Rivaroxaban Tablets Instructions

Date of approval.
Date of revision.
Rivaroxaban Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
 Warnings
A. Early discontinuation of rivaroxaban will increase the risk of thromboembolic events.
Early discontinuation of any oral anticoagulant, including rivaroxaban, will increase the risk of thromboembolic events. To reduce this risk, consider giving another anticoagulant if early discontinuation of rivaroxaban is necessary for reasons other than pathologic bleeding or completed therapy.
B. Spinal/epidural hematoma.
Spinal/epidural hematomas have occurred in patients treated with rivaroxaban while undergoing epidural anesthesia or spinal puncture. These hematomas may result in long-term or permanent paralysis. These risks need to be considered when scheduling patients for spinal surgery. Factors that may place these patients at increased risk for epidural or spinal hematomas include: use of indwelling catheters; concomitant use of other medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; history of traumatic or repeated epidural or spinal punctures; and history of spinal deformity or spinal surgery. The optimal interval between rivaroxaban administration and intralesional surgery is unknown (see [PRECAUTIONS] and [ADVERSE REACTIONS]).
Close observation of the patient is required to detect signs and symptoms of neurological impairment. If neurological impairment is detected, emergency treatment must be administered. For patients who have received or are about to receive anticoagulation to prevent thrombosis, an assessment of benefit and risk should be performed prior to epidural anesthesia or spinal tap (see [Precautions] Spinal Tap/Epidural Anesthesia).
Drug Name]
Generic name: Rivaroxaban Tablets
English name: Rivaroxaban Tablets
Hanyu Pinyin：Lifashaban Pian
Ingredients
Main ingredients: Rivaroxaban
Chemical Name.
5-Chloro-azo-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-azolidin-5-yl}methyl)-2-thiophene-carboxamide
Chemical structure formula.
Molecular formula: C19H18ClN3O5S
Molecular weight: 435.89
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Used for adult patients with elective hip or knee replacement surgery to prevent venous thrombosis (VTE).
For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults; for reducing the risk of DVT and/or PE recurrence in patients with a persistent risk of DVT and/or PE recurrence after completion of at least 6 months of initial therapy. (See [Caution] for patients with hemodynamically unstable PE)
For use in adult patients with non-valvular atrial fibrillation with one or more risk factors (e.g., congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, history of stroke or transient ischemic attack) to reduce the risk of stroke and body circulation embolism.
There are limited data on the relative effectiveness of rivaroxaban in reducing the risk of stroke and embolism of the body circulation compared with warfarin under well-controlled conditions treated with warfarin.
Specification
10mg
Dosage]
Rivaroxaban Mode of administration.
Oral.
Rivaroxaban 10mg can be taken with food or alone.
Rivaroxaban 15mg or 20mg tablets should be taken with food.
Prevention of venous thrombosis in adult patients undergoing elective hip or knee replacement surgery.
The recommended dose is 10 mg of oral rivaroxaban once daily. If the wound has stopped bleeding, the first dose should be administered between 6 and 10 hours after surgery.
For patients undergoing major hip surgery, the recommended course of treatment is 35 days.
For patients who have undergone major knee surgery, the recommended course of treatment is 12 days.
In the event of a missed dose, patients should take rivaroxaban immediately and continue to take it once daily the following day.
Treating DVT and PE and reducing the risk of DVT and PE recurrence
The recommended dose for initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks; after the initial treatment period, the recommended dose for subsequent treatment is 20 mg orally once daily, given at approximately the same time each day. Short-term therapy (at least 3 months) should be considered for patients with DVT or PE caused by a significant transient risk factor (e.g., recent major surgery or trauma). Patients with DVT or PE caused by something other than a significant one-off risk factor, patients with unprovoked DVT or PE, or patients with a history of recurrent DVT or PE should be considered for longer-term treatment.
For patients with persistent risk of DVT and/or PE after completion of at least 6 months of standard anticoagulation therapy, to reduce the risk of DVT and/or PE recurrence, rivaroxaban 10 mg orally once daily is recommended. For patients at high risk of DVT or PE recurrence (e.g., patients with complex comorbidities or patients receiving rivaroxaban 10 mg once daily who develop DVT or PE recurrence), rivaroxaban 20 mg once daily should be considered.
After careful assessment of treatment benefit versus bleeding risk, treatment duration and dose selection should be determined on an individual basis (see [Caution]). As shown in Table 1.
Table 1. Dosing regimens for rivaroxaban tablets for DVT and PE
 Time Period Dosing Regimen Total Daily Dose for Treatment and Reduction of Risk of DVT and PE Recurrence Day 1 – Day 21 15 mg twice daily 30 mg from Day 22 onwards 20 mg once daily 20 mg to reduce the risk of DVT and PE recurrence after completion of at least 6 months of DVT or PE treatment 10 mg once daily, or
20 mg once daily 10 mg
or 20 mg If a missed dose occurs during the 15 mg twice daily treatment period (days 1 – 21), the patient should immediately take rivaroxaban to ensure that 30 mg of rivaroxaban is taken daily. Two 15 mg tablets at a time may be required in this situation. Thereafter, the patient should continue to receive the regular twice-daily 15 mg dose in accordance with dosing recommendations.
If a missed dose occurs during the 20 mg once-daily treatment, the patient should immediately take rivaroxaban and continue to receive the recommended once-daily dose the following day. Avoid doubling the dose over the course of the day to compensate for missed doses.
For adult patients with non-valvular atrial fibrillation to reduce the risk of stroke and embolism of the body circulation
The recommended dose is 20 mg once daily, which is also the maximum recommended dose. For patients with low body weight and advanced age (> 75 years), 15 mg once daily may be used at the discretion of the physician, depending on the patient’s condition.
Long-term therapy should be received in cases where the benefit of rivaroxaban for stroke and body circulation embolism prevention outweighs the risk of bleeding (see [Precautions]).
If a missed dose occurs, the patient should take rivaroxaban immediately and continue to receive once-daily dosing the following day. The dose should not be doubled within a day to compensate for the missed dose.
Discontinuation for surgery and other interventions
If anticoagulation therapy must be discontinued to reduce the risk of bleeding during surgery or other interventions, rivaroxaban must be discontinued at least 24 hours prior to the intervention to reduce the risk of bleeding. The elevated risk of bleeding must be weighed against the urgency of the intervention when deciding whether to delay an intervention until 24 hours after the last dose of rivaroxaban. Given the rapid onset of rivaroxaban, rivaroxaban should be reintroduced as soon as it is determined that adequate hemostasis has been achieved after a surgical or other interventional procedure. Consider giving a non-oral anticoagulant if oral medications cannot be taken during or after the surgical intervention.
Dosing options
For patients who cannot swallow the entire tablet, 10 mg, 15 mg, or 20 mg rivaroxaban tablets may be crushed and mixed with applesauce and taken orally immediately prior to dosing. Crushed rivaroxaban 15mg or 20mg tablets should be eaten immediately after administration.
Administration via nasogastric (NG) or gastric feeding tube: When the position of the gastric tube in the stomach is determined, 10mg, 15mg or 20mg rivaroxaban tablets can also be crushed and mixed with 50mL of water to form a suspension and administered via nasogastric or gastric feeding tube. Since the absorption of rivaroxaban is dependent on the site of drug release, administration distal to the stomach should be avoided, as administration distal to the stomach may decrease drug absorption and thus drug exposure. Food should be given by enteral nutrition immediately after administration of crushed rivaroxaban 15 mg or 20 mg tablets.
Crushed 10 mg, 15 mg, or 20 mg rivaroxaban tablets are stable in water or applesauce for up to 4 hours. In vitro compatibility studies have shown that rivaroxaban does not adsorb from the suspension into PVC or silicone nasogastric tubes.
Conversion from vitamin K antagonist (VKA) to rivaroxaban
For patients at reduced risk of stroke and embolism in the body circulation, VKA should be discontinued and rivaroxaban therapy initiated at an international normalized ratio (INR) ≤3.0.
For patients treated for DVT and PE to reduce the risk of recurrence of DVT and PE, discontinue VKA and initiate rivaroxaban therapy at an international normalized ratio (INR) ≤ 2.5.
Conversion of patients receiving treatment from VKA to rivaroxaban results in a pseudo-elevation of INR values, but is not a valid indicator of rivaroxaban anticoagulant activity; therefore, the use of INR to evaluate the anticoagulant activity of rivaroxaban is not recommended.
Conversion from rivaroxaban to vitamin K antagonist (VKA)
Inadequate anticoagulation may occur during the conversion of rivaroxaban to VKA. Conversion to any other anticoagulant should be done to ensure continued adequate anticoagulation. It should be noted that rivaroxaban can promote an increased INR.
For patients converting from rivaroxaban to VKA, VKA and rivaroxaban should be administered in combination until INR ≥ 2.0. The standard starting dose of VKA should be used for the first two days of the conversion period, and the dose of VKA administered should subsequently be adjusted based on INR findings. When patients are given rivaroxaban in combination with VKA, the INR should be tested 24 hours after the administration of rivaroxaban and before the next administration of rivaroxaban. After discontinuation of rivaroxaban, a reliable INR value can be detected at least 24 hours after the last dose.
Conversion from non-oral anticoagulant to rivaroxaban
For patients receiving non-oral anticoagulants, non-continuous administration (e.g. subcutaneous low molecular heparin), the non-oral anticoagulant should be discontinued at the next scheduled dose and rivaroxaban should be started 0 to 2 hours prior, and for continuous administration (e.g. regular heparin IV), rivaroxaban should be started at the time of discontinuation.
Switch from rivaroxaban to a non-oral anticoagulant
Discontinue rivaroxaban and give the first dose of a non-oral anticoagulant at the next scheduled dosing time of rivaroxaban.
Special Populations
Patients with renal impairment
Patients with mild renal impairment (creatinine clearance CrCl: 50-80 mL/min) do not need to adjust the dose of rivaroxaban.
In patients with moderate (creatinine clearance 30 – 49 mL/min) or severe renal impairment (creatinine clearance 15-29 mL/min), the following is recommended.
