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XARELTO
(rivaroxaban) Tablets
WARNING
(A)PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Clinical Studies].
Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see WARNINGS AND PRECAUTIONS].
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see WARNINGS AND PRECAUTIONS].
Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:
 |
Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
Each XARELTO tablet contains 2.5 mg, 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 2.5 mg is Opadry® Light Yellow, containing ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies].
XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
XARELTO is indicated for the treatment of pulmonary embolism (PE).
XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.
XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.
XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular (CV) death, myocardial infarction (MI) and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
Table 1: Recommended Dosage
| Indication | Renal Considerations* | Dosage | Food/Timingf |
| Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation | CrCl >50 mL/min | 20 mg once daily | Take with evening meal |
| CrCl ≤50 mL/min | 15 mg once daily | Take with evening meal | |
| Treatment of DVT and/or PE | CrCl ≥ 30 mL/min | 15 ms twice daily " after 21 days, transition to " 20 me once daily | Take with food, at the same time each day |
| CrCl <30 mL/min | Avoid Use | ||
| Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE | CrCl ≥ 30 mL/min | 10 mg once daily, after at least 6 months of standard anticoagulant treatment | Take with or without food |
| CrCl < 30 mL/min | Avoid Use | ||
| Prophylaxis of DVT Following: | |||
| - Hip Replacement Surgery‡ | CrCl≥ 30 mL/min | 10 mg once daily for 35 days, 6-10 hours after surgery once hemostasis has been established | Take with or without food |
| CrCl <30 mL/min | Avoid Use | ||
| - Knee Replacement Surgery‡ | CrCl ≥ 30 mL/min | 10 mg once daily for 12 days, 6-10 hours after surgery once hemostasis has been established | Take with or without food |
| CrCl <30 mL/min | Avoid Use | ||
| Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in Chronic CAD or PAD | No dose adjustment needed based on CrCl | 2.5 mg twice daily, plus aspirin (75100 mg) once daily | Take with or without food |
| * See Use In Specific
Populations † See CLINICAL PHARMACOLOGY ‡ See Discontinuation for Surgery and other Interventions |
|||
When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.
No clinical trial data are available to guide converting patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.
For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken [see DRUG INTERACTIONS].
For patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.
If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see WARNINGS AND PRECAUTIONS]. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see WARNINGS AND PRECAUTIONS]. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
For patients who are unable to swallow whole tablets, XARELTO tablets may be crushed and mixed with applesauce immediately prior to use and administered orally. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food [see CLINICAL PHARMACOLOGY].
After confirming gastric placement of the tube, XARELTO tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding [see CLINICAL PHARMACOLOGY].
Crushed XARELTO tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing.
XARELTO (rivaroxaban) Tablets are available in the strengths and packages listed below:
NDC 50458-577-60 Bottle
containing 60 tablets
NDC 50458-577-18 Bottle
containing 180 tablets
NDC 50458-577-10 Blister
package containing 100 tablets (10 blister cards containing 10 tablets each)
NDC 50458-580-30 Bottle
containing 30 tablets
NDC 50458-580-90 Bottle
containing 90 tablets
NDC 50458-580-10 Blister
package containing 100 tablets (10 blister cards containing 10 tablets each)
NDC 50458-578-30 Bottle
containing 30 tablets
NDC 50458-578-90 Bottle
containing 90 tablets
NDC 50458-578-10 Blister
package containing 100 tablets (10 blister cards containing 10 tablets each)
NDC 50458-579-30 Bottle
containing 30 tablets
NDC 50458-579-90 Bottle
containing 90 tablets
NDC 50458-579-89 Bulk bottle
containing 1000 tablets
NDC 50458-579-10 Blister
package containing 100 tablets (10 blister cards containing 10 tablets each)
NDC 50458-584-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg
Store at 25°C (77°F) or room temperature; excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Keep out of the reach of children.
