XARELTO Rivaroxaban 20mg Film-Coated Tablet 1's

2.5 mg: Rivaroxaban (Xarelto) is indicated for the prevention of cardiovascular death, myocardial infarction and stent thrombosis in patients after an acute coronary syndrome (ACS) (non-ST elevation or ST elevation myocardial infarction or unstable angina) in combination with acetylsalicylic acid (ASA) alone or with ASA plus thienopyridines clopidogrel or ticlopidine (see Dosage & Administration).
Rivaroxaban (Xarelto) is indicated for the prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) in combination with ASA (see Dosage & Administration).
10 mg: Rivaroxaban (Xarelto) is indicated for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.
Rivaroxaban (Xarelto) is indicated for the treatment of Deep Vein Thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE.
15 and 20 mg: Rivaroxaban (Xarelto) is indicated for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF).
Rivaroxaban (Xarelto) is indicated for the treatment of Deep Vein Thrombosis (DVT) and for the prevention of recurrent DVT and Pulmonary Embolism (PE).
Rivaroxaban (Xarelto) is indicated for the treatment of Pulmonary Embolism (PE) and for the prevention of recurrent PE and DVT.

 

2.5 mg: ACS: Method of administration: Oral use.
ACS: Recommended usual dose: After an acute coronary syndrome, the recommended vascular protection regimen is one tablet of 2.5 mg Rivaroxaban (Xarelto) twice daily. Patients should also take a daily dose of 75-100 mg ASA or a daily dose of 75-100 mg ASA in addition to a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine.
ACS: Duration of treatment: Treatment is recommended for at least 24 months.
Patients after ACS continue to be at risk for cardiovascular events and therefore may benefit from extended treatment.
ACS: Method and frequency of administration: Treatment with Rivaroxaban (Xarelto) 2.5 mg should be started as soon as possible after stabilization of the index ACS event (including revascularization procedures). Rivaroxaban (Xarelto) should be started earliest 24 hours after admission to hospital. Rivaroxaban (Xarelto) 2.5 mg should be started at the time when parenteral anticoagulation therapy would normally be discontinued.
One 2.5 mg tablet of Rivaroxaban (Xarelto) should be taken twice daily.
Rivaroxaban (Xarelto) 2.5 mg tablets may be taken with or without food.
For patients who are unable to swallow whole tablets, Rivaroxaban (Xarelto) tablet may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally.
The crushed Rivaroxaban (Xarelto) tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering Rivaroxaban (Xarelto). The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. (see Pharmacology: Pharmacokinetics under Actions).
ACS: Missed Dose: If a dose is missed the patient should continue with the regular 2.5 mg Rivaroxaban (Xarelto) dose as recommended at the next scheduled time.
CAD or PAD: Method of administration: Oral use.
CAD or PAD: Recommended usual dose: The recommended vascular protection regimen for patients with CAD or PAD is one tablet of 2.5 mg Rivaroxaban (Xarelto) twice daily in combination with a daily dose of 75-100 mg ASA.
CAD or PAD: Duration of treatment: Therapy with Rivaroxaban (Xarelto) should be continued long term provided the benefit outweighs the risk.
In patients with an acute thrombotic event or vascular procedure and a need for dual antiplatelet therapy, the continuation of Rivaroxaban (Xarelto) 2.5 mg twice daily should be evaluated depending on type of event or procedure and antiplatelet regimen. Safety and efficacy of Rivaroxaban (Xarelto) 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 (Xarelto) 2.5 mg twice daily in patients with CAD or PAD (see Pharmacology: Pharmacodynamics under Actions).
CAD or PAD: Method and frequency of administration: In patients diagnosed with CAD or PAD, treatment with Rivaroxaban (Xarelto) 2.5 mg twice daily in combination with ASA 75-100 mg once daily can be started at any time.
One 2.5 mg tablet of Rivaroxaban (Xarelto) should be taken twice daily.
Rivaroxaban (Xarelto) 2.5 mg tablets may be taken with or without food.
For patients who are unable to swallow whole tablets, Rivaroxaban (Xarelto) tablet may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally.
The crushed Rivaroxaban (Xarelto) tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering Rivaroxaban (Xarelto). The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water (see Pharmacology: Pharmacokinetics under Actions).
CAD or PAD: Missed Dose: If a dose is missed, the patient should continue with the regular Rivaroxaban (Xarelto) dose as recommended at the next scheduled time.
Additional information on special populations: Patients with hepatic impairment: Rivaroxaban (Xarelto) is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk (see Contraindications).
No dose adjustment is necessary in patients with other hepatic diseases (see Pharmacology: Pharmacokinetics under Actions).
Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child Pugh C) (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: No dose adjustment is required if Rivaroxaban (Xarelto) is administered in patients with mild (Creatinine clearance (CrC): ≤80-50 mL/min) or moderate (CrC: <50-30 mL/min) renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Limited clinical data for patients with severe renal impairment (CrC: <30-15 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore Rivaroxaban (Xarelto) must be used with caution in these patients (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Use of Rivaroxaban (Xarelto) is not recommended in patients with CrC <15 mL/min (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Converting from Vitamin K Antagonists (VKA) to Rivaroxaban (Xareltomisse): When converting patients from VKAs to Rivaroxaban (Xarelto), INR values will be falsely elevated after the intake of Rivaroxaban (Xarelto). The INR is not valid to measure the anticoagulant activity of Rivaroxaban (Xarelto), and therefore should not be used (see Interactions).
Converting from Rivaroxaban (Xarelto) to Vitamin K antagonists (VKA): There is a potential for inadequate anticoagulation during the transition from Rivaroxaban (Xarelto) to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban (Xarelto) can contribute to an elevated INR.
In patients converting from Rivaroxaban (Xarelto) to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard VKA dosing should be used followed by VKA dosing guided by INR testing. While patients are on both Rivaroxaban (Xarelto) and VKA, the INR should not be tested earlier than 24hours (after the previous dose but prior to the next dose of Rivaroxaban (Xarelto). Once Rivaroxaban (Xarelto) is discontinued INR testing may be done reliably 24 hours after the last dose (see Interactions).
Converting from parenteral anti-coagulants to Rivaroxaban (Xarelto): For patients currently receiving a parenteral anticoagulant, start Rivaroxaban (Xarelto) 0 to 2 hours before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin).
Converting from Rivaroxaban (Xarelto) to parenteral anti-coagulants: Discontinue Rivaroxaban (Xarelto) and give the first dose of parenteral anticoagulant at the time that the next Rivaroxaban (Xarelto) dose would be taken.
Children and adolescents (from birth to 16 or 18 years depending on local law): Safety and efficacy have not been established in children and adolescents below 18 years.
Geriatric patients: No dose adjustment is required based on age (see Pharmacology: Pharmacokinetics under Actions).
Gender: No dose adjustment is required based on gender (see Pharmacology: Pharmacokinetics under Actions).
Body weight: No dose adjustment is required based on body weight (see Pharmacology: Pharmacokinetics under Action).
Ethnic differences: No dose adjustment is required based on ethnic differences (see Pharmacology: Pharmacokinetics under Action).
10, 15 and 20 mg: Treatment and prevention of recurrent DVT and PE: Method of administration: Oral use.
Treatment and prevention of recurrent DVT and PE: Recommended usual dose: The recommended dose for the initial treatment of acute DVT and PE is Rivaroxaban (Xarelto) 15 mg twice daily for the first three weeks followed by Rivaroxaban (Xarelto) 20 mg once daily for the continued treatment and the prevention of recurrent DVT and PE. Following completion of at least 6 months treatment for DVT or PE, Rivaroxaban (Xarelto) 10 mg once daily or Rivaroxaban (Xarelto) 20 mg once daily is recommended based on an individual assessment of the risk of recurrent DVT or PE against the risk for bleeding. See Table 14.