– In adult patients undergoing elective hip or knee arthroplasty for the prevention of venous thrombosis, no dose adjustment is required in those with moderate renal impairment (creatinine clearance 30 – 49 mL/min). Avoid using rivaroxaban in patients with CrCl <30mL/min.
– When used to treat DVT and PE and reduce the risk of recurrence of DVT and PE: For patients with moderate renal impairment (creatinine clearance 30 – 49 mL/min), patients should receive 15 mg twice daily for the first three weeks. Thereafter, when the recommended dose is 20 mg once daily, if the assessment yields that the patient’s risk of bleeding exceeds the risk of DVT and PE recurrence, a dose reduction from 20 mg once daily to 15 mg once daily must be considered. The recommendation to use 15 mg is based on the PK model and has not been clinically studied. When the recommended dose is 10 mg once daily, no adjustment of the recommended dose is required. Rivaroxaban should be avoided in patients with CrCl <30 mL/min.
– The recommended dose is 15 mg once daily when used in adult patients with non-valvular atrial fibrillation to reduce the risk of stroke and embolism of the body circulation. Avoid rivaroxaban in patients with creatinine clearance <15mL/min.
Patients with hepatic impairment
Rivaroxaban is contraindicated in patients with liver disease with coagulation abnormalities and risk of clinically relevant bleeding, including patients with cirrhosis who have reached Child Pugh Class B and C.
Gender
No dose adjustment is required.
Adult patients with non-valvular atrial fibrillation undergoing cardioversion
Patients requiring cardioversion may be started or continued on rivaroxaban.
For patients who have not been previously treated with anticoagulants and are undergoing transesophageal echocardiography (TEE)-guided cardioversion, rivaroxaban should be initiated at least 4 hours prior to cardioversion to ensure adequate anticoagulation. For all patients, it should be confirmed that the patient has been pre-treated with rivaroxaban prior to cardioversion. For patients undergoing cardioversion, existing guideline recommendations should be considered when deciding when to initiate anticoagulation therapy and the duration of anticoagulation therapy.
Adverse reactions]
The following adverse reactions are also discussed in other sections of this instruction.
Increased risk of stroke after early discontinuation in patients with non-valvular atrial fibrillation (see [WARNINGS] and [PRECAUTIONS])
Risk of hemorrhage (see [Caution])
Spinal/epidural hematoma (see [Cautionary Note] and [Caution])
Clinical Trials
The incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared to the incidence observed in clinical trials of another drug due to the different conditions under which clinical trials are conducted and may not reflect the incidence observed in clinical practice.
During clinical development for approved indications, rivaroxaban was administered to 18,560 patients. This included 7111 patients who received rivaroxaban 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of non-valvular atrial fibrillation stroke and embolism in the body circulation (ROCKET AF); 6962 patients who received rivaroxaban 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or received 10 mg or 20 mg orally once daily (EINSTEIN Extension, Einstein Choice) for DVT and PE and to reduce the risk of DVT and/or PE recurrence; 4487 patients receiving rivaroxaban 10 mg oral, once-daily treatment to prevent DVT after hip or knee replacement surgery (RECORD 1-3).
Bleeding.
The most common adverse reaction with rivaroxaban was bleeding (see [PRECAUTIONS]).
Use in adult patients with non-valvular atrial fibrillation to reduce the risk of stroke and body circulation embolism
In the ROCKET AF trial, the most common adverse reaction associated with permanent discontinuation was bleeding events, with an incidence of 4.3% in the rivaroxaban group and 3.1% in the warfarin group. The incidence of discontinuation for non-bleeding adverse events was close in both treatment groups. Table 2 shows the number of patients who experienced various types of bleeding events in the ROCKET AF study.
Table 2: Bleeding events in the ROCKET AF* study – treatment period plus 2 days
Parameters Rivaroxaban
N = 7111
n (%/year) Warfarin
N = 7125
n (%/year) Rivaroxaban compared with warfarin
HR
(95% CI) major bleeding†395 (3.6) 386 (3.5) 1.04 (0.90, 1.20) intracranial hemorrhage (ICH)‡55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) hemorrhagic stroke§36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) other ICH19 (0.2) 26 (0.2) 0.74 (0.41, 1.34) Gastrointestinal bleeding (GI) ¶221 (2.0) 140 (1.2) 1.61 (1.30, 1.99) Fatal bleeding #27 (0.2) 55 (0.5) 0.50 (0.31, 0.79) ICH24 (0.2) 42 (0.4) 0.58 (0.35, 0.96) Non Intracranial hemorrhage 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82) Abbreviations: HR = risk ratio, CI = confidence interval, CRNM = clinically significant non-significant.
* For all subtypes of major bleeding events, individual patients were counted only once; however, patients may have events attributed to multiple subtypes. These events occurred during treatment or within 2 days of stopping treatment.
† Defined as clinically significant bleeding associated with a decrease in hemoglobin ≥2 g/dL, transfusion of ≥2 units of concentrated red blood cells or whole blood, bleeding from a critical site, or associated with a lethal outcome.
‡ Intracranial hemorrhagic events include intracerebral parenchymal, intraventricular, subdural, subarachnoid, and/or epidural hematomas.
§ For the purposes of this table, hemorrhagic stroke-specific refers to nontraumatic intraparenchymal and/or intracerebroventricular hematomas in patients within the treatment period plus 2 days.
¶ Gastrointestinal bleeding events include upper gastrointestinal, lower gastrointestinal, and rectal bleeding.
# Fatal hemorrhage was adjudged to be the primary cause of death from bleeding.
 Figure 1 provides the risk of major bleeding events in each major subgroup.
Figure 1: Risk of major bleeding events in ROCKET AF by baseline characteristics – treatment period plus 2 days
Note: The figure above provides the impact in each subgroup, all of which are classified as baseline characteristics and are prespecified (diabetes status is not prespecified, but is a criterion for CHADS2 scoring). The 95% confidence intervals given neither take into account how many comparisons were implemented nor reflect the effect of other factors adjusted for that factor. Apparent homogeneity or heterogeneity between groups should not be over-interpreted.
Treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE); reduction in risk of DVT and PE recurrence
EINSTEIN DVT and EINSTEIN PE Study
In the pooled EINSTEIN DVT and EINSTEIN PE clinical studies, the most common adverse event leading to permanent discontinuation was bleeding events, with an incidence of 1.7% versus 1.5% for rivaroxaban compared to enoxaparin/vitamin K antagonist (VKA), respectively. The mean duration of treatment was 208 days for patients treated with rivaroxaban and 204 days for patients treated with enoxaparin/VKA. Table 3 shows the number of patients who experienced major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 3. major bleeding events in the pooled analysis of EINSTEIN DVT and EINSTEIN PE clinical trial studies*
Parameter Rivaroxaban†
N = 4130
n (%) enoxaparin/VKA†
N = 4116
n (%) Major bleeding events40 (1.0)72 (1.7)Fatal bleeding3 (<0.1)8 (0.2)Intracranial2 (<0.1)4 (<0.1)Nonfatal vital organ bleeding10 (0.2)29 (0.7)Intracranial‡3 (<0.1)10 (0.2)Retroperitoneal‡1 (<0.1)8 (0.2) Intraocular‡3 (<0.1)2 (<0.1)Intra-articular‡04 (<0.1)Nonfatal nonvital organ bleeding§27 (0.7)37 (0.9)Hb reduction ≥ 2 g/dL28 (0.7)42 (1.0)Transfusion of ≥ 2 units of whole blood or concentrated red blood cells18 (0.4) 25 (0.6)Clinically relevant nonmajor bleeding357 ( 8.6)357 (8.7)Any bleeding1169 (28.3)1153 (28.0)* Bleeding events that occurred after random assignment and up to 2 days of the last study drug administration. Although 2 or more events may occur in a patient, that patient was counted only once in the same category.
† Treatment plan in the EINSTEIN DVT and EINSTEIN PE studies: rivaroxaban 15 mg twice daily for three weeks, followed by 20 mg orally once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individualized dose adjustment to achieve target INR 2.5 (range: 2.0-3.0)].
‡ At least >2 subjects in any pooled treatment group experienced an on-treatment major bleeding event.
§ Major bleeding resulting in ≥2 g/dL reduction in Hb and/or transfusion of ≥2 units of whole blood or concentrated red blood cells, except for lethal or intra-vital organ hemorrhage.EINSTEIN Extension Study
In the EINSTEIN Extension study, the most common adverse event leading to permanent discontinuation was bleeding, with an incidence of 1.8% in the rivaroxaban group compared to 0.2% in the placebo-treated group. The mean duration of treatment was 190 days in both the rivaroxaban and placebo treatment groups. Table 4 shows the number of patients in the EINSTEIN Extension study who experienced major bleeding events.
Table 4. bleeding events in the EINSTEIN Extension clinical trial study* Parameters Rivaroxaban†
20 mg
N = 598
n (%) placebo†
N = 590
n (%) Major bleeding events‡4 (0.7)0 Hb reduction ≥2 g/dL4 (0.7)0 transfusion of ≥2 units of whole blood or red blood cell concentrate2 (0.3)0 gastrointestinal3 (0.5)0 menorrhagia1 (0.2)0 clinically relevant non-major bleeding32 (5.4)7 (1.2)Any bleeding104 (17.4)63 (10.7)* After random assignment and bleeding events occurring up to 2 days of the last study drug administration. Although 2 or more events may occur in a patient, that patient is counted only once in the same category.
† Treatment plan: rivaroxaban 20 mg once daily; matching placebo once daily.
‡ No fatal or significant intra-organ hemorrhage events.EINSTEIN Choice Study
In the EINSTEIN Choice clinical study, the most common adverse event leading to permanent discontinuation was a bleeding event, which occurred at an incidence of 1% in the rivaroxaban 10 mg group compared to 2% in the rivaroxaban 20 mg treatment group and 1% in the acetylsalicylic acid (aspirin) 100 mg group. The mean duration of treatment for patients in the rivaroxaban 10 mg treatment group and the aspirin 100 mg treatment group was 293 and 286 days, respectively. Table 5 shows the number of patients in the EINSTEIN Choice study who experienced major bleeding events.