Finished Product Manufactured by: Janssen Ortho LLC, Gurabo, PR 00778 or Bayer AG 51368 Leverkusen, Germany. Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560. Revised: Oct 2018
The following adverse reactions are also discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
During clinical development for the approved indications, 27,694 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 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 stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).
The most common adverse reactions with XARELTO were bleeding complications [see WARNINGS AND PRECAUTIONS].
In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
Table 2 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
Table 2: Bleeding Events in ROCKET AF*-On Treatment
Plus 2 Days
| Parameter | XARELTO N=7111 n (%/year) |
Warfarin N=7125 n (%/year) |
XARELTO vs. 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 ICH | 19 (0.2) | 26 (0.2) | 0.74 (0.41, 1.34) |
| Gastrointestinal (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) |
| ICH | 24 (0.2) | 42 (0.4) | 0.58 (0.35, 0.96) |
| Non-intracranial | 3 (0.0) | 13 (0.1) | 0.23 (0.07, 0.82) |
| Abbreviations: HR = Hazard Ratio, CI = Confidence
interval, CRNM = Clinically Relevant Non-Major. * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding. |
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Figure 1 shows the risk of major bleeding events across major subgroups.
Figure 1: Risk of Major Bleeding Events by Baseline
Characteristics in ROCKET AF - On Treatment Plus 2 Days
 |
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.
Table 3 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 3: Bleeding Events* in the Pooled Analysis of
EINSTEIN DVT and EINSTEIN PE Studies
| Parameter | XARELTO†, N=4130 n (%) |
Enoxaparin/ VKA† N=4116 n (%) |
| Major bleeding event | 40 (1.0) | 72 (1.7) |
| Fatal bleeding | 3 (<0.1) | 8 (0.2) |
| Intracranial | 2 (<0.1) | 4 (<0.1) |
| Non-fatal critical organ bleeding | 10 (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‡ | 0 | 4 (<0.1) |
| Non-fatal non-critical organ bleeding§ | 27 (0.7) | 37 (0.9) |
| Decrease in Hb ≥ 2 g/dL | 28 (0.7) | 42 (1.0) |
| Transfusion of ≥2 units of whole blood or packed red blood cells | 18 (0.4) | 25 (0.6) |
| Clinically relevant non-major bleeding | 357 (8.6) | 357 (8.7) |
| Any bleeding | 1169 (28.3) | 1153 (28.0) |
| * Bleeding event occurred after randomization and up to 2
days after the last dose of study drug. Although a patient may have had 2 or
more events, the patient is counted only once in a category. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 g/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells |
||
In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.
Table 4 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.
Table 4: Bleeding Events* in EINSTEIN CHOICE
| Parameter | XARELTO† 10 mg N=1127 n (%) |
Acetylsalicylic Acid (aspirin)† 100 mg N=1131 n (%) |
| Major bleeding event | 5 (0.4) | 3 (0.3) |
| Fatal bleeding | 0 | 1 (<0.1) |
| Non-fatal critical organ bleeding | 2 (0.2) | 1 (<0.1) |
| Non-fatal non-critical organ bleeding§ | 3 (0.3) | 1 (<0.1) |
| Clinically relevant non-major (CRNM) bleeding¶ | 22 (2.0) | 20 (1.8) |
| Any bleeding | 151 (13.4) | 138 (12.2) |
| * Bleeding event occurred after the first dose and up to
2 days after the last dose of study drug. Although a patient may have had 2 or
more events, the patient is counted only once in a category. † Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily. § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. ¶ Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. |
||
In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.
In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO.
The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 5.