Treatment and prevention of recurrent DVT and PE: Duration of treatment: Therapy should be continued as long as the VTE risk persist (see Pharmacology: Pharmacodynamics: SPAF: Clinical efficacy and safety under Actions).
Treatment and prevention of recurrent DVT and PE: Method and frequency of administration: During the initial 3 weeks of acute treatment 15 mg of Rivaroxaban (Xarelto) should be taken twice daily.
After the initial 3 weeks treatment Rivaroxaban (Xarelto) should be continued at 20 mg once daily.
After at least 6 months treatment Rivaroxaban (Xarelto) should be taken at 10 mg once daily or 20 mg once daily (see Pharmacology: Pharmacodynamics under Actions).
Rivaroxaban (Xarelto) 15 mg tablets and Rivaroxaban (Xarelto) 20 mg tablets should be taken with food.
Rivaroxaban (Xarelto) 10 mg tablets may be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
For patients who are unable to swallow whole tablets, Rivaroxaban (Xarelto) tablet may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally. After the administration of crushed Rivaroxaban (Xarelto) 15 mg or Rivaroxaban (Xarelto) 20 mg tablets, the dose should be immediately followed by food.
The crushed Rivaroxaban (Xarelto) tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering Rivaroxaban (Xarelto). The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Rivaroxaban (Xarelto)15 mg or 20 mg tablets, the dose should then be immediately followed by enteral feeding (see Pharmacology: Pharmacokinetics under Actions).
Treatment and prevention of recurrent DVT and PE: Missed Dose: It is essential to adhere to the dosage schedule provided.
If a dose is missed during the 15 mg twice daily treatment phase the patient should take Rivaroxaban (Xarelto) immediately to ensure intake of 30 mg Rivaroxaban (Xarelto) per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
If a dose is missed during the once daily treatment phase the patient should take Rivaroxaban (Xarelto) immediately to ensure intake of the recommended daily dose. The patient should continue with the regular once daily dose as recommended on the following day.
Treatment and prevention of recurrent DVT and PE: Maximum daily dose: The recommended maximum daily dose is 30 mg during the first 3 weeks of treatment.
In the following treatment phase the recommended maximum daily dose is 20 mg.
Treatment and prevention of recurrent DVT and PE: Additional information on special populations: Treatment and prevention of recurrent DVT and PE: Patients with hepatic impairment: Rivaroxaban (Xarelto) is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk (see Contraindications).
No dose adjustment is necessary in patients with other hepatic diseases (see Pharmacology: Pharmacokinetics under Actions).
Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity (see Pharmacology: Pharmacokinetics under Actions).
No clinical data are available for patients with severe hepatic impairment (Child Pugh C) (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
Treatment and prevention of recurrent DVT and PE: Patients with renal impairment: No dose adjustment is required if Rivaroxaban (Xarelto) is administered in patients with mild (Creatinine clearance (CrC): ≤80-50 mL/min) or moderate (CrC: <50-30 mL/min) renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Limited clinical data for patients with severe renal impairment (CrC: <30-15 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore Rivaroxaban (Xarelto) must be used with caution in these patients (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Use of Rivaroxaban (Xarelto) is not recommended in patients with CrC: <15 mL/min (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Treatment and prevention of recurrent DVT and PE: Converting from Vitamin K Antagonists (VKA) to Rivaroxaban (Xarelto): VKA treatment should be stopped and Rivaroxaban (Xarelto) therapy should be initiated once the INR is ≤ 2.5.
When converting patients from VKAs to Rivaroxaban (Xarelto), INR values will be falsely elevated after the intake of Rivaroxaban (Xarelto). The INR is not valid to measure the anticoagulant activity of Rivaroxaban (Xarelto), and therefore should not be used (see Interactions).
Treatment and prevention of recurrent DVT and PE: Converting from Rivaroxaban (Xarelto) to Vitamin K antagonists (VKA): There is a potential for inadequate anticoagulation during the transition from Rivaroxaban (Xarelto) to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban (Xarelto) can contribute to an elevated INR.
In patients converting from Rivaroxaban (Xarelto) to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard VKA dosing should be used followed by VKA dosing guided by INR testing. While patients are on both Rivaroxaban (Xarelto) and VKA, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of Rivaroxaban (Xarelto). Once Rivaroxaban (Xarelto) is discontinued INR testing may be done reliably 24 hours after the last dose (see Interactions).
Treatment and prevention of recurrent DVT and PE: Converting from parenteral anti-coagulants to Rivaroxaban (Xarelto): For patients currently receiving a parenteral anticoagulant, start Rivaroxaban (Xarelto) 0 to 2 hours before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin).
Treatment and prevention of recurrent DVT and PE: Converting from Rivaroxaban (Xarelto) to parenteral anti-coagulants: Discontinue Rivaroxaban (Xarelto) and give the first dose of parenteral anticoagulant at the time that the next Rivaroxaban (Xarelto) dose would be taken.
Treatment and prevention of recurrent DVT and PE: Children and adolescents (from birth to 16 or 18 years depending on local law): Safety and efficacy have not been established in children and adolescents below 18 years.
Treatment and prevention of recurrent DVT and PE: Geriatric patients: No dose adjustment is required based on age (see Pharmacology: Pharmacokinetics under Actions).
Treatment and prevention of recurrent DVT and PE: Gender: No dose adjustment is required based on gender (see Pharmacology: Pharmacokinetics under Actions).
Treatment and prevention of recurrent DVT and PE: Body weight: No dose adjustment is required based on body weight (see Pharmacology: Pharmacokinetics under Actions).
