Xarelto (Page 3 of 10)

5.5 Use in Patients with Hepatic Impairment

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)].

5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers

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)].

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 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).

5.8 Patients with Prosthetic Heart Valves

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.

6 ADVERSE REACTIONS

The following 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, 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 (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.

Table 1: Bleeding Events in ROCKET AF *- On Treatment Plus 2 Days
ParameterXARELTON = 7111n (%/year)WarfarinN = 7125n (%/year)XARELTO vs. WarfarinHR(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.

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)

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.

Table 2: Bleeding Events * in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies
Parameter XARELTO N = 4130n (%) Enoxaparin/VKA N = 4116n (%)
*
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 ≥ 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.

Table 3: Bleeding Events * in EINSTEIN Extension Study
Parameter XARELTO 20 mgN = 598n (%) Placebo N = 590n (%)
*
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.
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)

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
*
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 = 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)
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.

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 XARELTON = 598n (%) PlaceboN = 590n (%)
*
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.
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)

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 XARELTO10 mg Enoxaparin
N = 4487n (%) N = 4524n (%)
*
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)

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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