Table 5: Bleeding Events* in Patients
Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)
| Total treated patients | XARELTO 10 mg N=4487 n (%) |
Enoxaparin† N=4524 n (%) |
| Major bleeding event | 14 (0.3) | 9 (0.2) |
| Fatal bleeding | 1 (<0.1) | 0 |
| Bleeding into a critical organ | 2 (<0.1) | 3 (0.1) |
| Bleeding that required reoperation | 7 (0.2) | 5 (0.1) |
| Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells | 4 (0.1) | 1 (<0.1) |
| Any bleeding event‡ | 261 (5.8) | 251 (5.6) |
| Hip Surgery Studies | N=3281 n (%) |
N=3298 n (%) |
| Major bleeding event | 7 (0.2) | 3 (0.1) |
| Fatal bleeding | 1 (<0.1) | 0 |
| Bleeding into a critical organ | 1 (<0.1) | 1 (<0.1) |
| Bleeding that required reoperation | 2 (0.1) | 1 (<0.1) |
| Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells | 3 (0.1) | 1 (<0.1) |
| Any bleeding event‡ | 201 (6.1) | 191 (5.8) |
| Knee Surgery Study | N=1206 n (%) |
N=1226 n (%) |
| Major bleeding event | 7 (0.6) | 6 (0.5) |
| Fatal bleeding | 0 | 0 |
| Bleeding into a critical organ | 1 (0.1) | 2 (0.2) |
| Bleeding that required reoperation | 5 (0.4) | 4 (0.3) |
| Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells | 1 (0.1) | 0 |
| Any bleeding event‡ | 60 (5.0) | 60 (4.9) |
| * Bleeding events occurring any
time following the first dose of double-blind study medication (which may have
been prior to administration of active drug) until two days after the last dose
of double-blind study medication. Patients may have more than one event. † Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) ‡ Includes major bleeding events |
||
Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.
In the COMPASS trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.
Table 6 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.
Table 6: Major Bleeding Events* in
COMPASS -On Treatment Plus 2 days
| Parameter | XARELTO plusaspirin† N=9134 n (%/year) |
Aspirin alone† N=9107 n (%/year) |
XARELTO plus aspirin vs. Aspirin alone HR (95 % CI) |
| Modified ISTH Major Bleeding‡ | 263 (1.6) | 144 (0.9) | 1.84 (1.50, 2.26) |
| - Fatal bleeding event | 12 (<0.1) | 8 (<0.1) | 1.51 (0.62, 3.69) |
| Intracranial hemorrhage (ICH) | 6 (<0.1) | 3 (<0.1) | 2.01 (0.50, 8.03) |
| Non-intracranial | 6 (<0.1) | 5 (<0.1) | 1.21 (0.37, 3.96) |
| - Symptomatic bleeding in critical organ (non-fatal) | 58 (0.3) | 43 (0.3) | 1.36 (0.91, 2.01) |
| ICH | 23 (0.1) | 21 (0.1) | 1.09 (0.61, 1.98) |
| Hemorrhagic Stroke | 18 (0.1) | 13 (<0.1) | 1.38 (0.68, 2.82) |
| Other ICH | 6 (<0.1) | 9 (<0.1) | 0.67 (0.24, 1.88) |
| - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) | 7 (<0.1) | 6 (<0.1) | 1.17 (0.39, 3.48) |
| - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) | 188 (1.1) | 91 (0.5) | 2.08 (1.62, 2.67) |
| Major GI bleeding | 117 (0.7) | 49 (0.3) | 2.40 (1.72, 3.35) |
| * Major bleeding events within each subcategory were
counted once per patient, but patients may have contributed events to multiple
subcategories. These events occurred during treatment or within 2 days of
stopping treatment. † Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg once daily ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization. CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis |
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Figure 2 shows the risk of modified ISTH major bleeding events across major subgroups.
Figure 2: Risk of Modified ISTH Major Bleeding Events
by Baseline Characteristics in COMPASS - On Treatment Plus 2 Days
|
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 7.