Treatment and prevention of recurrent DVT and PE: Ethnic differences: No dose adjustment is required based on ethnic differences (see Pharmacology: Pharmacokinetics under Actions).
15 and 20 mg: SPAF: Method of administration: Oral use.
SPAF: Recommended usual dose: The recommended dose is 20 mg once daily.
For patients with moderate renal impairment (creatinine clearance (CrC): <50-30 mL/min) the recommended dose is 15 mg once daily.
SPAF: Duration of treatment: Therapy should be continued as long as risk factors for stroke and systemic embolism persist.
SPAF: Method and frequency of administration: One 20 mg tablet of Rivaroxaban (Xarelto) should be taken once daily.
For patients with moderate renal impairment (CrC: <50-30 mL/min) one 15 mg tablet of Rivaroxaban (Xarelto) should be taken once daily.
Rivaroxaban (Xarelto) 15 mg tablets and Rivaroxaban (Xarelto) 20 mg tablets should be taken with food (see Pharmacology: Pharmacokinetics under Actions).
For patients who are unable to swallow whole tablets, Rivaroxaban (Xarelto) tablet may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally. After the administration of crushed Rivaroxaban (Xarelto) 15 mg or Rivaroxaban (Xarelto) 20 mg tablets, the dose should be immediately followed by food.
The crushed Rivaroxaban (Xarelto) tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering Rivaroxaban (Xarelto). The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Rivaroxaban (Xarelto) 15 mg or 20 mg tablets, the dose should then be immediately followed by enteral feeding (see Pharmacology: Pharmacokinetics under Actions).
SPAF: Missed Dose: If a dose is missed the patient should take Rivaroxaban (Xarelto) immediately and continue with the once daily intake as recommended on the following day.
The dose should not be doubled to make up for a missed dose within the same day.
SPAF: Maximum daily dose: The recommended maximum daily dose is 20 mg.
SPAF: Additional information on special populations: SPAF: Patients with hepatic impairment: Rivaroxaban (Xarelto) is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk (see Contraindications).
No dose adjustment is necessary in patients with other hepatic diseases (see Pharmacology: Pharmacokinetics under Actions).
Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child Pugh C) (see Pharmacology: Pharmacokinetics under Actions and Contraindications).
SPAF: Patients with renal impairment: No dose adjustment is required if Rivaroxaban (Xarelto) is administered in patients with mild (creatinine clearance (CrC): ≤80-50 mL/min) renal impairment (see Pharmacology: Pharmacokinetics under Actions).
For patients with moderate (CrC: <50-30 mL/min) renal impairment the recommended dose is 15 mg once daily (see Pharmacology: Pharmacokinetics under Actions).
Limited clinical data for patients with severe renal impairment (CrC: <30-15 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore, Rivaroxaban (Xarelto) 15 mg must be used with caution in these patients (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Use of Rivaroxaban (Xarelto) is not recommended in patients with CrC <15 mL/min (see Pharmacology: Pharmacokinetics under Actions and Precautions).
SPAF: Converting from Vitamin K Antagonists (VKA) to Rivaroxaban (Xarelto): VKA treatment should be stopped and Rivaroxaban (Xarelto) therapy should be initiated when the INR is ≤ 3.0.
When converting patients from VKAs to Rivaroxaban (Xarelto), INR values will be falsely elevated after the intake of Rivaroxaban (Xarelto). The INR is not valid to measure the anticoagulant activity of Rivaroxaban (Xarelto), and therefore should not be used (see Interactions).
SPAF: Converting from Rivaroxaban (Xarelto) to Vitamin K antagonists (VKA): There is a potential for inadequate anticoagulation during the transition from Rivaroxaban (Xarelto) to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban (Xarelto) can contribute to an elevated INR.
In patients converting from Rivaroxaban (Xarelto) to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard VKA dosing should be used followed by VKA dosing guided by INR testing. While patients are on both Rivaroxaban (Xarelto) and VKA, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of Rivaroxaban (Xarelto). Once Rivaroxaban (Xarelto) is discontinued INR testing may be done reliably 24 hours after the last dose (see Interactions).
SPAF: Converting from parenteral anti-coagulants to Rivaroxaban (Xarelto): For patients currently receiving a parenteral anticoagulant, start Rivaroxaban (Xarelto) 0 to 2 hours before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin).
SPAF: Converting from Rivaroxaban (Xarelto) to parenteral anticoagulants: Discontinue Rivaroxaban (Xarelto) and give the first dose of parenteral anticoagulant at the time that the next Rivaroxaban (Xarelto) dose would be taken.
SPAF: Cardioversion: Rivaroxaban (Xarelto) can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Rivaroxaban (Xarelto) treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
SPAF: Patients who undergo PCI (percutaneous coronary intervention) with stent placement: Patients with non-valvular atrial fibrillation who undergo PCI with stent placement should receive reduced dose of 15 mg Rivaroxaban (Xarelto) once daily (or 10 mg Rivaroxaban (Xarelto) once daily for patients with moderate renal impairment [CrCl: <50-30 mL/min]) in addition to a P2Y12 inhibitor. This treatment regimen is recommended for a maximum of 12 months after PCI with stent placement (see Pharmacology: Pharmacodynamics under Actions and Precautions). After completion of the antiplatelet therapy, rivaroxaban dosage should be increased to the standard dose for patients with non-valvular atrial fibrillation.
SPAF: Children and adolescents (from birth to 16 or 18 years depending on local law): Safety and efficacy have not been established in children and adolescents below 18 years.
SPAF: Geriatric patients: No dose adjustment is required based on age (see Pharmacology: Pharmacokinetics under Actions).
SPAF: Gender: No dose adjustment is required based on gender (see Pharmacology: Pharmacokinetics under Actions).
SPAF: Body weight: No dose adjustment is required based on body weight (see Pharmacology: Pharmacokinetics under Actions).
SPAF: Ethnic differences: No dose adjustment is required based on ethnic differences (see Pharmacology: Pharmacokinetics under Actions).