Table 5: Bleeding events in the EINSTEIN CHOICE study*
Parameters Rivaroxaban†
10 mg
N = 1127
n (%) Rivaroxaban†
20 mg
N = 1107
n (%) Acetylsalicylic acid (aspirin)† 100 mg
N = 1131
n (%) Major bleeding events45 (0.7)4)64 (0.57))3 (0.3)Lethal bleeding4 (0.7)1 (<0.1)4 (.7)1 (<0.1)Nonlethal vital organ bleeding2 (0.3)2)4 (0.43))1 (<0.1)Nonlethal nonvital organ bleeding§3 (0.5)3)1 (&lt ;0.1)1 (<0.1)Clinically relevant nonmajor (CRNM) bleeding¶32 (5.4)22 (2.0)3032 (5.4) (2.7)720 (1.2)8)Any bleeding104 (17151 (13.4)104 (17188 (17.0)63 (10.7)138 (12.2)* After random assignment and up to 2 days of the last study drug administration for bleeding events. Although 2 or more events may occur in a patient, that patient is counted only once in the same category.
† Treatment plan: rivaroxaban 10 mg or 20 mg once daily or aspirin 100 mg once daily.
§ Non-fatal or non-vital intra-organ hemorrhage, but resulting in a reduction in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or concentrated red blood cells.
¶
Bleeding that is clinically apparent and does not meet the criteria for major bleeding but is associated with a medical intervention, unanticipated visit, temporary cessation of therapy, patient discomfort, or interference with daily activities. Prevention of deep vein thrombosis after hip or knee replacement surgery
In the RECORD clinical trial, the overall incidence of adverse reactions leading to permanent discontinuation was 3.7% in the rivaroxaban group. The incidence of major bleeding events and any bleeding events observed in patients in the RECORD clinical trial are presented in Table 6.
Table 6. Bleeding events in patients undergoing hip and knee replacement surgery* (RECORD 1-3)
 Rivaroxaban 10 mg enoxaparin† All patients treated N=4487
n (%) N=4524
n (%) Major bleeding events14 (0.3) 9 (0.2) Fatal bleeding1 (<0.1) 0 Bleeding from vital organs2 (<0.1) 3 (0.1) Bleeding requiring reoperation7 (0.2) 5 (0.1) Bleeding outside the site of surgery requiring transfusion of >2 units of whole blood or concentrated red blood cells4 (0.1) 1 (<0.1) Any bleeding event‡ 261 (5.8) 251 (5.6) Hip surgery studyN = 3281
n (%) N = 3298
n (%) Major bleeding events7 (0.2) 3 (0.1) Fatal bleeding1 (<0.1) 0 Bleeding from vital organs1 (<0.1) 1 (<0.1) Bleeding requiring reoperation2 (0.1) 1 (<0.1) Bleeding outside the surgical site requiring transfusion of >2 units of whole blood or concentrated red blood cells3 (0.1) 1 (<0.1) Any bleeding event‡201 (6.1) 191 (5.8) Knee surgery studyN = 1206
n (%) N = 1226
n (%) Major bleeding events7 (0.6) 6 (0.5) Fatal bleeding00 Vital organ bleeding1 (0.1) 2 (0.2) Bleeding requiring reoperation5 (0.4) 4 (0.3) Bleeding outside the surgical site requiring transfusion of >2 units of whole blood or concentrated red blood cells1 (0.1)
0
Any bleeding event‡60 (5.0) 60 (4.9) * Bleeding events occurring at any time after the first dose of double-blind study dosing (which may be prior to active drug administration) up to two days after the last dose of double-blind study dosing. Patients may have had more than one event.
†Includes the placebo-controlled phase of RECORD 2 with enoxaparin at a dose of 40 mg once daily (RECORD 1-3)
‡Including major bleeding events
After rivaroxaban treatment, most major bleeding (≥60%) occurred within the first week after surgery.
Other adverse events
See Table 7 for ≥1% of non-hemorrhagic adverse reactions reported in patients treated with rivaroxaban in the EINSTEIN Extension study.
 Table 7. ≥1% of other adverse reactions reported in patients treated with rivaroxaban in the EINSTEIN Extension clinical trial study* Systemic organ classification
Preferred term Rivaroxaban
N = 598
n (%) placebo
N = 590
n (%) Gastrointestinal disorders Epigastric pain 10 (1.7)1 (0.2) Dyspepsia 8 (1.3)4 (0.7) Toothache 6 (1.0)0 Systemic and site of administration disorders Fatigue 6 (1.0)3 (0.5) Infectious and invasive diseases Sinusitis 7 (1.2)3 (0.5) Urinary tract infections 7 (1.2)3 (0.5) Musculoskeletal and connective tissue disorders Back pain 22 (3.7)7 (1.2)Osteoarthritis10 (1.7)5 (0.8)Respiratory, thoracic and mediastinal disorders Oropharyngeal pain6 (1.0)2 (0.3)* Adverse reactions occurring after the first dose and up to 2 days after the last dose (relative risk of rivaroxaban compared to placebo >1.5). Incidence is based on the number of patients, not the number of events. Although 2 or more clinical adverse reactions may occur in a single patient, that patient was counted only once in the same category. The same patient may appear in different categories. Table 8. Other adverse reactions reported in ≥1% of patients treated with rivaroxaban in the EINSTEIN DVT and EINSTEIN PE clinical trial studies*
System organ classification
Adverse reactions EINSTEIN DVT study Rivaroxaban 20 mg
N = 1718
n (%) enoxaparin/VKA
N = 1711
n (%) Gastrointestinal disorders Abdominal pain 46 (2.7) 25 (1.5) Systemic and administration site disorders Fatigue 24 (1.4) 15 (0.9) Musculoskeletal and connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle cramps 23 (1.3) 13 (0.8) Various neurological disorders  
Dizziness 38 (2.2) 22 (1.3) Psychiatric category Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) EINSTEIN PE study Rivaroxaban 20 mg
N=2412
N (%) Enoxaparin/VKA
N=2405
N (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Relative risk of adverse reactions of rivaroxaban compared to control drugs >1.5
 Table 9 lists the ≥1% of non-hemorrhagic adverse reactions reported by patients treated with rivaroxaban in the RECORD 1-3 study.
Table 9. ≥1% of other adverse reactions* reported by patients treated with rivaroxaban in the RECORD 1-3 clinical trial study
System organ classification
Adverse reactions Rivaroxaban
10 mg
N=4487
n (%) enoxaparin†
 N=4524
n (%) Injury, poisoning, and surgical complications Wound discharge 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Extremity pain 74 (1.7) 55 (1.2) Muscle cramps 52 (1.2) 32 (0.7) Neurologic disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blistering63 (1.4) 40 (0.9) * Adverse reactions occurring at any time after the first dose of double-blind administration (possibly prior to active drug administration) up to two days after the last dose of double-blind study dosing.
† including the placebo-controlled phase of RECORD 2, with enoxaparin at a dose of 40 mg once daily (RECORD 1-3)
Other clinical trials: in a study of patients with medical emergencies receiving rivaroxaban 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.
Postmarketing Adverse Reactions
The following adverse reactions were identified after rivaroxaban was approved. Because these reactions were reported spontaneously (group size is uncertain), their frequency and causal relationship to drug exposure often cannot be accurately assessed.
Blood and lymphatic system disorders: granulocyte deficiency, thrombocytopenia
Gastrointestinal disorders: retroperitoneal hemorrhage
Hepatobiliary disorders: jaundice, cholestasis, hepatitis (with hepatocyte damage)
Immune system disorders: hypersensitivity reactions, allergic reactions, anaphylaxis, angioedema
Neurological disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, mild hemiparesis
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
 Contraindications
Rivaroxaban is contraindicated in patients who
Patients who are hypersensitive to rivaroxaban or any of the excipients in the tablets.
Patients with clinically significant active bleeding.
Lesions or conditions with significant risk of major bleeding, such as current or recent gastrointestinal ulcers, presence of malignancy with a high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or significant intravertebral or intracerebral vascular malformations.
Concomitant therapy with any other anticoagulant, such as UFH, low molecular heparin (enoxaparin, dalteparin, etc.), heparin derivatives (sodium fondaparinux, etc.), oral anticoagulants (warfarinux, apixaban, dabigatran, etc.) is contraindicated, except in the special case of conversion to anticoagulation therapy or administration of the dose of normal heparin (UFH) required to maintain central venous or arterial catheter patency.
Patients with liver disease with coagulation abnormalities and clinically relevant bleeding risk, including patients with cirrhosis who have reached Child Pugh grades B and C.
Pregnant and lactating women.
 [Caution].
Close observation throughout the course of anticoagulation therapy is recommended.
Early discontinuation of rivaroxaban will increase the risk of thromboembolic events
Early discontinuation of any oral anticoagulant, including rivaroxaban, in the absence of adequate alternative anticoagulant therapy will increase the risk of thromboembolic events. In clinical trials, an increased incidence of stroke was observed during the switch from rivaroxaban to warfarin in patients with non-valvular atrial fibrillation. Consider giving another anticoagulant if early discontinuation of rivaroxaban is necessary for pathologic bleeding or reasons other than completed therapy.
Risk of hemorrhage
Rivaroxaban will increase the risk of bleeding and may cause severe or fatal bleeding. The risk of thromboembolic events must be weighed against the risk of bleeding when deciding whether to administer rivaroxaban to a patient with a higher risk of bleeding.
As with other anticoagulants, patients taking rivaroxaban should be closely monitored for signs of bleeding. Caution is recommended when the risk of bleeding is high. If severe bleeding occurs, rivaroxaban must be discontinued.
In clinical studies, more mucosal bleeding (i.e., epistaxis, gingival bleeding, gastrointestinal bleeding, genitourinary bleeding [including abnormal vaginal bleeding or increased menstrual flow]) and anemia occurred in patients receiving long-term treatment with rivaroxaban compared with VKA therapy. Therefore, in addition to performing adequate clinical observations, proper judgment of laboratory findings of hemoglobin/erythrocyte pressure can help detect occult bleeding as well as quantify overt bleeding and determine clinical relevance.
For some patients at higher risk of bleeding, close monitoring of these patients for bleeding complications and signs and symptoms of anemia should be implemented after the start of treatment. In the postoperative population, timely detection of bleeding can be achieved by regular physical examination of the patient, close observation of surgical wound drainage and regular hemoglobin measurement.
