhibit or induce any of the major CYP isoforms, such as CYP3A4.

Impact on laboratory parameters
Rivaroxaban affects blood coagulation parameters (PT, aPTT, HepTest) due to its mechanism of action.
If you are taking other medicines at the same time, you should consult your healthcare provider.

The efficacy and safety of rivaroxaban have been studied in patients with ACS in combination with acetylsalicylic acid only or with acetylsalicylic acid and clopidogrel or ticlopidine. Combination with other antiaggregants such as prasugrel or ticagrelor has not been studied and is not recommended.
In accordance with generally accepted rules for the use of anticoagulants, clinical observation is recommended throughout the entire period of treatment.

Before taking Rivaxan
Tell your healthcare provider if you have been diagnosed with antiphospholipid syndrome (an immune system disorder that causes an increased risk of blood clots). Your healthcare provider will decide whether you need to change your treatment.

Risk of bleeding
As with other anticoagulants, patients taking rivaroxaban should be closely monitored for signs of bleeding. Rivaxan is recommended to be used with caution in patients with an increased risk of bleeding. Rivaroxaban should be discontinued if severe bleeding occurs.
It has been found in clinical studies that during long-term treatment with rivaroxaban, at the stage of achieving the maximum effect of antithrombotic therapy using one or two medicines, mucosal bleeding (nosebleeds, bleeding gums, gastrointestinal bleeding, bleeding from the urinary tract) and anemia were reported more often. Thus, in addition to proper clinical surveillance, laboratory testing of hemoglobin/hematocrit to detect occult bleeding is considered appropriate.

As indicated below, there is an increased risk of bleeding in certain categories of patients. These patients should be carefully monitored for signs and symptoms of bleeding complications and anemia after initiation of treatment (see Section Possible side effects). In patients receiving rivaroxaban for prevention of VTE after elective hip or knee replacement surgery, this can be done by regular physical examination of patients, careful monitoring of surgical wound drainage, and periodic assessment of hemoglobin levels. Any unexplained decrease in hemoglobin or blood pressure should initiate a search for the source of bleeding.

Although regular monitoring of the drug action is not required during treatment with rivaroxaban, assessment of rivaroxaban levels using a calibrated anti-factor Xa analysis may be useful in exceptional situations where information on rivaroxaban exposure can help guide clinical decision-making (e.g. overdose, and emergency surgery).

Impaired kidney function
In patients with severe renal impairment (CC <30 ml/min), the plasma concentration of rivaroxaban can be significantly increased (1.6-fold on average). It can lead to an increased risk of bleeding. Rivaroxaban should be used with caution in patients with CC 15-29 ml/min. Rivaroxaban is not recommended for use in patients with CC <15 ml/min (see Section Dosage and administration). Rivaroxaban should be used with caution in patients with moderate renal impairment (CC 30-49 ml/min) receiving concomitant therapy. It can lead to an increase in plasma concentrations of rivaroxaban (see Section Interaction with other medicines).

Interaction with other medicines
The use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole antifungals (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These medicines are strong inhibitors of CYP3A4 and P-glycoprotein. Thus, these medicinal products may increase the plasma concentration of rivaroxaban to clinically significant values ​​(2.6-fold on average). This may lead to an increased risk of bleeding.
Caution should be exercised if the patient is simultaneously taking medicines that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors or SSRIs and SNRIs. In patients at risk of developing peptic ulcer in the gastrointestinal tract, appropriate prophylactic treatment can be used (see Section Interaction with other medicines).

Other risk factors for bleeding
As with other antithrombotic agents, rivaroxaban is not recommended for use in patients with an increased risk of bleeding that can be initiated by:

• congenital or acquired clotting disorders
• uncontrolled severe arterial hypertension
• gastrointestinal disease without active ulceration that can potentially lead to bleeding (e.g. inflammatory bowel disease, esophagitis, gastritis, gastroesophageal reflux disease)
• vascular retinopathy
• history of bronchiectasis or an episode of pulmonary hemorrhage.

Rivaroxaban should be used with caution in patients with ACS:

• at the age of ≥ 75 years when combined with acetylsalicylic acid only or with acetylsalicylic acid in combination with clopidogrel or ticlopidine. An individual assessment of the risk-benefit ratio for the treatment being carried out should be carried out regularly.
• with low body weight (<60 kg) when used together with acetylsalicylic acid only or with acetylsalicylic acid in combination with clopidogrel or ticlopidine.

Patients with artificial heart valves
Rivaroxaban should not be used to prevent thrombus formation in patients who have recently undergone transcatheter aortic valve replacement. The efficacy and safety of rivaroxaban have not been studied in patients with artificial heart valves. Therefore, there is no data confirming the adequacy of anticoagulant therapy in this patient population while taking Rivaxan. Rivaxan is not recommended for these patients.

Surgery for hip fracture
Efficacy and safety of rivaroxaban has not been studied in interventional clinical trials in patients undergoing hip fracture surgery.

Patients with non-valvular atrial fibrillation after PCI with stent placement
Clinical data are available from an intervention study which primary purpose is to evaluate safety in patients with non-valvular atrial fibrillation after PCI with stent placement. Efficacy data in this population are limited (see Section Dosage and administration). There are no data on such patients after stroke / transient ischemic attack (TIA).

Hemodynamically unstable patients with PE or patients requiring thrombolysis or pulmonary embolectomy
Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism and hemodynamic instability or when thrombolysis or pulmonary embolectomy is possible. Safety and efficacy of rivaroxaban in these clinical settings have not been established.