Table 7: Other Adverse Reactions* Reported by
≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies
| Body System Adverse Reaction | XARELTO 20 mg N=1718 n (%) |
Enoxaparin/VKA N=1711 n (%) |
| EINSTEIN DVT Study | ||
| Gastrointestinal disorders | ||
| Abdominal pain | 46 (2.7) | 25 (1.5) |
| General disorders and administration site conditions | ||
| Fatigue | 24 (1.4) | 15 (0.9) |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 50 (2.9) | 31 (1.8) |
| Muscle spasm | 23 (1.3) | 13 (0.8) |
| Nervous system disorders | ||
| Dizziness | 38 (2.2) | 22 (1.3) |
| Psychiatric disorders | ||
| Anxiety | 24 (1.4) | 11 (0.6) |
| Depression | 20 (1.2) | 10 (0.6) |
| Insomnia | 28 (1.6) | 18 (1.1) |
| EINSTEIN PE Study | XARELTO 20 mg N=2412 n (%) |
Enoxaparin/VKA N=2405 n (%) |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | 53 (2.2) | 27 (1.1) |
| * Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator | ||
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 8.
Table 8: Other Adverse Drug Reactions* Reported
by ≥1% of XARELTO-Treated Patients in RECORD 1-3 Studies
| Body System Adverse Reaction | XARELTO 10 mg N=4487 n (%) |
Enoxaparin† N=4524 n (%) |
| Injury, poisoning and procedural complications | ||
| Wound secretion | 125 (2.8) | 89 (2.0) |
| Musculoskeletal and connective tissue disorders | ||
| Pain in extremity | 74 (1.7) | 55 (1.2) |
| Muscle spasm | 52 (1.2) | 32 (0.7) |
| Nervous system disorders | ||
| Syncope | 55 (1.2) | 32 (0.7) |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | 96 (2.1) | 79 (1.8) |
| Blister | 63 (1.4) | 40 (0.9) |
| * Adverse reaction occurring
any time following the first dose of double-blind medication, which may have
been prior to administration of active drug, until two days after the last dose
of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) |
||
In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.
The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia
Gastrointestinal disorders: retroperitoneal hemorrhage
Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)
Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema
Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.
Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see CLINICAL PHARMACOLOGY].
XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see CLINICAL PHARMACOLOGY].
Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see WARNINGS AND PRECAUTIONS].
Included as part of the PRECAUTIONS section.
Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see DOSAGE AND ADMINISTRATION and Clinical Studies].
XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.
Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see DRUG INTERACTIONS], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.
Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see DRUG INTERACTIONS].
An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see CLINICAL PHARMACOLOGY]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant 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 [see BOXED WARNING].
To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see CLINICAL PHARMACOLOGY]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see CLINICAL PHARMACOLOGY]. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.
Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see DOSAGE AND ADMINISTRATION]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use In Specific Populations].
Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use In Specific Populations].
Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use In Specific Populations].
No clinical data are available for patients with severe hepatic impairment.
Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use In Specific Populations].
Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see DRUG INTERACTIONS].
Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see DRUG INTERACTIONS].
In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Risk of Bleeding].
The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.
Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
See FDA-approved patient labeling (Medication Guide).
Instruct patients to inform their healthcare professional that they are taking XARELTO before any invasive procedure (including dental procedures) is scheduled.
Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions [see DRUG INTERACTIONS].
Advise patients to discuss with their physician the benefits and risks of XARELTO for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment [see Use In Specific Populations].
Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use In Specific Populations].
Active Ingredient Made in Germany
Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1-and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2-and 4-times, respectively, the human exposure.
Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.
No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.
The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see WARNINGS AND PRECAUTIONS].
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.
Fetal/Neonatal Adverse Reactions
Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.
Labor Or Delivery
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see WARNINGS AND PRECAUTIONS]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.
Human Data
There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.
Animal Data
Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).
Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).
Animal Data
Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.
Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the COMPASS study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see CLINICAL PHARMACOLOGY and Clinical Studies].
In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see CLINICAL PHARMACOLOGY].
Patients With Chronic Kidney Disease Not On Dialysis
In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl ≤30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see CLINICAL PHARMACOLOGY].
Patients With End-Stage Renal Disease On Dialysis
Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see CLINICAL PHARMACOLOGY]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.
In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.
The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.
Patients With Chronic Kidney Disease Not On Dialysis
Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15-30 mL/min. In patients with CrCl ≤30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment [see CLINICAL PHARMACOLOGY], whose efficacy and safety outcomes were similar to those with preserved renal function.