The site of bleeding should be sought for any unexplained decrease in hemoglobin or blood pressure.
Signs and symptoms of blood loss should be promptly evaluated and the need for blood replacement therapy should be considered. Discontinue rivaroxaban in patients with active pathologic bleeding. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
The combination of other drugs that affect hemostasis will increase the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytics, and nonsteroidal anti-inflammatory drugs (NSAIDs).
Combined use of combination P-gp and potent CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) will result in increased exposure to rivaroxaban and may elevate the risk of bleeding.
Although daily exposure monitoring of rivaroxaban therapy is not required, in certain circumstances, such as drug overdose and emergency surgery, levels of rivaroxaban can be measured using standard anti-Factor Xa kits, and knowledge of rivaroxaban exposure can assist in clinical decision making.
Reversal of anticoagulant effects
There are no specific antagonists for rivaroxaban. Rivaroxaban is not expected to be dialyzed due to high binding to plasma proteins. Fisetin sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Partial reversal of prolonged prothrombin time was observed after administration of prothrombin complex concentrator (PCC) in healthy subjects. The use of other procoagulant reversal agents, such as activated prothrombin complex concentrator (APCC) or recombinant factor VIIa (rFVIIa), has not been evaluated in trials. See [drug overdose].
 Spinal/epidural anesthesia or puncture
Patients receiving antithrombotic agents to prevent thrombotic complications during axial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture are at risk of developing epidural or spinal hematomas, which may result in long-term or permanent paralysis.
Postoperative use of indwelling epidural catheters or concomitant use of medications that affect hemostasis may increase the risk of these events. Trauma or repeated epidural or spinal punctures may also increase the risk of these events. Patients should be monitored frequently for signs and symptoms of neurologic impairment (e.g., leg numbness or weakness, bowel or bladder dysfunction). If neurologic impairment is observed, it must be diagnosed and treated immediately. For patients receiving anticoagulation and for patients scheduled to receive anticoagulation for thrombosis prevention, physicians should weigh the potential benefits and risks prior to performing axon-related maneuvers. There is no clinical experience with the use of rivaroxaban 15 mg and 20 mg in these situations.
To reduce the potential risk of bleeding associated with the combined use of rivaroxaban with epidural or spinal anesthesia/analgesia or during spinal puncture, attention should be paid to the pharmacokinetic profile of rivaroxaban. The best time to place or remove an epidural catheter or perform a lumbar puncture is when the anticoagulant effect of rivaroxaban is low; however, the exact time to achieve a sufficiently low anticoagulant effect on a per-patient basis is not known. For epidural catheter removal, based on general pharmacokinetic properties, at least 2 times the half-life, i.e., at least 18 hours after the last dose of rivaroxaban in younger patients and at least 26 hours in older patients, should be used for removal. Rivaroxaban should not be administered until at least 6 hours after removal of the catheter. If an invasive puncture was performed, rivaroxaban administration is delayed by 24 hours.
 Renal impairment
Prevention of venous thrombosis in adult patients undergoing elective hip or knee arthroplasty
Avoid administration of rivaroxaban in patients with CrCl <30 mL/min, as elevated exposure and enhanced pharmacodynamic effects of rivaroxaban would be expected in this patient population. Closely observe and promptly assess for any signs and symptoms of blood loss in patients with CrCl 30-50 mL/min. Patients who develop acute renal failure while taking rivaroxaban must discontinue therapy.
Treat DVT and PE and reduce the risk of DVT and PE recurrence
Avoid the use of rivaroxaban in patients with CrCl <30 mL/min, as elevated exposure to rivaroxaban and enhanced pharmacodynamic effects would be expected in this patient population.
Use in adult patients with non-valvular atrial fibrillation to reduce the risk of stroke and embolism of the body circulation
In patients with CrCl <15 mL/min, rivaroxaban should be avoided because of elevated drug exposure. Periodically assess renal function according to clinical indications (i.e., more frequently in cases of potentially diminished renal function) and adjust therapy accordingly. Consider dose adjustment or discontinuation of rivaroxaban in the event of acute renal failure during the use of rivaroxaban.
 Interactions with other drugs
Concomitant use of rivaroxaban is not recommended for patients on systemic medications such as pyrrole antifungals (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors (e.g., ritonavir). Because the above drugs are potent inhibitors of CYP3A4 and P-gp, concomitant use may cause a clinically meaningful increase in rivaroxaban blood levels (mean 2.6-fold) and increase the risk of bleeding.
Caution is required in the administration of medications in combination with drugs that affect hemostasis (e.g., NSAIDs, acetylsalicylic acid (ASA), platelet aggregation inhibitors, or selective 5-hydroxytryptamine reuptake inhibitors (SSRI) and 5-hydroxytryptamine norepinephrine reuptake inhibitors (SNRI)). Appropriate prophylactic therapy should be considered in patients at risk of developing ulcerative gastrointestinal disease.
Other Bleeding Risks
As with other antithrombotic agents, rivaroxaban is not recommended for patients at high risk of bleeding from: congenital or acquired bleeding disorders; uncontrolled severe hypertension; other gastrointestinal disorders not associated with active ulcers but which can lead to bleeding complications (e.g., inflammatory bowel disease, esophagitis, gastritis, and gastroesophageal reflux disease); retinopathy of vascular origin; and a history of bronchiectasis or pulmonary hemorrhage.
    
Venous thrombosis prophylaxis in hip fracture surgery
There are no interventional clinical studies of rivaroxaban in patients undergoing hip fracture surgery to evaluate the efficacy and safety of rivaroxaban.
 Patients with Prosthetic Heart Valves
The safety and efficacy of rivaroxaban have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that rivaroxaban may provide adequate anticoagulation in this patient population. Rivaroxaban is not recommended for use in this patient population.
 Patients with hemodynamically unstable PE or those requiring thrombolysis or pulmonary artery tamponade
Rivaroxaban is not recommended as an alternative therapy to regular heparin in patients with hemodynamically unstable PE or who may require thrombolysis or pulmonary embolectomy because the safety and efficacy of rivaroxaban have not been studied in these clinical situations.
 Dosing recommendations before and after invasive procedures and surgical treatment (except for elective hip or knee replacement surgery)
If invasive manipulation or surgical treatment is required, interventions should be performed at least 24 hours after rivaroxaban has been discontinued, as circumstances permit and based on the physician’s clinical judgment.
If this cannot be postponed, the increased risk of bleeding should be weighed against the urgency of the intervention.
Rivaroxaban therapy should be restarted as soon as possible after the completion of an invasive procedure or surgery, if the clinical situation permits and adequate hemostasis has been achieved.
Excipient Information
Rivaroxaban tablets contain lactose. Patients with rare hereditary lactose or galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.
Effects on the ability to drive and operate machinery
Rivaroxaban has had minimal effect on the ability to drive and operate machinery.
Adverse reactions such as syncope (frequency: rare) and dizziness (frequency: common) have been reported. Patients should not drive or operate machinery when these adverse reactions occur.
[For pregnant and lactating women].
Pregnancy
The safety and efficacy of rivaroxaban for use in women during pregnancy have not been established. Animal studies have shown reproductive toxicity.
Rivaroxaban is contraindicated in women during pregnancy due to potential reproductive toxicity, risk of endogenous hemorrhage, and the fact that rivaroxaban can cross the placenta.
Women of childbearing potential should use contraception during treatment with rivaroxaban.
Delivery
The safety and efficacy of rivaroxaban during delivery have not been studied in clinical trials. However, maternal hemorrhage and maternal and fetal death have occurred in animal studies at a dose of 40 mg/kg of rivaroxaban (approximately 6 times the maximum human unconjugated drug exposure at a human dose of 20 mg/day).
Lactation
The safety and efficacy of rivaroxaban for use in nursing women has not been established. Data from animal studies indicate that rivaroxaban can pass into breast milk. Therefore, rivaroxaban is contraindicated in nursing women. A decision must be made whether to discontinue breastfeeding or to discontinue rivaroxaban therapy.
Fertility
No specific studies have been conducted in humans to evaluate the effects of rivaroxaban on fertility. In a study of fertility in male and female rats, no effect was observed.
Women of childbearing potential
Women of childbearing age who require anticoagulation therapy must consult a physician.
Pediatric Dosage]
There is no evidence to clarify the safety and efficacy of rivaroxaban for use in children 0-18 years of age. Therefore, rivaroxaban is not recommended for use in children under 18 years of age.
Geriatric use]
The dose for the elderly should be determined by the risk of bleeding, renal function and systemic status, and in most cases no dose adjustment is necessary.
Approximately 54% of all patients in the RECORD 1-3 clinical study of rivaroxaban were 65 years of age and older, with approximately 15% of these patients being older than 75 years of age. In the ROCKET AF study, approximately 77% were patients 65 years and older, of which approximately 38% were older than 75 years. In the EINSTEIN DVT, PE and Extension study, approximately 37% of patients were 65 years and older, of which approximately 16% were older than 75 years. In the EINSTEIN CHOICE, approximately 39% of patients were 65 years and older, of which approximately 12% were older than 75 years. In clinical trials, the efficacy of rivaroxaban in older adults (65 years of age or older) was close to that observed in patients younger than 65 years of age. The incidence of thrombosis and bleeding events was higher in these older patients, but the risk-benefit profile was evaluated as beneficial in all age groups.
[Drug Interactions].
CYP3A4 and P-gp inhibitors
When combining rivaroxaban with ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily), the mean AUC of rivaroxaban increased by 2.6-fold/2.5-fold and the mean Cmax of rivaroxaban increased by 1.7-fold/1.6-fold, along with a significant increase in potency, which may lead to an increased risk of bleeding. Therefore, combining rivaroxaban with pyrrole-antifungal agents (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors when administered systemically is not recommended. These active substances are potent inhibitors of CYP3A4 and P-gp.
A potent inhibitor of one of the two elimination pathways of rivaroxaban (CYP3A4 or P-gp) will cause a mild increase in blood levels of rivaroxaban, for example, clarithromycin (500 mg twice daily), which is considered a potent CYP3A4 inhibitor and a moderate P-gp inhibitor, increased the mean AUC of rivaroxaban by 1.5-fold and increased the Cmax by 1.4-fold. The above elevations were not considered to be clinically significant.