 

Overdosage

2.5-mg & 10-mg tab: May be taken with or without food. 15- & 20-mg tab: Should be taken with food. For patients unable to swallow, tab may be crushed & mixed w/ water or soft foods eg, applesauce immediately prior to taking. The crushed tab may also be administered in a small amount of water via gastric tube then flushed w/ water. After administration of crushed 15 mg or 20 mg tab, the dose should then be immediately followed by food/enteral feeding.

Rivaroxaban (Xarelto) is contraindicated in patients with hypersensitivity to rivaroxaban or any excipient of the tablet (see Excipients/Inactive Ingredients under Description).
Rivaroxaban (Xarelto) is contraindicated in patients with clinically significant active bleeding (e.g., intracranial bleeding, gastrointestinal bleeding).
Rivaroxaban (Xarelto) is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk (see Pharmacology: Pharmacokinetics under Actions).
Safety and efficacy of Rivaroxaban (Xarelto) have not been established in pregnant women. Animal data show that rivaroxaban crosses the placental barrier. Therefore use of Rivaroxaban (Xarelto) is contraindicated throughout pregnancy (see Pharmacology: Toxicology: Preclinical Safety Data under Actions and Use in Pregnancy & Lactation).
Safety and efficacy of Rivaroxaban (Xarelto) have not been established in nursing mothers. Animal data indicate that rivaroxaban is secreted into breast milk. Therefore Rivaroxaban (Xarelto) may only be administered after breastfeeding is discontinued (see Pharmacology: Toxicology: Preclinical Safety Data under Actions and Use in Pregnancy & Lactation).

