No clinical data are available for 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 (8.8)].
Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan) [see Drug Interactions (7.1)].
Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Drug Interactions (7.2)].
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 nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.
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.
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 (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)]
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).
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 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
|Parameter||XARELTON = 7111n (%/year)||WarfarinN = 7125n (%/year)||XARELTO vs. WarfarinHR(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.
Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days
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), 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.
|Parameter||XARELTO †N = 4130n (%)||Enoxaparin/VKA †N = 4116n (%)|
|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)|
EINSTEIN Extension Study
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.
|Parameter||XARELTO †20 mgN = 598n (%)||Placebo †N = 590n (%)|
|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|
|Clinically relevant non-major bleeding||32 (5.4)||7 (1.2)|
|Any bleeding||104 (17.4)||63 (10.7)|
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.
|XARELTO 10 mg||Enoxaparin †|
|Total treated patients||N = 4487n (%)||N = 4524n (%)|
|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 = 3281n (%)||N = 3298n (%)|
|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 = 1206n (%)||N = 1226n (%)|
|Major bleeding event||7 (0.6)||6 (0.5)|
|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.
Other Adverse Reactions
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN Extension study are shown in Table 5.
|System Organ Class Preferred Term||XARELTON = 598n (%)||PlaceboN = 590n (%)|
|Abdominal pain upper||10 (1.7)||1 (0.2)|
|Dyspepsia||8 (1.3)||4 (0.7)|
|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)|
Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 6.
|System/Organ Class Adverse Reaction||XARELTO10 mg||Enoxaparin †|
|N = 4487n (%)||N = 4524n (%)|
|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)|
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.
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