Erythromycin (500 mg three times daily), which moderately inhibits CYP3A4 and P-gp, increased the mean AUC and Cmax of rivaroxaban by 1.3-fold. The above elevations were not considered to be clinically significant.
Erythromycin (500 mg three times daily) increased the mean AUC of rivaroxaban by 1.8-fold and Cmax by 1.6-fold in those with mild renal impairment compared with those with normal renal function. Erythromycin increased the mean AUC of rivaroxaban by 2.0-fold and the Cmax by 1.6-fold in patients with moderate renal impairment compared with those with normal renal function. The degree of renal impairment may accrue to the effect of erythromycin (see [Precautions]).
Fluconazole (400 mg once daily, moderate CYP3A4 inhibitor) resulted in a 1.4-fold mean AUC increase and a 1.3-fold mean Cmax increase for rivaroxaban. These elevations were not considered clinically significant.
Because of the limited clinical data on dronedarone, it should be avoided in combination with rivaroxaban.
Anticoagulants
The combination of enoxaparin (40 mg, single dose) and rivaroxaban (10 mg, single dose) had an additive effect on anti-Factor Xa activity without any additive effect on coagulation tests (PT, aPTT). Enoxaparin does not affect the pharmacokinetics of rivaroxaban.
If patients are receiving concomitant therapy with any other anticoagulant, the drug should be administered with caution due to the elevated risk of bleeding.
Non-steroidal anti-inflammatory drugs/platelet aggregation inhibitors
No clinically meaningful prolongation of bleeding time was observed when combining rivaroxaban (15 mg) with 500 mg naproxen. Nevertheless, a more pronounced pharmacodynamic effect may be produced in some individuals.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was combined with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban tablets (15 mg), but an associated prolongation of bleeding time was observed in a subgroup of patients, which was not associated with platelet aggregation, P-selectin, or GP IIb/IIIa receptor levels.
Caution should be exercised when combining NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors in patients on rivaroxaban, as these agents often raise the risk of bleeding.
SSRI/SNRI
Rivaroxaban, like other anticoagulants, may put patients at increased risk of bleeding when combined with an SSRI or SNRI because of its effect on platelets. In the rivaroxaban clinical program, a numerically higher incidence of major bleeding or clinically relevant non-major bleeding was observed in all treatment groups when the combination was administered.
Warfarin
Prolongation of prothrombin time/INR (Neoplastin) beyond the superimposed effect (individual INR values up to 12 may be observed) was observed when patients switched from the vitamin K antagonist warfarin (INR 2.0-3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0-3.0) therapy, while for activated partial effect on activated partial thromboplastin time (aPTT), inhibition of factor Xa activity and endogenous thrombin generation potential (ETP) have a superimposed effect.
To test the pharmacodynamic effects of rivaroxaban during drug exchange, anti-Factor Xa activity, PiCT and Heptest can be used, as these assays are not affected by warfarin. At day 4 after the last warfarin dose, all assays (including prothrombin time (PT), aPTT, inhibition of factor Xa activity and ETP) reflect only the effects produced by rivaroxaban.
If the efficacy of warfarin is to be tested during the switching period, the INR assay can be used at the trough concentration (Ctrough) of rivaroxaban (24 hours after the last intake of rivaroxaban), as this test is least affected by rivaroxaban at this time point.
No pharmacokinetic interactions were observed between warfarin and rivaroxaban.
CYP3A4 inducers
The potent CYP3A4 inducer rifampicin, when combined with rivaroxaban, decreased the mean AUC of rivaroxaban by approximately 50% with a parallel decrease in efficacy. Combining rivaroxaban with other potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may also reduce rivaroxaban blood levels. Therefore, concomitant use of potent CYP3A4 inducers and rivaroxaban should be avoided unless the patient is closely monitored for signs and symptoms of thrombosis.
Other combinations of drugs
No clinically meaningful pharmacokinetic or pharmacodynamic interactions have been observed when combining rivaroxaban with midazolam (CYP3A4 substrate), digoxin (P-gp substrate) or atorvastatin (CYP3A4 and P-gp substrate), and omeprazole (proton pump inhibitor). Rivaroxaban was neither inhibitory nor inducible for any of the major CYP isoforms (e.g., CYP3A4).
 No clinically meaningful interactions were observed between rivaroxaban 10 mg and food.
Laboratory Parameters
As expected, coagulation parameters (e.g., PT, aPTT, HepTest) were affected by the mode of action of rivaroxaban.
[Drug overdose].
A few cases of overdose (up to 600 mg) have been reported, but without bleeding complications or other adverse effects. Because of the limited degree of absorption, a ceiling effect is expected to be observed after administration of supratherapeutic doses of rivaroxaban of 50 mg or higher, with no further increase in mean plasma exposure levels.
No specific antagonists are available to counteract the effects of rivaroxaban. The use of activated charcoal may be considered to reduce the absorption of rivaroxaban after overdose.
Management of hemorrhage
If bleeding complications occur in patients receiving rivaroxaban, the next dose of rivaroxaban should be delayed appropriately or should be discontinued. The half-life of rivaroxaban is approximately 5-13 hours. Individualized management should be given according to the severity and site of bleeding. Appropriate symptomatic treatment such as mechanical compression (e.g., for severe epistaxis), surgical hemostasis using bleeding control procedures, rehydration and hemodynamic support, blood products (concentrated red blood cells or fresh frozen plasma, depending on the associated anemia or clotting abnormalities), or platelets should be administered as needed.
If the above measures fail to control bleeding, specific procoagulant reversal agents such as prothrombin complex (PCC), activated prothrombin complex (APCC), or recombinant factor VIIa (r-FVIIa) should be considered. However, there is currently very limited clinical experience with the use of these agents in patients treated with rivaroxaban. The above recommendations are based on limited non-clinical data. Dose adjustment of recombinant factor VII a may be considered based on bleeding improvement.
Fisetin sulfate and vitamin K do not affect the anticoagulant activity of rivaroxaban. There is limited experience with the use of tranexamic acid in patients on rivaroxaban, and there is no experience with the use of aminocaproic acid and peptidase in patients on rivaroxaban. There is a lack of scientific basis and experience with the benefit of using the systemic hemostatic agent desmopressin in patients taking rivaroxaban. Due to the high plasma protein binding rate of rivaroxaban, it is not easily dialyzed.
 [Clinical Trials].
Prevention of venous thrombosis in adult patients undergoing elective hip or knee arthroplasty
Clinical trials were designed to verify the efficacy of rivaroxaban in preventing venous thromboembolic events (VTE) in patients undergoing major orthopaedic surgery of the lower extremities, namely: proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE). In the randomized, controlled, double-blind phase III clinical study (RECORD study), more than 9,500 patients (7,050 underwent total hip replacement and 2,531 total knee replacement) were studied.
In the studies, patients were given either rivaroxaban 10 mg once daily (administered at least 6 hours after surgery) or enoxaparin 40 mg once daily (administered 12 hours before surgery), and the efficacy of both was compared.
In all three phase III studies (see Table 10), rivaroxaban significantly reduced the incidence of all VTE (all or symptomatic DVT detected by venography, nonfatal PE, and death) and major VTE events (proximal DVT, nonfatal PE, and VTE-related death), which were prespecified primary and secondary efficacy endpoints. In addition, the incidence of symptomatic VTE (symptomatic DVT, non-fatal PE, and VTE-related death) was lower in the rivaroxaban group than in the enoxaparin group in all three studies.
The incidence of major bleeding, the primary safety endpoint, was comparable between the rivaroxaban 10 mg treatment group and the enoxaparin 40 mg treatment group.
Table 10. efficacy and safety results from phase III clinical trial studies
 RECORD 1RECORD 2RECORD 3Study population 4541 patients who underwent total hip
replacement 2509 patients who underwent total hip
2531 patients who underwent total knee replacement
Dose and duration of postoperative treatment in patients with total knee replacement Rivaroxaban
10 mg od
35 ± 4 days enoxaparin
40 mg od
35 ± 4 days pRivaroxaban
10 mg od
35 ± 4 days enoxaparin
40 mg od
12 ± 2 days p rivaroxaban
10 mg od
12 ± 2 days enoxaparin
40 mg od
12 ± 2 days pTotal VTE18 (1.1%)58 (3.7%)<0.00117 (2.0%)81 (9.3%)<0.00179 (9.6%)166 (18.9%)<0.001 major VTE4 (0.2%)33 (2.0%)<0.0016 (0.6%)49 (5.1% )<0.0019(1.0%)24(2.6%)0.01 Symptomatic VTE6(0.4%)11(0.7%) 3(0.4%)15(1.7%) 8(1.0%)24(2.7%) Major bleeding6(0.3%)2(0.1%) 1(0.1%)1(0.1%) 7(0.6%)6(0.5%) For phase III The combined analysis of clinical studies further corroborated the data obtained in the individual studies: compared to enoxaparin 40 mg once daily, rivaroxaban 10 mg once daily significantly reduced total VTE, major VTE and symptomatic VTE.
In addition to the Phase III RECORD program, a post-marketing, non-interventional, open cohort study (XAMOS) was conducted in 17,413 patients undergoing major orthopedic surgery of the hip or knee to compare rivaroxaban with other thromboprophylactic drug therapies (standard therapy) in a clinical practice setting. In the rivaroxaban (n=8,778) and standard therapy groups (n=8,635), 57 (0.6%) and 88 (1.0%) patients, respectively, developed symptomatic VTE (HR 0.63; 95% CI 0.43-0.91; safety analysis set population); 35 (0.4%) and 29 (0.3%) patients, respectively, developed major bleeding ( HR 1.10; 95% CI 0.67-1.80). Therefore, the results of this study are consistent with the results of established pivotal randomized clinical studies.
