Therapeutic Indications

• RIVAROX is co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers.
• RIVAROX, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischemic events.
• Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Posology and Method of Administration

Posology

• ACS: Patients taking RIVAROX 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA or a daily dose of 75 - 100 mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine. Treatment should be regularly evaluated in the individual patient weighing the risk for ischemic events against the bleeding risks. Extension of treatment beyond 12 months should be done on an individual patient basis as experience up to 24 months is limited. Treatment with RIVAROX should be started as soon as possible after stabilization of the ACS event (including revascularization procedures); at the earliest 24 hours after admission to hospital and at the time when parenteral anticoagulation therapy would normally be discontinued.
• CAD/PAD: Patients taking RIVAROX 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA.
• Prevention of VTE in Adult Patients Undergoing Elective Hip or Knee Replacement Surgery
• The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that hemostasis has been established.
• The duration of treatment depends on the individual risk of the patient for venous thromboembolism which is determined by the type of orthopedic surgery.
• For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.
• For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended.
• If a dose is missed the patient should take RIVAROX immediately and then continue the following day with once daily intake as before.
• Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
• The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.
• Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.
• When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with RIVAROX 10 mg once daily, a dose of RIVAROX 20 mg once daily should be considered.
• The duration of therapy and dose selection should be individualized after careful assessment of the treatment benefit against the risk for bleeding.

• Aspirin, salicylates or other NSAID (anti-inflammatory) medicines
• Medicines used to thin your blood (such as warfarin, unfractionated heparins, heparin derivatives, low molecular weight heparins (enoxaparin), clopidogrel, tirofiban, bivalirudin, prasugrel, ticagrelor, eptifibatide, ticlopidine, dextran, sulfinpyrazone, rivaroxaban and apixaban).
• Amiodarone, dronedarone, medicines used to treat irregular heartbeats.
• Verapamil, a calcium channel blocker used to treat high blood pressure and angina
• Quinidine, a medicine used to treat malaria and irregular heartbeats
• Clarithromycin or rifampicin, medicines used to treat infections
• Lopinavir, nelfinavir, ritonavir, tipranavir or saquinavir, medicines used to treat HIV infections.
• Cyclosporine or tacrolimus, medicines used to help the body's immune system.
• Selective serotonin re-uptake inhibitors (SSRI) (e.g. citalopram, escitalopram, fluoxetine), selective serotonin norepinephrine re-uptake inhibitors (SNRI) (e.g. duloxetine, venlafaxine, desvenlafaxine), medicines used to treat mood disorders.
• Herbal medicines derived from St John's wort (Hypericum perforatum).
• Carbamazepine, a medicine used to treat fits or convulsions.
• Medicines used to treat reflux and stomach ulcers (such as pantoprazole and ranitidine).

• Prevention of venous thromboembolic events in adult patients who have undergone major orthopedic surgery of the lower limb (elective total hip or knee replacement).
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults.

If a dose is missed the patient should continue with the regular dose as recommended at the next scheduled time. The dose should not be doubled to make up for a missed dose.

Special Populations

• Renal Impairment: Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, RIVAROX is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min. No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min).
• Hepatic Impairment: RIVAROX is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients.
• Elderly Population: No dose adjustment .The risk of bleeding increases with increasing age.
• Body Weight: No dose adjustment
• Gender: No dose adjustment.
• Pediatric Population: The safety and efficacy of RIVAROX in children aged 0 to 18 years have not been established. No data are available. Therefore, RIVAROX is not recommended for use in children below 18 years of age.

RIVAROX is for oral use. The tablets can be taken with or without food.
For patients who are unable to swallow whole tablets, RIVAROX tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally.
The crushed RIVAROX tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water.

• Hypersensitivity to the active substance or to any of the excipients.
• Active clinically significant bleeding.
• Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
• Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
• Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischemic attack (TIA).
• Concomitant treatment of CAD/PAD with ASA in patients with previous hemorrhagic or lacunar stroke, or any stroke within a month.
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.
• Pregnancy and breast-feeding.

In ACS patients, efficacy and safety of RIVAROX 2.5 mg 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 is not recommended.
In patients at high risk of ischemic events with CAD/PAD, efficacy and safety of RIVAROX 2.5 mg have only been investigated in combination with ASA.
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.

