Xarelto Side Effects Center

Last updated on RxList: 2/21/2023
Xarelto Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Xarelto?

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.

What Are Side Effects of Xarelto?

Xarelto may cause serious side effects including:

  • back pain,
  • numbness or muscle weakness in your lower body,
  • loss of bladder or bowel control,
  • easy bruising or bleeding (nosebleeds, bleeding gums, heavy menstrual bleeding),
  • pain, swelling, new drainage or excessive bleeding from a wound or where a needle was injected,
  • any bleeding that will not stop,
  • headaches,
  • dizziness,
  • weakness,
  • lightheadedness,
  • urine that looks red, pink or brown,
  • bloody or tarry stools, and
  • coughing up blood or vomit that looks like coffee grounds

Get medical help right away, if you have any of the symptoms listed above.

Common side effects of Xarelto include:

  • bleeding complications, including major bleeding events.

Other side effects of Xarelto include:

  • fainting,
  • itching,
  • pain in your arms or legs,
  • muscle pain, and
  • muscle spasms.

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

Seek medical care or call 911 at once if you have the following serious side effects:

  • Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
  • Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
  • Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

Dosage for Xarelto

The recommended dose of Xarelto is 10 mg taken orally once daily with or without food.

What Drugs, Substances, or Supplements Interact with Xarelto?

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,
  • and
  • warfarin

Tell your doctor all medications and supplements you use.

Xarelto During Pregnancy and Breastfeeding

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.

Additional Information

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.

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Heart Disease: Causes of a Heart Attack See Slideshow
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, new drainage, or excessive bleeding from a wound or where a needle was injected in your skin;
  • 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.

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Atrial fibrillation is a(n) ... See Answer
Xarelto Professional Information

SIDE EFFECTS

The following clinically significant 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, 34,947 adult patients were exposed to XARELTO.

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 5 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

Table 5: 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 6 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

Table 6: 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 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

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 7 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Table 7: 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 8.

Table 8: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

XARELTO 10 mg Enoxaparin
Total treated patients N=4487
n (%)
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 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)
    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.

Prophylaxis Of Venous Thromboembolism In Acutely Ill Medical Patients At Risk For Thromboembolic Complications Not At High Risk Of Bleeding

In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 9. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo.

Table 9 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.

Table 9: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2 Days

MAGELLAN Study XARELTO 10 mg
N=3218
n (%)
Enoxaparin 40 mg /placebo
N=3229
n (%)
Major bleeding 22 (0.7) 15 (0.5)
  Critical site bleeding 7 (0.2) 4 (0.1)
  Fatal bleeding§ 3 (<0.1) 1 (<0.1)
Clinically relevant non-major bleeding events (CRNM) 93 (2.9) 34 (1.1)
* Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded.
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 drop 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.
§ Fatal bleeding is adjudicated death with the primary cause of death from bleeding.
Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital.

Reduction Of Risk Of Major Cardiovascular Events In Patients With CAD

In the COMPASS trial overall, 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 vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar.

Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

Table 10: Major Bleeding Events in COMPASS - On Treatment Plus 2 Days*

Parameter XARELTO
N=9134
n (%/year)
Placebo
N=9107
n (%/year)
XARELTO vs.
Placebo
HR (95 % CI)
Modified ISTH Major Bleeding 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3)
  • Fatal bleeding event
12 (<0.1) 8 (<0.1) 1.5 (0.6, 3.7)
  Intracranial hemorrhage (ICH) 6 (<0.1) 3 (<0.1) 2.0 (0.5, 8.0)
  Non-intracranial 6 (<0.1) 5 (<0.1) 1.2 (0.4, 4.0)
  • Symptomatic bleeding in critical
organ (non-fatal) 58 (0.3) 43 (0.3) 1.4 (0.9, 2.0)
  • ICH (fatal and non-fatal)
23 (0.1) 21 (0.1) 1.1 (0.6, 2.0)
  Hemorrhagic Stroke 18 (0.1) 13 (<0.1) 1.4 (0.7, 2.8)
  Other ICH 6 (<0.1) 9 (<0.1) 0.7 (0.2, 1.9)
  • Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ)
7 (<0.1) 6 (<0.1) 1.2 (0.4, 3.5)
  • Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation)
188 (1.1) 91 (0.5) 2.1 (1.6, 2.7)
Major GI bleeding 117 (0.7) 49 (0.3) 2.4 (1.7, 3.4)
* 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 in the safety analysis set in COMPASS patients.
Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with 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

Reduction Of Risk Of Major Thrombotic Vascular Events In Patients With Peripheral Artery Disease (PAD), Including Patients After Lower Extremity Revascularization Due To Symptomatic PAD

The incidence of premature permanent discontinuation due to bleeding events for XARELTO 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively.

Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.

Table 11: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 Days

Parameter XARELTO
N=3256
Placebo
N=3248
XARELTO vs. Placebo HR (95 % CI)
n (%) Event rate %/year n (%) Event rate %/year
TIMI Major Bleeding
(CABG/non-CABG)
62 (1.9) 0.96 44 (1.4) 0.67 1.4
(1.0, 2.1)
  Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1.0
(0.3, 3.2)
  Intracranial bleeding 13 (0.4) 0.20 17 (0.5) 0.26 0.8
(0.4, 1.6)
  Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15% 46 (1.4) 0.71 24 (0.7) 0.36 1.9
(1.2, 3.2)
* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.
Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.
CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria

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 12.

Table 12: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies

Body System Adverse Reaction
EINSTEIN DVT Study XARELTO
20 mg
N=1718
n (%)
Enoxaparin/ VKA
N=1711
n (%)
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 13.

Table 13: 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)

Pediatric Patients

Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients

The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weightadjusted doses of XARELTO or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA).

Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the XARELTO group and 3 (1.9%) patients in the comparator group.

Table 14 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study. In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the XARELTO group and 5 (10%) female patients in the comparator group.

Table 14: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period*

Parameter XARELTO
N=329
n (%)
Comparator Group
N=162
n (%)
Major bleeding§ 0 2 (1.2)
Clinically relevant non-major bleeding 10 (3.0) 1 (0.6)
Trivial bleeding 113 (34.3) 44 (27.2)
Any bleeding 119 (36.2) 45 (27.8)
* These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event.
Treatment schedule: body weight-adjusted doses of XARELTO; randomized 2:1 (XARELTO: Comparator).
Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA.
§ 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.
Defined as clinically overt bleeding, which 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.

Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 15.

Table 15: Other Adverse Reactions* Reported in XARELTO-Treated Patients by ≥5% in EINSTEIN Junior Study

Adverse Reaction XARELTO
N=329
n (%)
Comparator Group
N=162
n (%)
Pain in extremity 23 (7) 7 (4.3)
Fatigue 23 (7) 7 (4.3)
* Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator.
The following terms were combined: fatigue, asthenia.

A clinically relevant adverse reaction in XARELTO-treated patients was vomiting (10.6% in the XARELTO group vs 8% in the comparator group).

Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure

The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of XARELTO for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg).

Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the XARELTO group and no patients in the aspirin group.

Table 16 shows the number of patients experiencing bleeding events in the UNIVERSE study.

Table 16: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days

Parameter XARELTO*
N=64
n (%)
Aspirin*
N=34
n (%)
Major Bleeding 1 (1.6) 0
  Epistaxis leading to transfusion 1 (1.6) 0
Clinically relevant non-major (CRNM) bleeding§ 4 (6.3) 3 (8.8)
Trivial bleeding 21 (32.8) 12 (35.3)
Any bleeding 23 (35.9) 14 (41.2)
* Treatment schedule: body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg); randomized 2:1 (XARELTO: Aspirin).
Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.
§ Defined as clinically overt bleeding, which 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.

Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 17.

Table 17: Other Adverse Reactions* Reported by ≥5% of XARELTO-Treated Patients in UNIVERSE Study (Part B)

Adverse Reaction XARELTO
N=64
n (%)
Aspirin
N=34
n (%)
Cough 10 (15.6) 3 (8.8)
Vomiting 9 (14.1) 3 (8.8)
Gastroenteritis 8 (12.5) 1 (2.9)
Rash 6 (9.4) 2 (5.9)
* Adverse reaction with Relative Risk >1.5 for XARELTO versus aspirin.
The following terms were combined:
Gastroenteritis: gastroenteritis, gastroenteritis viral
Rash: rash, rash maculo-papular, viral rash

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

Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders: hemiparesis

Renal disorders: Anticoagulant-related nephropathy

Respiratory, thoracic and mediastinal disorders: Eosinophilic pneumonia

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

DRUG INTERACTIONS

General Inhibition And Induction Properties

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.

Drugs That Inhibit Cytochrome P450 3A Enzymes And Drug Transport Systems

Interaction With Combined P-gp And Strong CYP3A Inhibitors

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].

Interaction With Combined P-gp And Moderate CYP3A Inhibitors In Patients With Renal Impairment

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].

Drugs That Induce Cytochrome P450 3A Enzymes And Drug Transport Systems

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].

Anticoagulants And NSAIDs/Aspirin

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].

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

© 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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