 Treating DVT and PE; Reducing the Risk of DVT and PE Recurrence
EINSTEIN DVT and EINSTEIN PE Study
In the two international, open-label, non-inferiority studies of EINSTEIN DVT and EINSTEIN PE, VKA was administered by combining rivaroxaban (an initial dose of 15 mg twice daily with food for the first three weeks, followed by rivaroxaban 20 mg once daily with food) and enoxaparin 1 mg/kg (for at least five days) and The effect of rivaroxaban in the treatment of DVT and/or PE and in reducing the risk of recurrence of DVT and PE was studied by continuing VKA only after reaching the target INR (2.0-3.0). Patients requiring thrombectomy, implantation of a vena cava filter, or use of fibrinolytics, as well as patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the study. The expected treatment period before randomization was 3, 6, or 12 months based on the investigator’s assessment.
A total of 8,281 patients (3449 with EINSTEIN DVT and 4832 with EINSTEIN PE) were randomly assigned and received continuous treatment for a mean duration of 208 days in the rivaroxaban group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. About 73% and 92% of patients treated with rivaroxaban in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received a mean duration of 2 days of initial nonoral anticoagulation therapy. Patients treated with enoxaparin/VKA received an average of 8 days of initial non-oral anticoagulation. Approximately 12% of patients in both treatment groups were treated with aspirin antithrombotic therapy in combination. The mean percentage of time that the INR was within the target range of 2.0 to 3.0 (uncorrected) in patients randomly assigned to receive VKA was 58% in the EINSTEIN DVT study and 60% in the EINSTEIN PE study, with lower values during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had idiopathic DVT/PE at baseline. other risk factors included previous history of DVT/PE (19%), recent surgery or trauma (18%), braking (16%), use of estrogen-containing medications (8%), known embolism-prone disease (6%), or active tumor (5%).
The EINSTEIN DVT and EINSTEIN PE studies demonstrated that rivaroxaban was noninferior to enoxaparin/VKA for the primary composite endpoint (time to first recurrent DVT or nonfatal or fatal PE) [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR ( 95% CI): 1.12 (0.75, 1.68)]. In each study, non-inferiority was concluded on the basis of an upper 95% confidence interval for the risk ratio below 2.0.
Table 11 shows the overall results for the primary composite endpoint and its components for the EINSTEIN DVT and EINSTEIN PE studies.
Table 11: Results of the primary composite endpoint in the EINSTEIN DVT and EINSTEIN PE studies* – Intent-to-treat population
Event Rivaroxaban 20 mg† Enoxaparin/VKA† Rivaroxaban vs Enoxaparin/VKA
HR
(95% CI) EINSTEIN DVT study N = 1731
n (%) N = 1718
n (%) Primary composite endpoint 36 (2.1) 51 (3.0) 0.68 (0.44, 1.04) Death (PE) 1 (<0.1) 0 Death (cannot exclude PE) 3 (0.2) 6 (0.3) Symptomatic PE and DVT 1 (<0.1) 0 Symptomatic PE recurrence only 20 (1.2) 18 (1.0) Symptomatic DVT recurrence only 14 (0.8) 28 (1.6) EINSTEIN PE study N = 2419
n (%) N = 2413
n (%) Primary composite endpoint 50 (2.1) 44 (1.8) 1.12 (0.75, 1.68) Death (PE) 3 (0.1) 1 (<0.1) Death (cannot exclude PE) 8 (0.3) 6 (0.2) Symptomatic PE and DVT 02 (<0.1) Symptomatic PE recurrence only 23 (1.0) 20 (0.8) Symptomatic DVT recurrence18 (0.7) 17 (0.7) * For primary effectiveness analysis, calculated as all confirmed events from random assignment to the end of the planned course of treatment (3, 6, or 12 months), not as actual treatment duration. If multiple events occur in the same patient, that patient may be double counted into multiple subcategories.
† Treatment regimen for the EINSTEIN DVT and EINSTEIN PE studies: rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individualized dose adjustment to achieve a target INR value of 2.5 (range: 2.0-3.0)]
 The time from random assignment to the occurrence of the first primary efficacy endpoint event in the two treatment groups of the EINSTEIN DVT and EINSTEIN PE studies are plotted in Figures 2 and 3.
Figure 2: Time to first occurrence of the composite endpoint of recurrent DVT or non-fatal or fatal PE for each treatment group (intention-to-treat population) – EINSTEIN DVT study
Figure 3: Time to first occurrence of the composite endpoint of recurrent DVT or non-fatal or fatal PE by treatment group (intention-to-treat population) – EINSTEIN PE Study
 EINSTEIN Extention Study
The EINSTEIN Extension Study, an international, double-blind, superiority study, investigated the effect of rivaroxaban (20 mg once daily with food) compared with placebo on the risk of DVT and PE recurrence in patients with acute DVT and/or PE after completing 6 to 14 months of treatment. The planned course of treatment was 6 or 12 months based on the investigator’s assessment prior to random assignment.
A total of 1196 patients were randomly assigned and continued to receive study treatment, with a mean duration of 190 days in both the rivaroxaban and placebo treatment groups. The mean age was approximately 58 years. The population was 58% male, 78% Caucasian, 8% Asian, and 2% Black. About 12% of patients in both treatment groups were treated with combined aspirin antithrombotic therapy. In the EINSTEIN Extension study, approximately 60% of patients had a proximal DVT-indicating event without a PE event, while 29% had a PE without a symptomatic DVT event. Approximately 59% of patients had idiopathic DVT/PE. other risk factors included previous history of DVT/PE (16%), braking (14%), known embolism susceptibility (8%), or active tumor (5%).
The EINSTEIN Extension study demonstrated that rivaroxaban was superior to placebo for the primary composite endpoint (time to first recurrent DVT or non-fatal or fatal PE) [HR (95% CI): 0.18 (0.09, 0.39)].
Table 12 shows the overall results of the EINSTEIN Extension study primary composite endpoint and its components.
Table 12: Results of the primary composite endpoint in the EINSTEIN Extension study* – Intent-to-treat population
Event Rivaroxaban 20 mg
N = 602
n (%) Placebo
N = 594
n (%) Rivaroxaban versus placebo
Risk ratio
(95% CI) primary composite endpoint 8 (1.3) 42 (7.1) 0.18 (0.09, 0.39)
p-value = <0.0001 Death (PE) 01 (0.2) Death (PE cannot be excluded) 1 (0.2) 0 Symptomatic PE recurrence 2 (0.3) 13 (2.2) Symptomatic DVT recurrence 5 (0.8) 31 (5.2) * For the primary efficacy analysis, calculated as all confirmed events from random assignment to the end of the planned course of treatment (6 or 12 months), and not by the actual duration of treatment. Figure 4 shows a graph of the time from random assignment to the occurrence of the first primary efficacy endpoint event for both treatment groups.
Figure 4 Time to first occurrence of the composite endpoint of recurrent DVT or non-fatal or fatal PE in each treatment group (intention-to-treat population) – EINSTEIN Extension Study
Einstein Choice Study
In the Einstein Choice study, 3,396 patients who had completed 6-12 months of anticoagulation therapy and had proven symptomatic DVT and/or PE were enrolled to study the prevention of lethal PE or non-lethal symptomatic recurrent DVT or PE. Patients requiring continuation of therapeutic doses of anticoagulants were excluded from the study. The maximum duration of treatment was 12 months (median: 351 days) based on the date of randomization of each patient. Rivaroxaban 20 mg once daily and rivaroxaban 10 mg once daily were compared with aspirin 100 mg once daily.
The primary efficacy endpoint was symptomatic VTE recurrence, defined as a composite endpoint consisting of recurrent DVT or lethal or nonlethal PE.
In the Einstein Choice study (Table 13), rivaroxaban 20 mg and 10 mg were superior to aspirin 100 mg for the primary efficacy endpoint. for the primary safety endpoint (major bleeding events), rivaroxaban 20 mg and 10 mg once daily were similar to aspirin 100 mg.
Table 13: Efficacy and safety results in the Phase III Einstein Choice clinical trial study
Study population of 3,396 patients receiving ongoing treatment to prevent recurrence of venous thromboembolism at therapeutic doses of rivaroxaban 20 mg od
N = 1,107 Rivaroxaban 10 mg od
N = 1,127 ASA 100 mg od
N = 1,131 Median duration of therapy [interquartile distance] 349 [189-362] days 353 [190-362] days 350 [186-362] days Symptomatic VTE recurrence 17 (1.5%) *13 (1.2%) **50 (4.4%) Symptomatic PE recurrence 6 (0.5%) 6 (0.5%) 19 (1.7%) Symptomatic DVT recurrence 9 ( (0.8%) 8 (0.7%) 30 (2.7%) Fatal PE/deaths where PE cannot be excluded 2 (0.2%) 0
(0.0%) 2 (0.2%) Symptomatic VTE recurrence, MI, stroke, or non-CNS somatic circulation embolism19 (1.7%) 18 (1.6%) 56 (5.0%) Major bleeding events6 (0.5%) 5 (0.4%) 3 (0.3%) Clinically relevant non-major bleeding30 (2.7) 22 (2.0) 20 (1.8) Symptomatic VTE recurrence or major bleeding ( Net clinical benefit)23 (2.1%)+17 (1.5%)++53 (4.7%)* p<0.001 (superiority) Rivaroxaban 20 mg od vs ASA 100 mg od; HR = 0.34 (0.20-0.59)
** p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR = 0.26 (0.14-0.47)
+ Rivaroxaban 20 mg od vs. ASA 100 mg od; HR = 0.44 (0.27-0.71), p = 0.0009 (nominal)
++
Rivaroxaban 10 mg od vs. ASA 100 mg od; HR = 0.32 (0.18-0.55), p<0.0001 (nominal) In addition to the phase III EINSTEIN project, a prospective, post-market, non-interventional, open, cohort study (XALIA) was conducted with central endpoint adjudication included VTE recurrence, major bleeding and death. 5,142 patients with acute DVT were studied for the long-term safety of rivaroxaban and compared with standard anticoagulation therapy in clinical practice. The major bleeding, VTE recurrence and all-cause mortality rates for rivaroxaban were 0.7%, 1.4% and 0.5%, respectively. There were differences in patient baseline characteristics, including age, cancer, and renal injury. A prespecified propensity score stratified analysis was used to adjust for baseline differences in measurements, but even so, residual confounding factors may have affected the results. Comparing major bleeding, VTE recurrence, and all-cause mortality with rivaroxaban and standard therapy, the adjusted risk ratios were 0.77 (95% CI 0.40-1.50), 0.91 (95% CI 0.54-1.54), and 0.51 (95% CI 0.24-1.07), respectively.