Patients with prosthetic heart valves: Rivaroxaban (Xarelto) is not recommended for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR) based on data from a randomized controlled clinical study comparing a Xarelto-regimen to an antiplatelet regimen (see Pharmacology: Pharmacodynamics under Actions).
The safety and efficacy of Rivaroxaban (Xarelto) have not been studied in patients with other prosthetic heart valves or other valve procedures; therefore, there are no data to support that Xarelto provides adequate anticoagulation in those patient populations.
Concomitant medication: Rivaroxaban (Xarelto) is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These drugs are strong inhibitors of both CYP 3A4 and P-gp. Therefore, these drugs may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6-fold on average) which may lead to an increased bleeding risk (see Interactions).
The Azole-antimycotic fluconazole, a moderate CYP 3A4 inhibitor, has however less effect on rivaroxaban exposure and can be co-administered (see Interactions).
Renal Impairment: Rivaroxaban (Xarelto) is to be used with caution in patients with moderate renal impairment (CrC: <50-30 mL/min) receiving co-medications leading to increased rivaroxaban plasma concentrations (see Interactions).
In patients with severe renal impairment (CrC: <30 mL/min), rivaroxaban plasma levels may be significantly elevated (1.6-fold on average) which may lead to an increased bleeding risk. Due to the underlying disease these patients are at an increased risk of both bleeding and thrombosis.
Due to limited clinical data Rivaroxaban (Xarelto) should be used with caution in patients with CrCl <30-15 mL/min (see Pharmacology: Pharmacokinetics under Actions).
No clinical data are available for patients with severe renal impairment (CrCl <15 mL/min). Therefore, use of Rivaroxaban (Xarelto) is not recommended in these patients (see Pharmacology and Pharmacokinetics under Actions and Dosage & Administration).
Patients with severe renal impairment or increased bleeding risk and patients receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors are to be carefully monitored for signs of bleeding complications after initiation of treatment (see Interactions).
Effects on ability to drive or use machines: Syncope and dizziness have been reported and may affect the ability to drive and use machines (see Adverse Reactions). Patients experiencing these adverse reactions should not drive or use machines.
2.5 mg: This may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of hemoglobin.
10 mg: In patients receiving Rivaroxaban (Xarelto) for the prevention of venous thromboembolism (VTE) after elective hip or knee replacement surgery, this may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of hemoglobin.
In ACS patients, efficacy and safety of Rivaroxaban (Xarelto) 2.5 mg twice daily have been investigated in combination with the antiplatelet agents ASA alone or ASA plus clopidogrel/ticlopidine. Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and therefore, is not recommended.
Neuraxial (epidural/spinal) anesthesia: When neuraxial (epidural/spinal) anesthesia or spinal puncture is performed, patients treated with antithrombotics for prevention of thromboembolic complications are at risk for development of an epidural or spinal hematoma which may result in long-term paralysis.
The risk of these events is even further increased by use of indwelling epidural catheters or the concomitant use of drugs affecting hemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are noted, urgent diagnosis and treatment is necessary.
The physician should consider the potential benefit versus the risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
There is no clinical experience with the use of 2.5 mg twice daily with ASA alone or with ASA plus clopidogrel or ticlopidine in these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
The concomitant use of platelet aggregation inhibitors should be considered and such medication discontinued as appropriate.
10 mg: An epidural catheter should not be withdrawn earlier than 18 hours after the last administration of Rivaroxaban (Xarelto).
15 and 20 mg: There is no clinical experience with the use of 15 mg and 20 mg rivaroxaban in these situations.
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life should elapse, i.e. at least 18 hour in young patients and 26 hours in elderly patients, after the last administration of Rivaroxaban (Xarelto) (see Pharmacology: Pharmacokinetics under Actions).
Rivaroxaban (Xarelto) should be administered at earliest 6 hours after the removal of the catheter.
If traumatic puncture occurs, the administration of Rivaroxaban (Xarelto) should be delayed for 24 hours.
