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Xarelto

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are also discussed in other sections of the labeling:

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).

Hemorrhage

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*

Parameter XARELTO
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

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 ≥ 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 (%)
Placebo†
N = 590
n (%)
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
  Gastrointestinal 3 (0.5) 0
  Menorrhagia 1 (0.2) 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 category.
† 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)

  XARELTO 10 mg Enoxaparin†
Total treated patients N = 4487 N = 4524
n (%) 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 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 = 3298
n (%) 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 = 1226
n (%) 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 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 (%)
Placebo
N = 590
n (%)
Gastrointestinal disorders
  Abdominal pain upper 10 (1.7) 1 (0.2)
  Dyspepsia 8 (1.3) 4 (0.7)
  Toothache 6 (1.0) 0
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 Studies

System/Organ Class
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)

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.

Postmarketing Experience

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.

Blood and lymphatic system disorders: agranulocytosis

Gastrointestinal disorders: retroperitoneal hemorrhage

Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis

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

Read the Xarelto (rivaroxaban film-coated oral tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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: 11/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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