• Hemorrhagic Risk: As with other anticoagulants, patients taking RIVAROX are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. RIVAROX administration should be discontinued if severe haemorrhage occurs. In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anemia were seen more frequently during long term rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in addition to adequate clinical surveillance, laboratory testing of hemoglobin/hematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use of RIVAROX in combination with dual antiplatelet therapy in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. In addition these patients are to be carefully monitored for signs and symptoms of bleeding complications and anemia after initiation of treatment. Any unexplained fall in hemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery.
• Renal Impairment: In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. RIVAROX is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min. In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations RIVAROX is to be used with caution.

The use of RIVAROX is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk. Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered.

Other Hemorrhagic Risk Factors As with other antithrombotic, rivaroxaban is not recommended in patients with an increased bleeding risk such as:

• Congenital or acquired bleeding disorders
• Uncontrolled severe arterial hypertension
• Other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, esophagitis, gastritis and gastro esophageal reflux disease)
• Vascular retinopathy
• Bronchiectasis or history of pulmonary bleeding
• It should be used with caution in ACS and CAD/PAD patients:
• ≥ 75 years of age if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine. The benefit-risk of the treatment should be individually assessed on a regular basis.
• With lower body weight (< 60 kg) if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine.
• CAD patients with severe symptomatic heart failure. Study data indicate that such patients may benefit less from treatment with rivaroxaban.

Patients with Prosthetic Valves
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of RIVAROX have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that RIVAROX provides adequate anticoagulation in this patient population. Treatment with RIVAROX is not recommended for these patients.

Patients with Antiphospholipid Syndrome
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Patients with prior stroke and/or TIA Patients with ACS
RIVAROX 2.5 mg is contraindicated 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 indicate that these patients do not benefit from treatment.

Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of RIVAROX 2.5 mg 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.
Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer's prescribing information.

If an invasive procedure or surgical intervention is required, RIVAROX should be stopped at least 12 hours before the intervention, if possible and based on the clinical judgment of the physician. If a patient 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.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
RIVAROX should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician.

Elderly Population: Increasing age may increase hemorrhagic risk.
Dermatological Reactions: Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.

CYP3A4 and P-Gp Inhibitors

Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamics effects which may lead to an increased bleeding risk. Therefore, the use of RIVAROX is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp.
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment.
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.
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 CRmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in CRmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment.
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (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.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants.

NSAIDs/Platelet Aggregation Inhibitors

No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamics response.
No clinically significant pharmacokinetic or pharmacodynamics interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selection or GPIIb/IIIa receptor levels.
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk.

SSRIs/SNRIs

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 programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.

Warfarin

Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (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 pharmacodynamics effects of rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamics effects of warfarin during the conversion period, INR measurement can be used at the Ctrough 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.

CYP3A4 Inducers

Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamics effects. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.

Other Concomitant Therapies

No clinically significant pharmacokinetic or pharmacodynamics interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.
No clinically relevant interaction with food was observed.

Laboratory Parameters

Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban.

• Pregnancy: Safety and efficacy of RIVAROX have not been established in pregnant women. Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, RIVAROX is contraindicated during pregnancy. Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
• Breast-Feeding: Safety and efficacy of RIVAROX have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore RIVAROX is contraindicated during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.
• Fertility: No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).
• Effects on Ability to Drive and Use Machines: RIVAROX has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported. Patients experiencing these adverse reactions should not drive or use machines.

Tabulated List of Adverse Reactions

• 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)
• Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)
All adverse reactions reported in patients in phase III clinical trials or through post-marketing use*

Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.

• Pharmacodynamics properties: Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors,
• Mechanism of Action: Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.
• Pharmacodynamics Effects: Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.
  In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC.
  The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamics effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated, rivaroxaban levels can be measured by calibrated quantitative anti-factor-Xa tests.

• Absorption: Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after tablet intake. Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state than in fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %) ranging from 30% to 40%. Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure. Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.
• Distribution: Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 liters.
• Biotransformation and Elimination: Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the fecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
  Rivaroxaban is metabolized via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
  Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

• This medicinal product does not require any special storage conditions.