Patients with high risk triple positive antiphospholipid syndrome: Rivaroxaban (Xarelto) is not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome and are persistently triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies) as treatment with rivaroxaban is associated with an increased rate of recurrent thrombotic events compared with vitamin K antagonists (VKA) (see Pharmacology: Pharmacodynamics under Actions).
Bleeding risk: Rivaroxaban (Xarelto) like other antithrombotics should be used with caution in patients with an increased bleeding risk such as: congenital or acquired bleeding disorders; uncontrolled severe arterial hypertension; active ulcerative gastrointestinal disease; recent gastrointestinal ulcerations; vascular retinopathy; recent intracranial or intracerebral hemorrhage; intraspinal or intracerebral vascular abnormalities; recent brain, spinal or ophthalmological surgery; bronchiectasis or history of pulmonary bleeding.
Care should be taken if patients are treated concomitantly with drugs affecting hemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other antithrombotics, or selective serotonin reuptake inhibitors (SSRI), and serotonin norepinephrine reuptake inhibitors (SNRIs), (see Interactions).
Patients on treatment with Rivaroxaban (Xarelto) and ASA or with Rivaroxaban (Xarelto) and ASA plus clopidogrel/ticlopidine should only receive chronic concomitant treatment with NSAIDS if the benefit outweighs the bleeding risk.
For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see Interactions).
Any unexplained fall in hemoglobin or blood pressure should lead to a search for a bleeding site.
Surgery and interventions: If an invasive procedure or surgical intervention is required, Rivaroxaban (Xarelto) should be stopped at least 24 hours before the intervention, if possible and based on clinical judgment of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
If a patient concomitantly receiving platelet aggregation inhibitors is to undergo elective surgery and anti-platelet effect is not desired, platelet aggregation inhibitors should be discontinued as directed by the manufacturer's prescribing information.
Rivaroxaban (Xarelto) should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate hemostasis has been established (see Pharmacology: Pharmacokinetics under Actions).
Women of childbearing potential: Rivaroxaban (Xarelto) should be used in women of childbearing potential only with effective contraception.
QTc prolongation: No QTc prolonging effect was observed with Rivaroxaban (Xarelto) (see Pharmacology: Pharmacokinetics under Actions).
Information about excipients: Since this medicinal product contains lactose, patients with rare hereditary problems of lactose or galactose intolerance (e.g., the Lapp lactase deficiency or glucose-galactose malabsorption) should not take Rivaroxaban (Xarelto) (see Description).
2.5 mg: ACS, CAD or PAD: Patients with prior stroke and/or TIA: ACS: Rivaroxaban (Xarelto) 2.5 mg twice daily should be avoided for the treatment of ACS in patients with a prior stroke or TIA. Few ACS patients with a prior stroke or TIA have been studied, but the limited efficacy data available indicates that these patients may not benefit from treatment.
CAD or PAD: Patients with haemorrhagic or lacunar stroke: CAD or PAD patients with previous haemorrhagic or lacunar stroke were not studied. Treatment with Rivaroxaban (Xarelto) 2.5 mg twice daily in combination with ASA should be avoided in these patients.
Patients with ischemic, non-lacunar stroke: CAD or PAD patients who have experienced an ischemic, non-lacunar stroke within the previous month were not studied. Treatment with Rivaroxaban (Xarelto) 2.5 mg twice daily in combination with ASA should be avoided in the first month after stroke (see Pharmacology: Pharmacokinetics under Actions).
10, 15 and 20 mg: Treatment and prevention of recurrent DVT and PE: Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Rivaroxaban (Xarelto) is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Rivaroxaban (Xarelto) have not been established in these clinical situations.
10 mg: Hip fracture surgery: Rivaroxaban (Xarelto) has not been studied in interventional clinical trials in patients undergoing hip fracture surgery. Limited clinical data from a non-interventional study are available for patients undergoing fracture related surgery of the lower limbs such as hip fracture surgery (see Pharmacology: Pharmacodynamics under Actions).
15 and 20 mg: SPAF: Patients who undergo PCI with stent placement: Clinical data are available from an interventional study with the primary objective to assess safety in patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see Pharmacology: Pharmacodynamics under Actions and Dosage & Administration).

