XARELTO SIDE EFFECTS
- Generic Name: rivaroxaban film-coated oral tablets
- Brand Name: Xarelto
- Drug Class: Anticoagulants, Cardiovascular, Factor Xa Inhibitors
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
- Bleeding Risk
- Spinal/Epidural Hematoma
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, 31,691 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); 3997 patients who received 10 mg orally once daily for prophylaxis of VTE and VTE-related death in acutely ill medical patients (MAGELLAN) 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.
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*-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. |
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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
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 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 ≥ 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 |
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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 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.
Table 3: 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. |
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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 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 (%) |
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 |
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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 6. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo.
Table 5 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.
Table 5: 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. |
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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 plus aspirin† 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) |
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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) |
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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) |
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7 (<0.1) | 6 (<0.1) | 1.17 (0.39, 3.48) |
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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 |
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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
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 |
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| 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 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) |
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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
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)
SRC: NLM .