Patients With End-Stage Renal Disease On Dialysis
No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see CLINICAL PHARMACOLOGY]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.
In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).
The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see CLINICAL PHARMACOLOGY].
Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.
Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.
XARELTO is contraindicated in patients with:
XARELTO is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.
Dose-dependent inhibition of FXa activity was observed in humans. Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are also prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban.
The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in subjects with renal impairment relative to healthy control subjects [see Use In Specific Populations].
Table 9: Percentage Increase in Rivaroxaban PK and PD
Measures in Subjects with Renal Impairment Relative to Healthy Subjects from
Clinical Pharmacology Studies
| Measure | Parameter | Creatinine Clearance (mL/min) | ||||
| 50-79 | 30-49 | 15-29 | ESRD (on dialysis)* | ESRD (post-dialysis)* | ||
| Exposure | AUC | 44 | 52 | 64 | 47 | 56 |
| FXa Inhibition | AUEC | 50 | 86 | 100 | 49 | 33 |
| PT Prolongation | AUEC | 33 | 116 | 144 | 112 | 158 |
| *Separate stand-alone study. PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve |
||||||
Anti-Factor Xa activity was similar in subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A class). There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety.
The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. XARELTO 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food [see DOSAGE AND ADMINISTRATION].
The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 4).
Absorption of rivaroxaban is dependent on the site of drug release in the GI 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 drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.
Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.
Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.
In a Phase 1 study, following the administration of [14C]-rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.
Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 3.
Figure 3: Effect of Specific Populations on the
Pharmacokinetics of Rivaroxaban
 |
Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.
Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.
The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [see Use In Specific Populations].
The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Figure 3). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Use In Specific Populations].
Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (postdialysis) is 56% higher when compared to subjects with normal renal function (see Table 9). The systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow rate in the range of 320 to 400 mL/min is 47% higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure. Protein binding was similar (86% to 89%) in healthy controls and ESRD subjects in this study.
The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Figure 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) (see Figure 3). Increases in pharmacodynamic effects were also observed [see Use In Specific Populations].
In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.
The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure 4 [see DRUG INTERACTIONS].
Figure 4: Effect of Coadministered Drugs on the
Pharmacokinetics of Rivaroxaban
 |
In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 4).
In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 4).
In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.
In a pharmacokinetic trial, XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to XARELTO administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively. Similar trends in pharmacodynamic effects were also observed.
In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for XARELTO (15 mg and 45 mg, single-dose).
The evidence for the efficacy and safety of XARELTO was derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [NCT00403767], a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:
ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin’s effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.
Table 10 displays the overall results for the primary composite endpoint and its components.
Table 10: Primary Composite
Endpoint Results in ROCKET AF Study (Intent-to-Treat Population)
| Event | XARELTO | Warfarin | XARELTO vs. Warfarin | ||
| N=7081 n (%) | Event Rate (per 100 Pt-yrs) | N=7090 n (%) | Event Rate (per 100 Pt-yrs) | Hazard Ratio (95% CI) | |
| Primary Composite Endpoint* | 269 (3.8) | 2.1 | 306 (4.3) | 2.4 | 0.88 (0.74, 1.03) |
| Stroke | 253 (3.6) | 2.0 | 281 (4.0) | 2.2 | |
| Hemorrhagic Stroke† | 33 (0.5) | 0.3 | 57 (0.8) | 0.4 | |
| Ischemic Stroke | 206 (2.9) | 1.6 | 208 (2.9) | 1.6 | |
| Unknown Stroke Type | 19 (0.3) | 0.2 | 18 (0.3) | 0.1 | |
| Non-CNS Systemic Embolism | 20 (0.3) | 0.2 | 27 (0.4) | 0.2 | |
| *The primary endpoint was the time to first occurrence of
stroke (any type) or non-CNS systemic embolism. Data are shown for all
randomized patients followed to site notification that the study would end. † Defined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification |
|||||
Figure 5 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
Figure 5: Time to First
Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group
(Intent-to-Treat Population)
 |
Figure 6 shows the risk of stroke or non-CNS systemic embolism across major subgroups.
