Xarelto (Page 5 of 18)
5.5 Use in Patients with Hepatic Impairment
No clinical data are available for adult patients with severe hepatic impairment.
Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations (8.7)] .
No clinical data are available in pediatric patients with hepatic impairment.
5.6 Use with P-gp and Strong CYP3A Inhibitors or Inducers
Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2)] .
Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions (7.3)] .
5.7 Risk of Pregnancy-Related Hemorrhage
In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)] .
5.8 Patients with Prosthetic Heart Valves
On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves.
5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy
Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
5.10 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome
Direct-acting oral anticoagulants (DOACs), including XARELTO, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
6 ADVERSE REACTIONS
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 (5.1)]
- •
- Bleeding Risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
- •
- Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions (5.3)]
6.1 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 (5.2)] .
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.
Parameter | XARELTO N=7111 n (%/year) | Warfarin N=7125 n (%/year) | XARELTO vs. Warfarin HR (95% CI) |
---|---|---|---|
Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. | |||
| |||
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) |
Figure 1 shows the risk of major bleeding events across major subgroups.
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.
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) |
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.
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) |
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.
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) |
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.
MAGELLAN Study † | XARELTO 10 mg N=3218 n (%) | Enoxaparin 40 mg /placebo N=3229 n (%) |
---|---|---|
| ||
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) |
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.
Parameter | XARELTO † N=9134 n (%/year) | Placebo † N=9107 n (%/year) | XARELTO vs. Placebo HR (95 % CI) |
---|---|---|---|
CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis | |||
| |||
Modified ISTH Major Bleeding ‡ | 263 (1.6) | 144 (0.9) | 1.8 (1.5, 2.3) |
| 12 (<0.1) 6 (<0.1) 6 (<0.1) | 8 (<0.1) 3 (<0.1) 5 (<0.1) | 1.5 (0.6, 3.7) 2.0 (0.5, 8.0) 1.2 (0.4, 4.0) |
| 58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1) | 43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1) | 1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) |
| 7 (<0.1) | 6 (<0.1) | 1.2 (0.4, 3.5) |
| 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) |
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.
XARELTO † N=3256 | Placebo † N=3248 | XARELTO vs. Placebo HR (95 % CI) | |||
---|---|---|---|---|---|
Parameter | n (%) | Event rate %/year | n (%) | Event rate %/year | |
CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria | |||||
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) |
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.
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) |
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 13.
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) |
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 weight-adjusted 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.
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) |
Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 15.
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) |
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.
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) |
Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 17.
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) |
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