 

Use In Pregnancy & Lactation

Summary of the safety profile: 2.5 mg: The safety of rivaroxaban has been evaluated in thirteen phase III studies including 53,103 patients exposed to rivaroxaban, as listed in the following table: See Table 15.

In patients treated with 10 mg Rivaroxaban (Xarelto) undergoing hip or knee replacement surgery and in hospitalized medically ill patients, bleeding events occurred in approximately 6.8% and 12.6% of patients, respectively, and anemia occurred in approximately 5.9% and 2.1% of patients, respectively. In patients treated with either 15 mg twice daily Rivaroxaban (Xarelto) followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 23% of patients and anemia occurred in approximately 1.6% of patients. In patients treated for prevention of stroke and systemic embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and anemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of any type or severity was reported with an event rate of 22 per 100 patient years. Anemia was reported with an event rate of 1.4 per 100 patient years. In patients treated for prevention of stroke, myocardial infarction and cardiovascular death, and prevention of acute limb ischemia and mortality in patients with CAD or PAD, bleeding of any type or severity was reported with an event rate of 6.7 per 100 patient years. Anemia was reported with an event rate of 0.15 per 100 patient years*.
*A pre-specified selective approach to adverse event collection was applied.
Due to the pharmacological mode of action, Rivaroxaban (Xarelto) may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in post hemorrhagic anemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension and/or on concomitant medication affecting hemostasis (see Precautions).
The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anemia (see Overdosage).
Hemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnea, and unexplained shock. In some cases as a consequence of anemia, symptoms of cardiac ischemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for Rivaroxaban (Xarelto). Therefore, the possibility of a hemorrhage should be considered in evaluating the condition in any anticoagulated patient.
10, 15 and 20 mg: The safety of rivaroxaban has been evaluated in twelve phase III studies including 34,859 patients exposed to rivaroxaban, as listed in the following table: See Table 16.

In total about 65% of patients exposed to at least one dose of rivaroxaban were reported with treatment emergent adverse events. About 21% of patients experienced adverse events considered related to treatment as assessed by investigators. In patients treated with 10 mg Rivaroxaban (Xarelto) undergoing hip or knee replacement surgery and in hospitalized medically ill patients, bleeding events occurred in approximately 6.8% and 12.6% of patients, respectively, and anemia occurred in approximately 5.9% and 2.1% of patients, respectively. In patients treated with either 15 mg twice daily Rivaroxaban (Xarelto) followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 23% of patients and anemia occurred in approximately 1.6% of patients. In patients treated for prevention of stroke and systemic embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and anemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of any type or severity was reported with an event rate of 22 per 100 patient years. Anemia was reported with an event rate of 1.4 per 100 patient years.
Due to the pharmacological mode of action, Rivaroxaban (Xarelto) may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in post hemorrhagic anemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension and/or on concomitant medication affecting hemostasis (see Precautions).
The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anemia (see Overdosage).
Hemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnea, and unexplained shock. In some cases as a consequence of anemia, symptoms of cardiac ischemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for Rivaroxaban (Xarelto). Therefore, the possibility of a hemorrhage should be considered in evaluating the condition in any anticoagulated patient.
Tabulated list of adverse reactions: The frequencies of ADRs reported with Rivaroxaban (Xarelto) are summarized in the table as follows. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000).
2.5 mg: See Table 17.

10, 15 and 20 mg: See Table 18.

Post marketing observations: The following adverse reactions have been reported post-marketing in temporal association with the use of Rivaroxaban (Xarelto). The frequency of these adverse reactions reported from post-marketing experience cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III trials, these events were uncommon (≥1/1,000 to <1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III trials, these events were rare (≥1/10,000 to <1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events were uncommon (≥1/1,000 to <1/100)).