Figure 6: Risk of Stroke or
Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF*
(Intent-to-Treat Population)
 |
* Data are shown for all randomized patients followed to site notification that the study would end. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
The efficacy of XARELTO was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.
XARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT [NCT00440193] and EINSTEIN PE [NCT00439777], multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0-3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal 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 the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.
Table 11 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Table 11: Primary Composite
Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat
Population
| Event | XARELTO 20 mg† | Enoxaparin/ VKA† | XARELTO vs. Enoxaparin/VKA Hazard Ratio (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 (PE cannot be excluded) | 3 (0.2) | 6 (0.3) | |
| Symptomatic PE and DVT | 1 (<0.1) | 0 | |
| Symptomatic recurrent PE only | 20 (1.2) | 18 (1.0) | |
| Symptomatic recurrent DVT 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 (PE cannot be excluded) | 8 (0.3) | 6 (0.2) | |
| Symptomatic PE and DVT | 0 | 2 (<0.1) | |
| Symptomatic recurrent PE only | 23 (1.0) | 20 (0.8) | |
| Symptomatic recurrent DVT only | 18 (0.7) | 17 (0.7) | |
| * For the primary efficacy analysis, all confirmed events
were considered from randomization up to the end of intended treatment duration
(3, 6 or 12 months) irrespective of the actual treatment duration. If the same
patient had several events, the patient may have been counted for several
components. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] |
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Figures 7 and 8 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.
Figure 7: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study
 |
Figure 8: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study
 |
XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study [NCT02064439], a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded.
Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below.
A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the XARELTO and aspirin treatment groups. The mean age was approximately 59 years. The population was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16% had PE and DVT combined. Other risk factors included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic conditions (6%), Factor V Leiden gene mutation (4%), or active cancer (3%).
In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or nonfatal or fatal PE.
Table 12 displays the overall results for the primary composite endpoint and its components.
Table 12: Primary Composite
Endpoint and its Components Results* in EINSTEIN CHOICE Study – Full
Analysis Set
| Event | XARELTO 10 mg N=1,127 n (%) |
Acetylsalicylic Acid (Aspirin) 100 mg N=1,131 n (%) |
XARELTO 10 mg vs. Aspirin 100 mg Hazard Ratio (95% CI) |
| Primary Composite Endpoint | 13 (1.2) | 50 (4.4) | 0.26 (0.14, 0.47) p<0.0001 |
| Symptomatic recurrent DVT | 8 (0.7) | 29 (2.6) | |
| Symptomatic recurrent PE | 5 (0.4) | 19 (1.7) | |
| Death (PE) | 0 | 1 (<0.1) | |
| Death (PE cannot be excluded) | 0 | 1 (<0.1) | |
| * For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (12 months) irrespective of the actual treatment duration. The individual component of the primary endpoint represents the first occurrence of the event. | |||
Figure 9 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
Figure 9: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study
 |
XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) [NCT00329628, NCT00332020, NCT00361894] studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 13.
