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:

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.

Table 5: Bleeding Events in ROCKET AF *– On Treatment Plus 2 Days
ParameterXARELTO 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 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.
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 ICH19 (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)
ICH24 (0.2)42 (0.4)0.58 (0.35, 0.96)
Non-intracranial3 (0.0)13 (0.1)0.23 (0.07, 0.82)

Figure 1 shows the risk of major bleeding events across major subgroups.

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.
Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Figure 1
(click image for full-size original)

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 (%)
*
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
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.

Table 7: Bleeding Events * in EINSTEIN CHOICE
Parameter XARELTO 10 mg N=1127 n (%) Acetylsalicylic Acid (aspirin) 100 mg N=1131 n (%)
*
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.
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.

Table 8: Bleeding Events * in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1–3)
XARELTO 10 mg Enoxaparin
*
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
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.

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 (%)
*
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.
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.
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.
§
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.
Fatal bleeding is adjudicated death with the primary cause of death from bleeding.
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)

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)
CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis
*
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.
Modified ISTH Major Bleeding 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3)
  • Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial
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)
  • Symptomatic bleeding in critical organ (non-fatal)
  • ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH
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)
  • 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)

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
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
*
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.
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.

Table 12: Other Adverse Reactions * Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies
Body System Adverse Reaction
*
Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator
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.

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 (%)
*
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)
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.

Table 14: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set — Main Treatment Period *
Parameter XARELTO N=329 n (%) Comparator Group N=162 n (%)
*
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.
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.

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 (%)
*
Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator.
The following terms were combined: fatigue, asthenia.
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.

Table 16: Bleeding Events in UNIVERSE Study — Safety Analysis Set — On Treatment Plus 2 Days
Parameter XARELTO *N=64 n (%) Aspirin *N=34 n (%)
*
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.
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.

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 (%)
*
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
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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