Spinal/epidural anesthesia or puncture
When performing neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture, there is a risk of developing epidural or spinal hematoma for patients receiving antithrombotic agents to prevent thromboembolic complications. This can lead to prolonged or permanent paralysis. The risk of developing these phenomena may be increased in case of postoperative use of indwelling epidural catheters or the concomitant use of medicines that affect hemostasis. The risk may also be increased with traumatic or repeated epidural or spinal puncture. Patients should be monitored closely for signs and symptoms of neurological disorders (e.g. numbness or weakness in the legs, bowel or bladder dysfunction). If a neurological disorder is recognized, a diagnosis should be made immediately and treatment initiated. Before performing neuraxial intervention, a healthcare provider should evaluate the potential benefit, taking into account the risk, for patients receiving anticoagulants or for patients who are expected to be prescribed anticoagulants to prevent thrombosis. There is no clinical experience with rivaroxaban (15 mg and 20 mg) in such situations.

To reduce the potential risk of bleeding associated with simultaneous use of rivaroxaban and neuraxial (epidural/spinal) anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. Placement or removal of an epidural catheter or lumbar puncture is best done when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact time to achieve a sufficient level of anticoagulant effect for each patient is unknown.

To remove the epidural catheter, taking into account the main pharmacokinetic characteristics, after the last dose of rivaroxaban, a time equal to at least 2 times the elimination half-life should elapse. It means at least 18 hours for young patients and 26 hours for elderly patients.

Rivaroxaban should not be given earlier than 6 hours after catheter removal.
In the event of a traumatic puncture, the prescription of rivaroxaban should be postponed for 24 hours.

Dosing recommendations before and after invasive procedures and surgery
If an invasive procedure or surgery is required, rivaroxaban 2.5 mg should be discontinued at least 12 hours prior to intervention. If possible rivaroxaban at other doses should be discontinued at least 24 hours prior to intervention, based on a clinical evaluation by a healthcare provider. If there is no need for an antiaggregant effect in a patient undergoing elective surgery, the use of platelet aggregation inhibitors should be discontinued. It is indicated in the patient information leaflet provided by the manufacturer. If the procedure cannot be delayed, the increased risk of bleeding should be assessed, taking into account the urgency of the intervention.
After an invasive procedure or surgery Rivaroxaban should be restarted as soon as possible. This decision should be taken by a healthcare provider if the clinical situation allows and adequate hemostasis has been achieved.

Elderly patients
The risk of bleeding may increase with age.

Dermatological reactions
Development of serious skin reactions, including Stevens-Johnson syndrome / toxic epidermal necrolysis and DRESS syndrome has been reported during post-marketing surveillance in connection with the use of rivaroxaban (see Section Possible side effects). Patients appear to be most at risk for these reactions early in the course of treatment. In most cases the onset of the reaction occurs during the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a serious skin rash (e.g. spreading, intense, and/or blistering rash) or any other sign of hypersensitivity associated with mucosal lesions.

Patients with antiphospholipid syndrome (APS)
It is not recommended to prescribe direct-acting oral anticoagulants, including rivaroxaban in patients diagnosed with antiphospholipid syndrome with a history of thrombosis. Treatment with direct-acting oral anticoagulants may be associated with an increased incidence of recurrent thrombotic events compared with vitamin K antagonist therapy, especially in patients with three positive antiphospholipid syndrome tests (lupus anticoagulant, anticardiolipin antibodies, and antibeta-2-glycoprotein-1 antibodies).

Special information on excipients
Rivaxan contains lactose. Patients with rare hereditary forms of galactose intolerance, lactase deficiency syndrome or glucose-galactose malabsorption syndrome should not take Rivaxan.

If you have one of the diseases or conditions listed above, be sure to consult your healthcare provider before taking Rivaxan.

Pregnancy
Safety and efficacy of rivaroxaban in pregnant women have not been established. Data obtained on experimental animals showed a pronounced toxicity of rivaroxaban for a maternal organism. Due to potential reproductive toxicity, the possible risk of bleeding, and the ability to cross the placenta rivaroxaban is contraindicated during pregnancy (see Section Contraindications).
Rivaroxaban in women of childbearing age should only be used in combination with effective contraceptive methods.

Breast-feeding
Data on the safety and efficacy of rivaroxaban in the treatment of breast-feeding women are not available. Data obtained in experimental animals show that rivaroxaban is excreted in breast milk. Rivaroxaban is contraindicated for use during breast-feeding (see Section Contraindications). The decision must be made whether to stop breast-feeding or to stop treatment.

Rivaroxaban has little effect on the ability to drive and use machines. Adverse reactions such as fainting (uncommon) and dizziness (common) have been reported (see Section Possible side effects). Patients who experience such adverse reactions should not drive vehicles or use mechanisms.

2.5 mg tablets
15 tablets in a blister pack of PVC or two-layer film (PVC/PVDC) and flexible packaging based on aluminum foil. 2 or 4 blister packs with a patient information leaflet in an outer carton.

10 mg, 15 mg, and 20 mg tablets
15 tablets in a blister pack of PVC or two-layer film (PVC/PVDC) and flexible packaging based on aluminum foil. 2 blister packs with a patient information leaflet in an outer carton.

Protect from light and moisture. Store at a temperature not exceeding 25°C.
Keep out of the reach of children.

2 years. Do not use after the expiry date.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en