Table 13: Summary of Key
Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery
-Modified Intent-to-Treat Population
| Treatment Dosage and Duration | RECORD 1 | RECORD 2 | ||||
| XARELTO 10 mg once daily | Enoxaparin 40 mg once daily | RRR*, p-value | XARELTO 10 mg once daily | Enoxaparin† 40 mg once daily | RRR*, p-value | |
| Number of Patients | N=1513 | N=1473 | N=834 | N=835 | ||
| Total VTE | 17 (1.1%) | 57 (3.9%) | 71% (95% CI: 50, 83), p<0.001 | 17 (2.0%) | 70 (8.4%) | 76% (95% CI: 59, 86), p<0.001 |
| Components of Total VTE | ||||||
| Proximal DVT | 1 (0.1%) | 31 (2.1%) | 5 (0.6%) | 40 (4.8%) | ||
| Distal DVT | 12 (0.8%) | 26 (1.8%) | 11 (1.3%) | 43 (5.2%) | ||
| Non-fatal PE | 3 (0.2%) | 1 (0.1%) | 1 (0.1%) | 4 (0.5%) | ||
| Death (any cause) | 4 (0.3%) | 4 (0.3%) | 2 (0.2%) | 4 (0.5%) | ||
| Number of Patients | N=1600 | N=1587 | N=928 | N=929 | ||
| Major VTE‡ | 3 (0.2%) | 33 (2.1%) | 91% (95% CI: 71, 97), p<0.001 | 6 (0.7%) | 45 (4.8%) | 87% (95% CI: 69, 94), p<0.001 |
| Number of Patients | N=2103 | N=2119 | N=1178 | N=1179 | ||
| Symptomatic VTE | 5 (0.2%) | 11 (0.5%) | 3 (0.3%) | 15 (1.3%) | ||
| * Relative Risk Reduction; CI =
confidence interval † Includes the placebo-controlled period of RECORD 2 ‡ Proximal DVT, nonfatal PE or VTE-related death |
||||||
One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 14.
Table 14: Summary of Key
Efficacy Analysis Results for Patients Undergoing Total Knee Replacement
Surgery -Modified Intent-to-Treat Population
| Treatment Dosage and Duration | RECORD 3 | ||
| XARELTO 10 mg once daily | Enoxaparin 40 mg once daily | RRR*, p-value | |
| Number of Patients | N=813 | N=871 | |
| Total VTE | 79 (9.7%) | 164 (18.8%) | 48% (95% CI: 34, 60), p<0.001 |
| Components of events contributing to Total VTE | |||
| Proximal DVT | 9 (1.1%) | 19 (2.2%) | |
| Distal DVT | 74 (9.1%) | 154 (17.7%) | |
| Non-fatal PE | 0 | 4 (0.5%) | |
| Death (any cause) | 0 | 2 (0.2%) | |
| Number of Patients | N=895 | N=917 | |
| Major VTEt | 9 (1.0%) | 23 (2.5%) | 60% (95% CI: 14, 81), p = 0.024 |
| Number of Patients | N=1206 | N=1226 | |
| Symptomatic VTE | 8 (0.7%) | 24 (2.0%) | |
| * Relative Risk Reduction; CI =
confidence interval † Proximal DVT, nonfatal PE or VTE-related death |
|||
The evidence for the efficacy and safety of XARELTO for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial (COMPASS) [NCT10776424]. A total of 27,395 patients were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone. Because the 5 mg dose alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are discussed below.
Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [eGFR] <60 mL per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier). Patients with PAD were either symptomatic with ankle brachial index <0.90 or had asymptomatic carotid artery stenosis ≥50%, a previous carotid revascularization procedure, or established ischemic disease of one or both lower extremities. Patients were excluded for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-lacunar stroke within 1 month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min. [see WARNINGS AND PRECAUTIONS].
The mean age was 68 years and 21% of the subject population were ≥75 years. Of the included patients, 91% had CAD, 27% had PAD, and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease.
The mean duration of follow-up was 23 months. Relative to aspirin alone, XARELTO plus aspirin reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death. The benefit was observed early with a constant treatment effect over the entire treatment period (see Table 15 and Figure 11).
A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical organ) in the XARELTO plus aspirin group versus the aspirin group. Compared to aspirin alone, during 10,000 patient-years of treatment, XARELTO plus aspirin would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks.
The results in patients with PAD, CAD, and both CAD and PAD were consistent with the overall efficacy and safety results (see Figure 10).
Figure 10 shows the risk of primary efficacy outcome across major subgroups.