 

Pharmacokinetic interactions: Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp) / breast cancer resistance protein (Bcrp) transporter systems.
CYP Inhibition: Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.
CYP Induction: Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.
Effects on rivaroxaban: The concomitant use of Rivaroxaban (Xarelto) with strong CYP 3A4 and P-gp inhibitors, may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure.
Co-administration of Rivaroxaban (Xarelto) with the azole-antimycotic ketoconazole (400 mg once daily) a strong CYP 3A4 and P-gp inhibitor, led to a 2.6-fold increase in mean rivaroxaban steady state AUC and a 1.7-fold increase in mean rivaroxaban C_max, with significant increases in its pharmacodynamic effects.
Co-administration of Rivaroxaban (Xarelto) with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP 3A4 and P-gp inhibitor, led to a 2.5-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in mean rivaroxaban C_max, with significant increases in its pharmacodynamic effects.
Therefore Rivaroxaban (Xarelto) is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see Precautions).
Other active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP 3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice daily), considered as strong CYP 3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in C_max. This increase, which is close to the magnitude of the normal variability of AUC and C_max, is considered as clinically not relevant.
Erythromycin (500 mg three times daily), which inhibits CYP 3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and C_max. This increase is within the magnitude of the normal variability of AUC and C_max and is considered as clinically not relevant.
In subjects with mild renal impairment, erythromycin (500 mg three times a day) led to a 1.8-fold increase in mean rivaroxaban AUC and 1.6-fold increase in C_max when compared to subjects with normal renal function without co-medication. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in mean rivaroxaban AUC and 1.6-fold increase in C_max when compared to subjects with normal renal function without co-medication (see Precautions).
Fluconazole (400 mg once daily), considered as moderate CYP 3A4 inhibitor, led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean C_max. This increase is within the magnitude of the normal variability of AUC and C_max and is considered as clinically not relevant (see Precautions).
Co-administration of Rivaroxaban (Xarelto) with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects (see Pharmacology: Pharmacokinetics under Actions).
The concomitant use of Rivaroxaban (Xarelto) with other strong CYP 3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbitone or St. John's Wort) may also lead to a decreased rivaroxaban plasma concentration.
2.5 mg: Strong CYP 3A4 inducers must be used with caution in ACS, or CAD or PAD patients treated with 2.5 mg Rivaroxaban (Xarelto) twice daily.
10 mg: The decrease in rivaroxaban plasma concentrations is considered as clinically not relevant for patients treated with 10 mg Rivaroxaban (Xarelto) once daily for prevention of VTE after major orthopedic surgery of the lower limbs.
15 mg and 20 mg: Strong CYP 3A4 inducers should be co-administered with caution (see Pharmacology: Pharmacokinetics under Actions).
Pharmacodynamic interactions: After combined administration of enoxaparin (40 mg single dose) with Rivaroxaban (Xarelto) (10 mg single dose), an additive effect on anti-factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban (see Precautions).
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction (with Rivaroxaban (Xarelto) 15 mg) but a relevant increase in bleeding times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see Precautions).
No clinically relevant prolongation of bleeding time was observed after concomitant administration of Rivaroxaban (Xarelto) (15 mg) and 500 mg naproxen. Nevertheless there may be individuals with more pronounced pharmacodynamic response (see Precautions).
Converting patients from warfarin (INR 2.0 to 3.0) to Rivaroxaban (Xarelto) (20 mg) or from Rivaroxaban (Xarelto) (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of Rivaroxaban (Xarelto) during the conversion period, anti-factor Xa activity, PiCT, and HepTest can be used as these tests were not affected by warfarin. From day 4 after stopping warfarin onwards, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of Rivaroxaban (Xarelto) (see Dosage & Administration).
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the C_trough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and Rivaroxaban (Xarelto).
As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical program, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.
Food and dairy products: 2.5 and 10 mg: 2.5 mg and 10 mg Rivaroxaban (Xarelto) can be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
15 and 20 mg: Rivaroxaban (Xarelto) 15 mg tablets and Rivaroxaban (Xarelto) 20 mg tablets should be taken with food (see Pharmacology: Pharmacokinetics under Actions).
Interactions shown not to exist: There were no mutual pharmacokinetic interactions between rivaroxaban and midazolam (substrate of CYP 3A4), digoxin (substrate of P-glycoprotein) or atorvastatin (substrate of CYP 3A4 and P-gp).
Co-administration of the proton pump inhibitor omeprazole, the H₂ receptor antagonist ranitidine, the antacid aluminum hydroxide/magnesium hydroxide, naproxen, clopidogrel or enoxaparin did not affect rivaroxaban bioavailability and pharmacokinetics.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Rivaroxaban (Xarelto) was co-administered with 500 mg acetylsalicylic acid.
Interactions with laboratory parameters: Clotting parameter tests (PT, aPTT, HepTest) are affected as expected by the mode of action of Rivaroxaban (Xarelto) (see Pharmacology: Pharmacodynamics under Actions).

 

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Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)