The above results in clinical practice are consistent with the established safety profile for this indication.
Reduced Risk of Stroke and Body Circulation Embolism in Adult Patients With Nonvalvular Atrial Fibrillation
The rivaroxaban clinical program was used to demonstrate the efficacy of rivaroxaban in reducing the risk of stroke and circulatory embolism in patients with non-valvular atrial fibrillation.
In the pivotal, double-blind ROCKET AF study, 14,264 patients were randomly assigned to receive rivaroxaban 20 mg once daily (15 mg once daily for patients with creatinine clearance 30 – 49 mL/min) or dose-adjusted warfarin (INR target value 2.5, range 2.0 – 3.0). The median duration of treatment was 19 months, with a maximum total duration of treatment of 41 months.
Acetylsalicylic acid was received by 34.9% of patients, and 11.4% received class III antiarrhythmic agents (including amiodarone).
For the primary composite endpoint (stroke and non-central nervous system (CNS) somatic circulation embolism), rivaroxaban was noninferior compared with warfarin. The number of stroke or somatic circulation embolic events in the treatment-eligible population was 188 (rivaroxaban group, 1.71% per year) and 241 (warfarin group, 2.16% per year), respectively (HR 0.79; 95% CI, 0.66-0.96; non-inferiority: P<0.001). Among all randomized patients undergoing intention-to-treat (ITT) analysis, the number of patients with a primary endpoint event was 269 (rivaroxaban group, 2.12% per year) and 306 (warfarin group, 2.42% per year), respectively (HR 0.88; 95% CI, 0.74-1.03; non-inferiority: P<0.001. (superiority: P=0.117). Please see Table 14 for the results of the secondary endpoints obtained from the stratified order test in the ITT analysis.
Among patients in the warfarin group, there was a mean of 55% of the time (median: 58%; interquartile spacing: 43 to 71) that INR values were within the treatment range (2.0 to 3.0). There was no difference in the effect of rivaroxaban between individual TTR (time within the target INR range 2.0 3.0) levels for centers within equivalent quartiles (interaction: P=0.74). The risk ratio for rivaroxaban versus warfarin in the highest quartile at each center was 0.74 (95% CI, 0.49 1.12).
The incidence of the primary safety endpoint events (major bleeding events and clinically relevant nonmajor bleeding events) was similar in both treatment groups (see Table 15).
Table 14. efficacy results in the phase III ROCKET AF clinical trial study
Efficacy in the study population of patients with non-valvular AF ITT Analysis of treatment dose Rivaroxaban 20 mg once daily
(15 mg once daily in patients with moderate renal impairment)
Event rate (per 100 patient-years) dose adjusted warfarin, target INR 2.5 (therapeutic range 2.0-3.0)
Event rate (per 100 patient-years) risk ratio
(95% CI)
p-value, test of superiority stroke, non-CNS somatic circulation embolism 269 (2.12) 306 (2.42) 0.88 (0.74 1.03) 0.117 stroke, non-CNS somatic circulation embolism, vascular death 572 (4.51) 609 (4.81) 0.94 (0.84 1.05) 0.265 stroke, non-CNS somatic circulation embolism, vascular death and myocardial infarction 659 (5.24) 709 (5.65) 0.93 (0.83 1.03) 0.158 Stroke 253 (1.99) 281 (2.22) 0.90 (0.76 1.07) 0.221 Non-CNS circulatory embolism 20 (0.16) 27 (0.21) 0.74 (0.42 1.32) 0.308 Myocardial infarction 130 (1.02) 142 (1.11) 0.91 (0.72 1.16) 0.464
 
 Table 15. Safety results in the phase III ROCKET AF clinical trial study
Study population of patients with non-valvular AFa Treatment dose of rivaroxaban 20 mg once daily
(15 mg once daily in patients with moderate renal impairment)
Event rate (per 100 patient-years) dose-adjusted warfarin, target INR 2.5 (therapeutic range 2.0 – 3.0)
Event rate (per 100 patient-years) Hazard ratio (95% CI)
p-value Major bleeding events and clinically relevant non-major bleeding events 1,475 (14.91) 1,449 (14.52) 1.03 (0.96 -1.11)
0.442 Major bleeding events 395(3.60)386(3.45)1.04 (0.90 – 1.20)
0.576 Deaths due to bleeding*27(0.24)55(0.48)0.50 (0.31 – 0.79)
0.003 Bleeding from vital organs*91(0.82)133(1.18)0.69 (0.53 – 0.91)
0.007 Intracranial hemorrhage* 55(0.49) 84(0.74) 0.67 (0.47 – 0.93)
0.019 Hemoglobin reduction*305(2.77)254(2.26)1.22 (1.03 – 1.44)
0.019 Input of ≥2 units of concentrated red blood cells or whole blood* 183 (1.65) 149 (1.32) 1.25 (1.01 – 1.55)
0.044 Clinically relevant non-major bleeding events1,185(11.80)1,151(11.37)1.04 (0.96 – 1.13)
0.345 All-cause deaths208(1.87)250(2.21)0.85 (0.70 1.02)
0.073a) Safety population receiving treatment
* Nominal significance In addition to the phase III ROCKET AF study, a prospective, single-arm, post-marketing, non-interventional, open, cohort study (XANTUS) was conducted with central outcome adjudication including thromboembolic events and major bleeding. The study enrolled 6,785 patients with non-valvular atrial fibrillation in clinical practice for the prevention of stroke and non-central nervous system (CNS) body circulation embolism. The mean CHADS2 and HAS-BLED scores in the XANTUS study were both 2.0, while the mean CHADS2 and HAS-BLED scores in the ROCKET AF study were 3.5 and 2.8, respectively. the incidence of major bleeding was 2.1 cases per 100 patient-years. Fatal bleeding was reported as 0.2 per 100 patient-years and intracranial bleeding as 0.4 per 100 patient-years. The incidence of stroke or non-CNS somatic circulation embolism was 0.8 per 100 patient-years.
The above results in clinical practice are consistent with the established safety profile for this indication.
Adult Patients With Non-Valvular Atrial Fibrillation Receiving Cardioversion
This product was completed in an international multicenter, prospective, randomized, open-ended, multicenter, exploratory study (the X-VERT study) in which 141 study centers in Belgium, Germany, Denmark, Spain, Finland, France, United Kingdom, Greece, Italy, Netherlands, Portugal, South Africa, Canada, United States, China, and Singapore participated, subjecting 1504 patients with non-valvular The subjects were randomized 2:1 to receive rivaroxaban and dose-adjusted VKA, with blinded evaluation of endpoints during the study designed to assess the preventive effect of both drugs on cardiovascular events. TEE-guided cardioversion (pretreatment for 1-5 days) or conventional cardioversion (pretreatment for at least 3 weeks) was used during the study. Five patients (0.5% and 1.0%, respectively) in each of the rivaroxaban (n=978) and VKA groups (n=492) had a primary effectiveness endpoint event (stroke, transient ischemic attack, non-CNS embolism of the body circulation, myocardial infarction (MI), and cardiovascular death) (RR 0.50; 95% CI: 0.15-1.73; modified ITT population). The primary safety endpoint event (major bleeding) occurred in 6 (0.6%) and 4 (0.8%) subjects each in the rivaroxaban (n=988) and VKA groups (n=499) (RR=0.76; 95% CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between the rivaroxaban and VKA treatment groups during the treatment of cardioversion.
 Pediatric Population
The European Agency for the Evaluation of Medicines (EAMA) has granted an extension for the submission of the results of a study of rivaroxaban in one or more pediatric subgroups for the treatment of thromboembolism. The European Agency for the Evaluation of Medicines has also waived the submission of results from studies in all pediatric subgroups for the prevention of thromboembolism. For information on pediatric use, see [Pediatric Use].
QT/QTc interval prolongation
In a comprehensive QT interval study in healthy men and women aged 50 years and older, no prolongation of the QTc interval was observed with the administration of rivaroxaban (15 mg and 45 mg, single dose).
 Pharmacology and Toxicology]
Pharmacological effects
Rivaroxaban is an orally administered, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require cofactors (e.g., antithrombin III) for its activity. It plays an important role in the coagulation cascade by activating factor X as factor Xa (FXa) through endogenous and exogenous pathways.
Rivaroxaban dose-dependently inhibits factor Xa activity in humans, with a dose-dependent prolongation of prothrombin time (PT), activated partial thromboplastin time (aPTT) and quantitative HepTest® heparin assay measured by Neoplastin® reagent. Anti-factor Xa activity was also affected by rivaroxaban.
Toxicological studies
Genotoxicity.
Results of rivaroxaban Ames test, in vitro V79 Chinese hamster lung cell chromosome aberration test, and mouse micronucleus test were all negative.
Reproductive toxicity.
No significant abnormalities in fertility were observed in males or females in rats given oral rivaroxaban up to 200 mg/kg/day. Based on unconjugated systemic exposure (AUC) of the drug, this dose resulted in exposure levels at least 13 times the drug exposure in humans at an oral dose of 20 mg. Embryo-fetal reproductive toxicity was seen in rats with maternal hemorrhage and pregnant rabbits with an increased incidence of post-implantation pregnancy loss. Toxicity in pregnant rabbits given oral rivaroxaban ≥10 mg/kg was manifested by an increased rate of reabsorption, reduced number of surviving fetuses, and reduced fetal weight, equivalent to approximately 4 times the highest recommended human dose of 20 mg/day unconjugated drug AUC. In pregnant rats, oral administration of rivaroxaban at 120 mg/kg resulted in a reduction in fetal body weight, which was about 14 times the AUC of unconjugated drug in humans. For perinatal reproductive toxicity, oral administration of rivaroxaban to rats up to 40 mg/kg (about 6 times the AUC of unconjugated drug in humans) was associated with maternal hemorrhage and maternal and fetal rat mortality.
Carcinogenicity.