Figure 10: Risk of Primary Efficacy Outcome by
Baseline Characteristics in COMPASS (Intent-to-Treat Population)
 |
Table 15: Efficacy results from COMPASS study
| Study Population | Patients with CAD or PAD* | ||||
| Event | Xarelto plus aspirin† N=9152 |
Aspirin alone† N=9126 |
Hazard Ratio (95% CI) ‡ | ||
| n (%) | Event Rate (%/year) | n (%) | Event Rate (%/year) | ||
| Stroke, MI or CV death | 379 (4.1) | 2.2 | 496 (5.4) | 2.9 | 0.76 (0.66, 0.86) |
| - Stroke | 83 (0.9) | 0.5 | 142 (1.6) | 0.8 | 0.58 (0.44, 0.76) |
| - MI | 178 (1.9) | 1.0 | 205 (2.2) | 1.2 | 0.86 (0.70, 1.05) |
| - CV death | 160 (1.7) | 0.9 | 203 (2.2) | 1.2 | 0.78 (0.64, 0.96) |
| Coronary heart disease death, MI, ischemic stroke, acute limb ischemia | 329 (3.6) | 1.9 | 450 (4.9) | 2.6 | 0.72 (0.63, 0.83) |
| - Coronary heart disease death§ | 86 (0.9) | 0.5 | 117 (1.3) | 0. 7 | 0.73 (0.55, 0.96) |
| - Ischemic stroke | 64 (0.7) | 0.4 | 125 (1.4) | 0.7 | 0.51 (0.38, 0.69) |
| - Acute limb ischemia# | 22 (0.2) | 0.1 | 40 (0.4) | 0.2 | 0.55 (0.32, 0.92) |
| CV death¶, MI, ischemic stroke, acute limb ischemia | 389 (4.3) | 2.2 | 516 (5.7) | 3.00 | 0.74 (0.65, 0.85) |
| All-cause mortality | 313 (3.4) | 1. 8 | 378 (4.1) | 2.2 | 0.82 (0.71, 0.96) |
| Lower extremity amputations for CV reasons | 15 (0.2) | <0.1 | 31 (0.3) | 0.2 | 0.48 (0.26, 0.89) |
| Patients with PAD | |||||
| Acute limb ischemia | 19 (0.8) | 0.4 | 34 (1.4) | 0.8 | 0.56 (0.32, 0.99) |
| * intention to treat analysis set, primary analyses. † Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg once daily. ‡ vs. aspirin 100 mg § Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure. ¶ CV death includes CHD death, or death due to other CV causes or unknown death. # Acute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention (i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or amputation). CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction |
|||||
Figure 11: Time to first occurrence of primary
efficacy outcome (stroke, myocardial infarction, cardiovascular death) in
COMPASS
 |
XARELTO®
(zah-REL-toe)
(rivaroxaban) tablets
What is the most important information I should know about XARELTO?
XARELTO may cause serious side effects, including:
Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.
Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:
What is XARELTO?
XARELTO is a prescription medicine used to:
XARELTO is used with low dose aspirin to:
It is not known if XARELTO is safe and effective in children.
Do not take XARELTO if you:
Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:
Tell all of your doctors and dentists that you are taking XARELTO. They should talk to the doctor who prescribed XARELTO for you before you have any surgery, medical or dental procedure.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Some of your other medicines may affect the way XARELTO works, causing side effects. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO?”
Especially tell your doctor if you take:
How should I take XARELTO?
What are the possible side effects of XARELTO?
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-FDA-1088.
How should I store XARELTO?
Keep XARELTO and all medicines out of the reach of children.
General information about the safe and effective use of XARELTO.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XARELTO for a condition for which it was not prescribed. Do not give XARELTO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about XARELTO that is written for health professionals.
What are the ingredients in XARELTO?
Active ingredient: rivaroxaban
Inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
The proprietary film coating mixture for XARELTO 2.5 mg tablets is Opadry® Light Yellow and contains: ferric oxide yellow, hypromellose, polyethylene glycol 3350, and titanium dioxide.
The proprietary film coating mixture for XARELTO 10 mg tablets is Opadry® Pink and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.
The proprietary film coating mixture for XARELTO 15 mg tablets is Opadry® Red and contains: ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide.
The proprietary film coating mixture for XARELTO 20 mg tablets is Opadry® II Dark Red and contains: ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
