"June 22, 2012 -- The FDA has decided -- for now -- against allowing the new blood thinner Xarelto to be used to treat patients with blocked coronary arteries.
Federal officials issued a complete response letter late Thursday, which me"...
The following adverse reactions are also discussed in other sections of the labeling:
- Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Bleeding risk [see WARNINGS AND PRECAUTIONS]
- Spinal/epidural hematoma [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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, 16326 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); 4728 patients who received either XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily (EINSTEIN DVT, EINSTEIN PE) or 20 mg orally once daily (EINSTEIN Extension) to treat DVT, PE, and to reduce the risk of recurrence of DVT and of PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).
The most common adverse reactions with XARELTO were bleeding complications [see WARNINGS AND PRECAUTIONS].
Nonvalvular Atrial Fibrillation
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 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
Table 1: Bleeding Events in ROCKET AF*
N = 7111 n (%)
|Event Rate (per 100 Pt-yrs)||Warfarin
N = 7125 n (%)
|Event Rate (per 100 Pt-yrs)|
|Major bleeding†||395 (5.6)||3.6||386 (5.4)||3.5|
|Bleeding into a critical organ‡||91 (1.3)||0.8||133 (1.9)||1.2|
|Fatal bleeding||27 (0.4)||0.2||55 (0.8)||0.5|
|Bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells||183 (2.6)||1.7||149 (2.1)||1.3|
|Gastrointestinal bleeding||221 (3.1)||2.0||140 (2.0)||1.2|
|* For all sub-types of major
bleeding, single events may be represented in more than one row, and individual
patients may have more than one event.
† Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin.
‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE
EINSTEIN DVT and EINSTEIN PE Studies
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 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
Table 2: Bleeding Events* in
the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies
N = 4130 n (%)
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 ≥ 2g/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 mg/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
EINSTEIN Extension Study
In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for XARELTO vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both XARELTO and placebo treatment groups.
Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study.
Table 3: Bleeding Events* in EINSTEIN Extension Study
|Parameter||XARELTO† 20 mg
N = 598
N = 590
|Major bleeding event‡||4 (0.7)||0|
|Decrease in Hb ≥2 g/dL||4 (0.7)||0|
|Transfusion of ≥2 units of whole blood or packed red blood cells||2 (0.3)||0|
|Clinically relevant non-major bleeding||32 (5.4)||7 (1.2)|
|Any bleeding||104 (17.4)||63 (10.7)|
|* 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
† Treatment schedule: XARELTO 20 mg once daily; matched placebo once daily
‡ There were no fatal or critical organ bleeding events.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
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 4.
Table 4: Bleeding Events* in Patients Undergoing Hip
or Knee Replacement Surgeries (RECORD 1-3)
|Total treated patients||XARELTO 10 mg
N = 4487
N = 4524
|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 re-operation||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 re-operation||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)|
|Bleeding into a critical organ||1 (0.1)||2 (0.2)|
|Bleeding that required re-operation||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.
Other Adverse Reactions
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN Extension study are shown in Table 5.
Table 5: Other Adverse Reactions* Reported by
≥1% of XARELTO-Treated Patients in EINSTEIN Extension Study
|System Organ Class Preferred Term||XARELTO
N = 598
N = 590
|Abdominal pain upper||10 (1.7)||1 (0.2)|
|Dyspepsia||8 (1.3)||4 (0.7)|
|General disorders and administration site conditions|
|Fatigue||6 (1.0)||3 (0.5)|
|Infections and infestations|
|Sinusitis||7 (1.2)||3 (0.5)|
|Urinary tract infection||7 (1.2)||3 (0.5)|
|Musculoskeletal and connective tissue disorders|
|Back pain||22 (3.7)||7 (1.2)|
|Osteoarthritis||10 (1.7)||5 (0.8)|
|Respiratory, thoracic and mediastinal disorders|
|Oropharyngeal pain||6 (1.0)||2 (0.3)|
|* Adverse reaction (with Relative Risk > 1.5 for XARELTO versus placebo) occurred after the first dose and up to 2 days after the last dose of study drug. Incidences are based on the number of patients, not the number of events. Although a patient may have had 2 or more clinical adverse reactions, the patient is counted only once in a category. The same patient may appear in different categories.|
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 6.
Table 6: Other Adverse Drug
Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD 1-3
|System/Organ Class Adverse Reaction||XARELTO 10 mg
N = 4487
N = 4524
|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)
Other clinical trial experience: 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 rivaroxaban. 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.
Gastrointestinal disorders: retroperitoneal hemorrhage
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
Read the Xarelto (rivaroxaban film-coated oral tablets) Side Effects Center for a complete guide to possible side effects
Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.
Drugs That Inhibit Cytochrome P450 3A4 Enzymes And Drug Transport Systems
In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin and fluconazole), increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. The increases in exposure ranged from 30% to 160%. Significant increases in rivaroxaban exposure may increase bleeding risk [see CLINICAL PHARMACOLOGY].
When data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors.
Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors [see WARNINGS AND PRECAUTIONS].
Drugs That Induce Cytochrome P450 3A4 Enzymes And Drug Transport Systems
Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of XARELTO with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 50%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy [see CLINICAL PHARMACOLOGY].
Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see WARNINGS AND PRECAUTIONS].
Anticoagulants And NSAIDs/Aspirin
Single doses of enoxaparin and XARELTO given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and XARELTO resulted in an additive effect on factor Xa (FXa) inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. Coadministration of the platelet aggregation inhibitor clopidogrel and XARELTO resulted in an increase in bleeding time for some subjects [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].
Drug-Disease Interactions With Drugs That Inhibit Cytochrome P450 3A4 Enzymes And Drug Transport Systems
Results from a pharmacokinetic trial with erythromycin indicated that patients with renal impairment coadministered XARELTO with drugs classified as combined P-gp and moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, dronedarone, and erythromycin) have increased exposure compared with patients with normal renal function and no inhibitor use. Significant increases in rivaroxaban exposure may increase bleeding risk.
While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to < 50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)] [see Use in Specific Populations].
XARELTO should not be used in patients with CrCl 15 to 80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors unless the potential benefit justifies the potential risk [see CLINICAL PHARMACOLOGY].
Read the Xarelto Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/28/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Xarelto Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.