Xarelto
FDA Advisory Panel Backs Xarelto to Prevent Strokes »
"Sept. 8, 2011 -- An FDA advisory panel has voted to recommend approval of a new blood thinner to prevent strokes and dangerous blood clots in patients with the heart rhythm disorder atrial fibrillation.
In a vote of nine to two, with "...
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Xarelto
Xarelto Side Effects Center
Medical Editor: Charles Patrick Davis, MD, PhD
Xarelto (rivaroxaban) is indicated for the prevention of deep vein thrombosis which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. Xarelto (rivaroxaban) is not available in the US in generic form. The most common adverse reactions with Xarelto are bleeding complications, including major bleeding events. Fainting, itching, and muscle spasms have been reported.
Xarelto (rivaroxaban) is supplied in 10 mg strength tablets. The recommended dose of Xarelto is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established. Dosing for pregnant women has not been established. Some antibiotics, antifungal medications, anticoagulants, blood thinners, NSAIDs, and aspirin may have adverse interactions when used with Xarelto. The anticoagulant effect of Xarelto cannot be monitored with standard laboratory testing nor readily reversed. Xarelto should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. Xarelto dosing in pregnancy has not been studied. It is not known if Xarelto is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xarelto, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Xarelto side effects that are severe are spinal hematomas that may develop after spinal surgery with this drug. Co-use with Ketoconazole, Clarithromycin, erythromycin, and other similar drugs may increase the risk of bleeding. Safety and effectiveness has not been determined in pediatric patients.
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.
What is Patient Information in Detail?
Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.
Xarelto in Detail - Patient Information: Side Effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Stop using rivaroxaban and call your doctor at once if you have a serious side effect such as:
- easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;
- feeling like you might pass out;
- black or bloody stools, coughing up blood or vomit that looks like coffee grounds;
- numbness, tingling, or muscle weakness (especially in your legs and feet); or
- loss of movement in any part of your body.
Less serious side effects may include:
- muscle pain;
- itching; or
- pain in your arms or legs.
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) »
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Xarelto FDA Prescribing Information: Side Effects
(Adverse Reactions)
SIDE EFFECTS
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).
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. |
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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 |
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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. |
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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 |
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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) |
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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 entire FDA prescribing information for Xarelto (Rivaroxaban Film-Coated Oral Tablets) »
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.
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