No drug-related carcinogenicity was seen in mice or rats administered orally for 2 years. In male and female mice administered at 60 mg/kg/day, the AUC of unconjugated drug was 1 and 2 times the AUC of unconjugated drug at a human dose of 20 mg/day, respectively. In male and female rats administered at 60 mg/kg/day, the AUC of unconjugated drug was 2 and 4 times of the corresponding human AUC, respectively.
 Pharmacokinetics
Absorption
Rivaroxaban is rapidly absorbed, reaching the maximum concentration (Cmax) 2-4 hours after administration.
Oral administration of rivaroxaban is almost completely absorbed. The oral bioavailability of 10 mg tablet is high (80%-100%), both in fasting and in satiated state. Eating has no effect on the AUC or Cmax of rivaroxaban 10 mg tablets, so the timing of taking rivaroxaban 10 mg tablets is not limited by the timing of meals.
Following administration of 20 mg tablets under fasting conditions, oral bioavailability was 66% due to reduced absorption. After taking rivaroxaban 20 mg tablets with food, the mean AUC was increased by 39% compared to fasting, suggesting almost complete absorption and a high oral bioavailability. Rivaroxaban 15mg and 20mg should be taken with food.
Under fasting conditions, rivaroxaban pharmacokinetics increase almost linearly until reaching approximately 15 mg (once daily). Under satiated conditions, the absorption of rivaroxaban 10 mg, 15 mg and 20 mg tablets shows a proportional dose. At higher dose levels, the absorption of rivaroxaban was limited; as the dose increased, there was a decrease in bioavailability as well as absorption.
The variability of rivaroxaban pharmacokinetics was moderate, with inter-individual variability (CV%) ranging from 30% to 40%, but high variability (70%) on the day of surgery and on the first postoperative day of exposure.
The pharmacokinetics of rivaroxaban are not affected by changes in gastric pH. Concomitant administration of rivaroxaban (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), aluminum hydroxide/magnesium hydroxide antacid (10 mL), or rivaroxaban (20 mg single dose) with the proton pump inhibitor (PPI) omeprazole (40 mg once daily) did not show an effect on rivaroxaban bioavailability and exposure.
The absorption of rivaroxaban depends on the site of drug release in the gastrointestinal tract. When rivaroxaban pellets were released in the proximal small intestine, the AUC and Cmax were reduced by 29% and 56% compared to the tablets. Exposure was further reduced when the drug was released in the distal small intestine or ascending colon. Avoid administering rivaroxaban in the distal stomach, which may lead to a reduction in absorption and associated drug exposure.
In a study involving 44 healthy subjects, the mean AUC and Cmax values for crushed 20 mg rivaroxaban tablets mixed with applesauce and taken orally were similar to those for whole tablets swallowed. However, after crushed tablets were prepared as a suspension in water and administered through a nasogastric tube followed by liquid food, only the mean AUC was similar to that of a whole swallowed tablet when administered in this manner, while the Cmax was reduced by 18%.
Distribution
The binding rate of rivaroxaban to human plasma proteins (mainly serum albumin) is high, about 92%-95%. The volume of distribution is moderate, with a steady-state volume of distribution of about 50 L.
Biotransformation and elimination
About 2/3 of the dose of rivaroxaban is metabolically degraded, half of which is then excreted through the kidney and the other half through the fecal route. The remaining 1/3 of the administered dose is excreted directly through the kidneys in the urine as the active drug prototype, mainly by active renal secretion.
Rivaroxaban is metabolized via CYP3A4, CYP2J2, and non-CYP-dependent mechanisms. Oxidative degradation of the morpholinone fraction and hydrolysis of the amide bond are the major sites of biotransformation. In vitro studies have shown that rivaroxaban is a substrate for the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer drug resistance protein).
The prototype rivaroxaban is the most important compound in human plasma, and no major or active circulating metabolites have been identified. The systemic clearance of rivaroxaban is about 10 L/h, which is a low clearance substance. The clearance half-life after intravenous administration at a 1 mg dose is approximately 4.5 hours. After oral administration of rivaroxaban tablets, drug elimination is limited by the absorption rate. The terminal half-life of elimination of rivaroxaban from plasma is as follows: 5-9 hours in young people and 11-13 hours in elderly people.
Special Populations
Gender
There are no clinically meaningful differences in pharmacokinetics and pharmacodynamics between male and female patients.
Geriatric patients
Plasma concentrations are higher in elderly patients than in younger patients, with mean AUC values approximately 1.5 times higher than in younger patients, mainly due to reduced (apparent) total and renal clearance in elderly patients. Dosing in the elderly needs to be determined based on bleeding risk, renal function and systemic status, and in most cases no dose adjustment is required. The terminal elimination half-life in elderly subjects aged 60-76 years is 11 to 13 hours.
Weight Differences
Extreme body weight (<50 kg or >120 kg) had a slight effect (less than 25%) on plasma concentrations of rivaroxaban.
Racial differences
No clinically significant interracial differences in the pharmacokinetics and pharmacodynamics of rivaroxaban were observed in Caucasian, African-American, Latino, Japanese, or Chinese patients.
Hepatic Impairment
In patients with cirrhosis with mild hepatic impairment (Child Pugh Class A), rivaroxaban pharmacokinetics were only slightly altered (mean 1.2-fold increase in AUC), similar to healthy controls. In cirrhotic patients with moderate hepatic impairment (Child Pugh Class B), the mean AUC of rivaroxaban was significantly elevated by 2.3-fold compared to healthy volunteers. The unconjugated AUC was elevated by 2.6-fold. Similar to patients with moderate renal impairment, renal clearance of rivaroxaban was reduced in patients with moderate hepatic impairment.
No data are available for patients with severe hepatic impairment.
Inhibition of factor Xa activity was 2.6-fold higher in patients with moderate hepatic impairment compared with healthy volunteers; similarly, PT was prolonged 2.1-fold. Patients with moderate liver impairment were more sensitive to rivaroxaban, resulting in a higher slope of the PK/PD relationship between concentration and PT.
Rivaroxaban is contraindicated in patients with liver disease associated with coagulation abnormalities and clinically relevant bleeding risk, including: cirrhotic patients with liver impairment of Child Pugh grades B and C.
Renal Impairment
Increased blood concentrations of rivaroxaban have been found to correlate with decreased renal function as measured by creatinine clearance. Rivaroxaban plasma concentrations (AUC) were 1.4-, 1.5-, and 1.6-fold higher in patients with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance 30-49 mL/min), and severe (creatinine clearance 15-29 mL/min) renal impairment, respectively. The corresponding enhancement in drug efficacy was more pronounced. Total inhibition of factor Xa was increased 1.5-, 1.9-, and 2.0-fold in patients with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects; similarly, prothrombin time was prolonged 1.3-, 2.2-, and 2.4-fold, respectively. Data are not yet available for patients with creatinine clearance <15 mL/min.
Rivaroxaban is not easily dialyzed because of its high plasma protein binding rate.
Prevention of Venous Thrombosis in Adult Patients Undergoing Elective Hip or Knee Arthroplasty
In patients with mild (creatinine clearance: 50-80 mL/min) or moderate renal impairment (creatinine clearance: 30-49 mL/min), no dose adjustment of rivaroxaban is required. Limited clinical data on patients with severe renal impairment (creatinine clearance: 15-29 mL/ min) suggest that blood levels of rivaroxaban are significantly elevated in this patient population. Therefore, rivaroxaban should be avoided in these patients. Avoid rivaroxaban in patients with creatinine clearance <30 mL/min.
Treatment of DVT and PE; reduce the risk of DVT and PE recurrence
Avoid rivaroxaban in patients with CrCl <30mL/min.
In adult patients with non-valvular atrial fibrillation, reduce the risk of stroke and embolism of the body circulation
Avoid rivaroxaban in patients with creatinine clearance <15mL/min Use rivaroxaban with caution in patients with creatinine clearance of 15-29 mL/min.
Patient Pharmacokinetic Data
In patients taking 10 mg once-daily rivaroxaban for VTE prophylaxis, the geometric mean concentrations were 101 (7-273) and 14 (4-51) μg/L at 2 to 4 hours (90% prediction interval) and 24 hours (roughly representing the highest and lowest concentrations between doses) after dosing, respectively.
In patients treated with 20 mg (once daily) rivaroxaban for acute DVT, the geometric mean (90% prediction interval) concentrations were 215 (22 to 535) and 32 (6239) μg/L at 2 to 4 h and at approximately 24 h after dosing (roughly representing the highest and lowest concentrations during the dosing period), respectively.
Pharmacokinetic/pharmacodynamic relationships
The pharmacokinetic/pharmacodynamic (PK/PD) relationships between rivaroxaban plasma concentrations and multiple pharmacodynamic endpoints (factor Xa inhibition, PT, aPTT, Heptest) were evaluated after a wide range of dose (5 to 30 mg twice daily) administration. The relationship between rivaroxaban concentration and factor Xa activity can be best described by an Emax model. For PT, the use of a linear intercept model usually provides a better description of the data. There is considerable variation in the slope depending on the PT reagent used. With Neoplastin® PT, the baseline PT was approximately 13 s and the slope was approximately 3 to 4 s/(100 µg/L.) The results of the PK/PD analysis in the Phase II and Phase III studies were consistent with the data determined in healthy subjects. In patients, baseline factors Xa and PT are affected by surgery, resulting in a difference in concentration-PT slope between the first day after surgery and steady state.
[Storage].
Keep sealed.
Package】
Polyvinyl chloride solid pharmaceutical rigid tablets and pharmaceutical aluminum foil packaging, 7 tablets/plate, 1 plate/box, 2 plates/box, 4 plates/box.
【Expiration date
24 months
【Execution standard
 【Approval number】
 【Manufacturer】
Enterprise name: Nanjing Zhengda Tianqing Pharmaceutical Co.
Production Address: No. 9 Huio Road, Nanjing Economic and Technological Development Zone
Zip code: 210038
Telephone number: 025-85109999
Fax number: 025-85803122
Web
Address: www.njcttq.com
[Drug Marketing Licensee
Company name: Nanjing Zhengda Tianqing Pharmaceutical Co.
Address
Address: No. 9, Huio Road, Nanjing Economic and Technological Development Zone
Zip code: 210038
Telephone number: 025-85109999
Fax number: 025-85803122
Web
Address: www.njcttq.com