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Xarelto

Last reviewed on RxList: 11/9/2018
Xarelto Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 11/9/2018

Xarelto (rivaroxaban) is a Factor Xa inhibitor indicated for the prevention of deep vein thrombosis which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. Common side effects of Xarelto include:

  • bleeding complications, including major bleeding events.

Other side effects of Xarelto include:

Xarelto side effects that are severe are spinal hematomas that may develop after spinal surgery with this drug.

The recommended dose of Xarelto is 10 mg taken orally once daily with or without food. Xarelto may interact with antibiotics, antifungal medications, anticoagulants, blood thinners, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin and other salicylates, bosentan, conivaptan, dexamethasone, rifamycins, St. John's wort, quinidine, verapamil, barbiturates, heart or blood pressure medications, HIV medications, medicines to treat narcolepsy, seizure medications, dextran, abciximab, eptifibatide, ticagrelor, tirofiban, alteplase, reteplase, tenecteplase, urokinase, anagrelide, cilostazol, clopidogrel, dipyridamole, eltrombopag, oprelvekin, prasugrel, romiplostim, ticagrelor, ticlopidine, argatroban, bivalirudin, dabigatran, lepirudin, dalteparin, enoxaparin, fondaparinux, heparin, tinzaparin, warfarin. Tell your doctor all medications and supplements you use. Xarelto could cause bleeding complications during childbirth. Tell your doctor if you are pregnant or plan to become pregnant while using Xarelto. It is unknown if Xarelto will harm a fetus. It is unknown if Xarelto passes into breast milk or if it could harm a nursing baby. Breastfeeding while using Xarelto is not recommended.

Our Xarelto Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Xarelto Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Also seek emergency medical attention if you have symptoms of a spinal blood clot: back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.

Rivaroxaban can cause you to bleed more easily. Call your doctor at once if you have signs of bleeding such as:

  • easy bruising or bleeding (nosebleeds, bleeding gums, heavy menstrual bleeding);
  • pain, swelling, or drainage from a wound or where a needle was injected in your skin;
  • bleeding from wounds or needle injections, any bleeding that will not stop;
  • headaches, dizziness, weakness, feeling like you might pass out;
  • urine that looks red, pink, or brown; or
  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

Bleeding is the most common side effect of rivaroxaban.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Xarelto (Rivaroxaban Film-Coated Oral Tablets)

Xarelto Professional Information

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, 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).

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 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.

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

Risk of Major Bleeding Events by Baseline
Characteristics in ROCKET AF - On Treatment Plus 2 Days - Illustration

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.

Treatment Of Deep Vein Thrombosis (DVT) And/Or Pulmonary Embolism (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 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

Reduction In The Risk Of Recurrence Of DVT And/Or PE

EINSTEIN CHOICE Study

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.

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 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.

Reduction Of Risk Of Major Cardiovascular Events In Patients With Chronic CAD Or PAD

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

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

Risk of Modified ISTH Major Bleeding Events
by Baseline Characteristics in COMPASS - On Treatment Plus 2 Days - Illustration

Other Adverse Reactions

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)

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 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

Read the entire FDA prescribing information for Xarelto (Rivaroxaban Film-Coated Oral Tablets)

Related Resources for Xarelto

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© Xarelto Patient Information is supplied by Cerner Multum, Inc. and Xarelto Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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